AGING IN BLOOD VESSELS. MEDICINAL AGENTS FOR SYSTEMIC ARTERIAL HYPERTENSION IN THE ELDERLY.
María Esther Rubio-Ruiz(a), Israel Pérez-Torres(b), María Elena Soto(c), Gustavo Pastelín (d), Verónica Guarner-Lans(a).
Department of Physiology,
Department of Pathology,
Department of Pharmacology, Instituto Nacional de Cardiología
“Ignacio Chávez”, México, D.F.
Short title: Medicinal agents in hypertension in the elderly
Corresponding author: Verónica Guarner Ph.D. Departamento de Fisiología Instituto Nacional de Cardiología “Ignacio Chávez” Juan Badiano 1 14080, Tlalpan, México D.F. Tel 55 55 73 29 11 ext. 1222 o 1278 fax: 55 55 73 09 94 e-mail: [email protected]
ABSTRACT Aging impairs blood vessel function and leads to cardiovascular disease. The mechanisms underlying the age-related endothelial, smooth muscle and extracellular matrix vascular dysfunction are discussed. Vascular dysfunction is caused by: 1) Oxidative stress enhancement. 2) Reduction of nitric oxide (NO) bioavailability, by diminished NO synthesis and/or augmented NO scavenging. 3) Production of vasoconstrictor/vasodilator factor imbalances. 4) Low-grade pro-inflammatory environment. 5) Impaired angiogenesis. 5) Endothelial cell senescence. The aging process in vascular smooth muscle is characterized by: 1) Altered replicating potential. 2) Change in cellular phenotype. 3) Changes in responsiveness to contracting and relaxing mediators. 4) Changes in intracellular signaling functions. Systemic arterial hypertension is an age-dependent disorder, and almost half of the elderly human population is hypertensive. The influence of hypertension on the aging cardiovascular system has been studied in models of hypertensive rats. Insulin resistance is associated with aging and hypertension and contributes to vascular malfunction. Treatment for hypertension is recommended in the elderly. Non-pharmacological treatment is used for initial hypertension
modifications, natural compounds and hormone therapies are useful. Since all antihypertensive agents can lower blood pressure in the elderly, therapy should be chosen based on its potential for side effects and drug interactions.
Keywords: Aging, endothelial cells, hypertension, medicinal agents
CONTENTS 1. Introduction 2. The aging endothelium. 2.1 The enhancement of oxidative stress. 2.2 The reduction of NO bioavailability. 2.3 Imbalance in the production of vasoconstrictor/vasodilator factors. 2.4 The development of a low-grade pro-inflammatory environment. 2.5 Impaired angiogenesis. 2.6 Endothelial cell senescence. 3. The aging vascular smooth muscle. 3.1 Altered replicating potential. 3.2 Change in cellular phenotype. 3.3 Changes in responsiveness to contracting and relaxing mediators. 3.4 Changes in intracellular signaling functions. 4. Changes in the extracellular vascular matrix with aging. 5. Arterial stiffness during aging 6. Aging and hypertension. 7. Vascular remodeling during hypertension 8. Aging, insulin resistance and hypertension. 9. Medicinal agents in hypertension during aging. 7.1 Natural Compounds. 7.2 Hormones. 7.3 Anti-oxidants. 7.4 Anti-inflammatory drugs. 7.5 Antihypertensive drugs.
10. Conclusions. 11. References.
1. Introduction Aging can be defined as a progressive deterioration of biological functions after the organism has attained its maximal reproductive competence (Guarner and Rubio-Ruiz, 2012). Aging is associated to an impairment of blood vessel function, which is a very early and important event leading to cardiovascular disease (El Assar et al., 2012). Dominant aspects of vascular aging include increased arterial stiffness, dilation of central elastic arteries and endothelial dysfunction (Kotsis et al., 2011). Vascular aging is associated with both structural and functional changes that take place at the level of the endothelium, vascular smooth muscle cells (VSMC) and the extracellular matrix of blood vessels. There are few studies on the aging of vascular contraction and relaxation responses. Age-related vascular changes may differ from one species to another and in blood vessels supplying individual organs. Therapies geared to retard the vascular aging process are of great clinical importance. In fact, there are numerous studies in process, aiming at determining the etiology of cardiovascular aging, as well as the prevention of its more noxious aspects.
2. The aging endothelium. The mechanisms underlying the age-related endothelial vascular dysfunction are: 2.1 The enhancement of oxidative stress. Reactive oxygen and nitrogen species are essential signaling molecules, regulating vascular homeostasis, and relevant changes related to age in the vascular wall are
driven by them (Bachschmid et al., 2012). There are several main systems proposed to be the sources for the reactive oxygen species (ROS) increased production in the human vasculature, namely NADPH oxidase, xantine oxidase, uncoupled nitric oxide synthase and the mitochondrial respiratory chain (Brandes et al., 2005; Lassegue and Griendling, 2010; Cau et al., 2012). The age-dependent increase in free radical formation causes deterioration of the nitric oxide (NO) signaling cascade, alters and activates prostaglandin metabolism, and promotes novel oxidative posttranslational protein modifications that interfere with vascular and cell signaling pathways. As a result, vascular dysfunction manifests itself. Compensatory mechanisms are initially activated to cope with age-induced oxidative stress, but become futile, which
macromolecules (Bachschmid et al., 2012; van der Loo et al., 2002). Several lines of evidence in experimental animal models indicate the central role of mitochondria both in lifespan determination and in cardiovascular aging. In aging, there is a reduction in the number of mitochondria and an increase in the generation of dysfunctional proteins, which leads to a depletion in the energy supply and even to an increase in the superoxide production (Pang et al., 2008). Mitochondrial oxidative stress, mitochondrial damage and biogenesis, as well as the crosstalk between mitochondria and cellular signaling, play a central role in cardiac and vascular aging (Dai et al., 2012). 2.2 The reduction of NO bioavailability. This can be caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO-) (El Assar et al., 2012). NO is synthesized from L-arginine through the action of the NO synthases, particularly
the endothelial synthase (eNOS), in the case of the vessels (Loscalzo, 2013). Reduced NO production may be due to: (1) a deficiency in NOS substrates and cofactors; (2) the presence of endogenous eNOS inhibitors; and (3) a lower expression and/or activity of eNOS. Enhanced NO degradation may be mostly due to excessive amounts of ROS such as superoxide anions that quench NO diminishing its functional activities. The lower availability of L-arginine with aging could be related to an increased expression and/or activity of arginase, the enzyme that degrades L-arginine (Santhanam et al., 2008). The synthesis of NO is blocked by the inhibition of the NOS active site with guanidine-substituted analogs of L-arginine such as asymmetric dimethylarginine (ADMA), which is a naturally occurring amino acid found in plasma and various tissues (Yamagishi and Matsui, 2011). There is a positive correlation between the plasmatic levels of ADMA and age (Schulze et al., 2005). Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis by eNOS and an inadequate availability of BH4 results in ‘uncoupling’ of eNOS and synthesis of superoxide anion instead of NO (Landmesser et al., 2003). There is a reduction in BH4 bioactivity with aging; however, the mechanism responsible for this reduction is unclear (Seals et al., 2011). Studies in experimental models and even humans reveal that constitutive production of NO is reduced with aging and this circumstance may be relevant to a number of diseases that plague the aging population (Torregrossa et al., 2011). NO is one of the most important signaling molecules in our body, and loss of NO function is one of the earliest indicators or markers of disease. Clinical studies provide evidence that insufficient NO production is
associated with all major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension (Torregrossa et al., 2011). Paradoxically, in rats the expression of eNOS in blood vessels increases significantly with age, but the levels of NO diminish, suggesting that this reduction is due to the rapid conversion of NO to peroxynitrates, through the action of superoxide radicals (Sun et al., 2004). Vascular and renal mRNA for inducible NO synthase, as well as for pro-endothelin, increase with age and favors functional and anatomic changes leading to age-related pathologies, including atherosclerosis. The activation of vascular endothelin-1 (ET-1) and iNOs are important independent factors promoting increase in blood pressure and thereby contributing to structural and functional anomalies during aging (Cau et al., 2012). NO bioavailability is compromised in the systemic circulation and in the musculature of sedentary aging humans due to increased oxidative stress. Lifelong physical activity counteracts this reduction. Furthermore, the reduced blood ﬂow to contracting muscles with aging does not appear to be related to changes in NO bioavailability, however higher protein expression of eNOS and bioavailability of NO in the physically active subjects might explain the higher vascular response to the endothelium-dependent vasodilator Acetylcholine (Ach) (Nyberg et al., 2012). Chronic oxidative stress and impairment of redox signaling are involved in vascular homeostasis and disease during aging. 2.3 Imbalance in the production of vasoconstrictor/vasodilator factors. One of the most important discoveries in recent decades in cardiovascular physiology has been the role of the endothelium as a generator of vasoactive substances. Factors described are NO, ET-1, the endothelium
derived hyperpolarizing factor (EDHF) and prostacyclin derived from the arachidonic acid metabolism (Versari et al., 2009; Seals et al., 2011). These findings have stimulated an enormous interest in this area, since a large number of other endothelium derived factors have been identified and their importance proven, both in normal physiology and in pathological processes. The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions, several substances with potent anti-atherosclerotic properties. Accordingly, the presence of endothelial dysfunction is associated with subclinical atherosclerosis and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of NO as the main endothelium-derived relaxing factor. However, in the presence of pathological conditions (such as hypertension) endothelial cells, in response to a number of agents and physical stimuli, become also a source of ET-1, Angiotensin II (Ang II) and particularly, cyclooxygenase-derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension (Versari et al., 2009). During aging, the vasodilator response to agonists in resistance and capacitance in rat arteries is reduced, and this change has been related to alterations in the secretion equilibrium of vasoconstrictor and vasodilator substances. A decrease in the NO or the EDHF-induced vasodilation or an increase in vasoconstriction induced by cyclooxygenase products, such as thromboxane A2 (TXA2), probably occur during aging (Long et al., 2005). The rennin-angiotensin system (RAS) is a critical vasoconstrictor system for
pathogenesis. Its major actions are mediated by Ang II, acting through its angiotensin receptors 1 and 2 (AT1 and AT2). There is evidence of increased vascular expression of Ang II and angiotensin converting enzyme (ACE) with aging (Yoon et al., 2014). Ang II is a potent inducer of endothelial dysfunction and vascular oxidative stress (Idris et al., 2012). Age-induced decline in EDHF-mediated vasodilation seems to be related to an up-regulated RAS, since chronic ACE inhibition, as well as AT1 receptor blockade, recovered EDHF-mediated responses in arteries from old rats (Goto et al., 2004). Ang II acting through AT1 is a mediator of normal aging processes by increasing oxidant damage to mitochondria and in consequences by affecting mitochondrial function. Inhibition of Ang II activity by targeted disruption of the Agtr1a gene encoding Ang II type 1A receptor (AT1A) in mice translates into marked prolongation of life span (Benigni et al., 2009 Cassis et al., 2010). Although the precise mechanisms of the longevity observed in AT1A receptordeficient mice have not yet been clarified, the concept that partial, but not complete, blockade of AT1 receptors will improve the mortality and lifespan of humans. Further studies are required to ascertain the precise mechanisms by which RAS blockade promotes longevity (Nishiyama et al., 2009). The classic enzymatic pathway to produce Ang II through the degradation of angiotensinogen by renin and ACE has been broadened and other enzymatic pathways whose final end products equilibrate the participation of the renin-angiotensin-aldosterone system in cardiovascular homeostasis have been discovered. Angiotensin 1-7 (Ang 1-7) is produced by a second angiotensin converting enzyme known as ACE-2 and it acts through special
MAS receptors (mitogenic activity signaling receptors) that have opposite actions to those of AT2. In the pathway producing angiotensin 1-12 (Ang 1-12) other kinases different from renin participate; therefore, this pathway is extra renal and it ends with the production of Ang II. The pathway giving rise to the heptapeptide alamandine acts through another type of MAS receptors and is independent from the Ang 1-7 pathway (Dell`Italia and Farrario, 2013). Aging is also associated with elevated plasma concentrations of ET-1 in humans (Donato et al., 2009). Aging has been associated with an anatomical heterogeneity of endothelial dysfunctions, increases in the expression of vascular mRNA of prepro-endothelin as well as vascular superoxide dismutase activity.
This alteration can induce functional and anatomical changes
conducive to pathologies typical of aging (Thijssen et al., 2008). Hydrogen sulfide (H2S) has recently attracted extensive attention for its multiple physiological functions and potential contribution to pathological states such as
hypertension, stroke, diabetes mellitus and Alzheimer’s
disease. H2S regulates cell cycle and survival in healthy cells suggesting it might play a role in cell fate and hence the aging process. In spontaneously hypertensive rats (SHR), plasma levels of sulphide are lower than in normotensive control WKY animals (WKY = 48 M; SHR= 20 M). Plasma H2S level in human individuals decline with age. However, the precise relationship between H2S and the physiological changes that constitute aging is largely unknown (Zhang Y et al., 2013). H2S acts as an antioxidant with antiatherogenic, anti-apoptotic, antiinflammatory, antiproliferative properties. It is also a signaling molecule, a neuromodulator and
endothelial and smooth muscle cell hyperpolarization and vasorelaxation (by opening ATP-sensitive K+ channels in vascular smooth muscle). Due to these actions, H2S could be an alternative approach for treatment of hypertension and age-related diseases (Zhang et al., 2013). In animal cells H2S is produced endogenously as a product of the transsulfuration (L-cysteine biosynthesis) pathway by the action of two enzymes: cystathionine -synthase (CBS) and cystathionine -lyase (CSE) (Qabazard, et al., 2013). CBS is the predominant H2S-generating enzyme in the brain and nervous system and is highly expressed in liver and kidney and its activity is regulated presumably at the transcriptional level by glucocorticoids and cyclic AMP. CSE is predominantly localized to the endothelial layer of blood vessels, liver and in vascular and non-vascular smooth muscle. The regulation of CSE is less understood, but there is
evidence that myeloid zinc finger 1 (MZF1) and
specificity protein 1 (SP1; also known as Sp1 transcription factor) play roles in its basal transcriptional activity, and the enzyme can be up-regulated by bacterial endotoxin (Szabó, 2007). 2.4
environment. Inflammation is described as an underlying mechanism of aging and age-related diseases, which may constitute a link between normal aging and age-related pathological processes. Many of the characteristics of vascular aging, including endothelial dysfunction, oxidative stress, increased apoptosis and pro-inflammatory gene expression profile can be mimicked by recombinant TNF- (Csiszar et al., 2007). Endothelium-synthesized prostaglandins and thromboxane are local hormones, which are inflammatory mediators and mediate vasodilation and
vasoconstriction, critically maintaining vascular homeostasis. Accumulating evidence indicates that the age-related changes in endothelial eicosanoids contribute to decline in endothelium function and are associated with pathological dysfunction, providing one molecular mechanism of age-associated endothelium dysfunction and cardiovascular diseases (Qian et al., 2012). In humans, the relevance of the endothelium-dependent contraction increases, becomes apparent through the observation that indomethacin potentiates the relaxation to Ach in isolated renal arteries of aged patients (Vessières et al., 2013). The vasodilator response to the muscarinic agonist in the forearm of people with essential hypertension suggests that endotheliumderived vasoconstrictor prostanoids also contribute to endothelial dysfunction in humans (Shalimova, 2014). This conclusion is supported by the ﬁnding that the tromboxane prostanoid-receptor inhibitor terutroban improves endothelial function in patients with coronary disease (Belhassen et al., 2003). To judge from the comparison of the effect of indomethacin in different age groups, the contribution of vasoconstrictor prostanoid increases with advancing age as it does in animal blood vessels (Seals et al., 2011). Cyclooxygenase (COX) plays an important role in the regulation of vascular tone under normal conditions by the synthesis of different vasoactive factors, which are particularly relevant since both vasodilators such as prostacyclin or vasoconstrictors could be produced. These factors are in a delicate balance in adults. During aging, a shift in the balance in favor of increased contractile factors occurs, and therefore endothelium-dependent contractions increase (Schrage et al., 2007).
2.5 Impaired angiogenesis. Impaired angiogenesis and endothelial dysfunction likely contribute to the increased prevalence of both cardiovascular diseases and their adverse consequences in the elderly. Angiogenesis is both an essential adaptive response to physiological stress and an endogenous repair mechanism after ischemic injury (Lähteenvuo and Rosenzweig 2012). 2.6 Endothelial cell senescence. Cellular senescence is a condition in which the cell loses the ability to proliferate, although it can be metabolically active. The underlying mechanism for this phenomenon is telomere length shortening that occurs during each cell division until a critical length is exceeded. When the telomeres are too short, cell signaling is triggered for the arrest of cell proliferation, senescence and apoptosis. Cellular age, calculated in vitro on the number of cellular replications, has been correlated with a decrease in NO synthase and an increase in the number of monocytes adhering to the endothelial cells. The stable expression of telomerase induces a younger endothelial cell phenotype with an increase of NO synthase and higher NO activity.
consequences in the endothelial cells (Farsetti et al., 2009). The number of circulating endothelial cells increases with age, reflecting an increased cellular turnover in rats. This alteration in endothelial function could contribute to a higher risk of pathological processes in the arterial wall (Thijssen et al., 2008). Age can increase the sensitivity of the endothelium to apoptotic stimuli. Thus, oxidized low density lipoproteins (LDL) and TNF- increase the caspase-3-like activity more than three times in old cells, in comparison with that in young cells. Besides, the levels of nitrosylated Sproteins are reduced, indicating that the protection exerted by NO against S-
nitrosylating caspases is not achieved efficiently. This effect is reversed when over-expression of eNOS is induced (Cau et al., 2012). Also the relationship between aging and progenitor cell-mediated repair is of great interest. Endothelial progenitor cells (EPCs) play an integral role in the cellular repair mechanisms for endothelial regeneration and maintenance. However, EPCs are subject to age-associated changes that diminish their number in circulation and function, thereby enhancing vascular disease risk (Williamson et al., 2012). Sirtuin (SIRT) genes and pathways can contribute to longevity. They are involved in the lower vascular repairing capacity observed in the elderly. SIRT1 is a key sensor system for regulating endothelial cell survival, proliferation and senescence. SIRT1 is a conserved NAD(+)-dependent deacetylase possessing beneficial effects against aging-related diseases. The protective activities of SIRT1 may be achieved at least in part by fine tuning the acetylation/deacetylation status and stabilities of LKB1, a serine/threonine kinase protein (Zu et al., 2010). At present, endothelial dysfunction in arteries from aged mice and humans is associated with a reduction of vascular expression of SIRT1 (Donato et al., 2011; Ota et al., 2008; Potente and Dimmeler, 2008). In addition to the lack of cell replication, senescent cells acquire distinct phenotypic characteristics associated to aging and age related diseases (Ungvari et al., 2010). Telomere dysfunction and vascular senescence are related to enhanced ROS, decreased NO, and increased pro-inflammatory molecules (Minamino et al., 2004,2007).
The dysregulation of various cellular signaling pathways in conjunction with oxidative stress induces cellular senescence. Endothelium senescent cells may have a negative impact on neighboring cells, furthering endothelial dysfunction. Cellular senescence can be induced by stress or by shortening of indispensable telomeres on nuclear chromosomes. Therefore studying the molecular basis of the link between DNA damage and vascular dysfunction will help a better understanding of vascular aging and ultimately its treatment.
3. The aging vascular smooth muscle. The aging process in vascular smooth muscle and dysfunction is characterized by: 3.1 Altered replicating potential. The vascular smooth muscle cells of individuals whose lives are ending show characteristics of elderly cells and a deterioration of their replicating potential (Ruiz-Torres et al., 2003). However, some situations such as atherosclerosis and restenosis have revealed that age increases the proliferation of vascular smooth muscle. An increase in c-fos activity during aging elevates cyclin A expression, enhancing proliferation. This phenomenon may contribute to an increased prevalence and worsening of atherosclerosis in aged animals (Moon et al., 2001). The rise of smooth muscle proliferation with age might be related to a calcium homeostasis imbalance or a platelet derived growth factor (PDGF) gene over-expression (Yang et al., 2009). Also the oxidative response determines the rate of VSMC proliferation (Moon et al., 2001). It has also been proposed that an increase in the sympathetic autonomous nervous system tone activity towards the vessels might play an
important role in renovation and proliferation of the muscle (Schiattarella et al., 2014). 3.2 Change in cellular phenotype. Characteristic morphological and molecular alterations such as vessel wall thickening and reduction of NO occur in the aging vasculature leading to the gradual loss of vascular homeostasis. Changes in function and redox status of VSMC contribute to age-related vascular remodeling (Bachschmid et al., 2012). During the aging of the vascular smooth muscle, the cellular phenotype changes from contractile to synthetizing. Old cells do not respond to some inhibiting factors such as transforming growth factor -1(TGF-1). They cease to interact normally with the extracellular matrix, due to changes in the expression of integrins or to changes in the extracellular matrix composition (Lundberg and Crow, 1999). 3.3 Changes in responsiveness to contracting and relaxing mediators. The responses of the vascular smooth muscle to the contracting or relaxing mediators secreted by the endothelium change with age. Aging does not significantly alter the vascular resistance, contractility or smooth muscle sensitivity (Lundberg and Crow, 1999). During aging there is a decrease in bioavailability of NO which is probably caused by increased oxidative stress as a consequence of a greater production of reactive oxygen species without a compensatory increase in antioxidant defenses in VSMC. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase and increased mitochondrial synthesis during oxidative phosphorylation (Seals et al., 2011). A reduced responsiveness to dilatory prostaglandins in older adults has also been reported (Mukherjee et al., 2007).
Studies done in resistance arteries such as the rat tail artery, show that the
noradrenaline (NA) fall during aging (Tabernero and Vila, 1995); however, the response to NA, phenylephrine and high potassium rises with age. The decline in sensitivity to NA in the rat aortic artery is due to a post receptor mechanism (Carvajal et al., 1995). There are contradictory reports of effects of aging on vascular contractility to different agonists in rats. Aortic KCl and NA-induced vascular contraction in control rats remained constant during aging (Rubio-Ruiz et al., 2006; Matz et al., 2003). Therefore, both unspecific contraction inducers such as KCl and neurotransmitters as NA have the same effect. However, important changes occur in vascular contraction depending on the strain of animals and on the artery used. There is also an increased bioactivity of the potent ET-1 and ET-1mediated vasoconstriction (Donato et al., 2009; Van Guilder et al., 2007; Thijssen et al., 2007). There is also an increased contractile response to KCl in the presence of insulin which is mediated by ET-1 (Nava et al., 1999). The response to KCl in the presence of insulin is not significantly modified with age in the control animals. In control rats, ET-1 receptor blockers ETA and ETB inhibited the increased response to KCl in the presence of insulin but only the ETA receptor participation diminished significantly with age (Rubio-Ruiz et al., 2006). The role of RAS, particularly of Ang II, holds high interest in the areas of cardiovascular and renal physiology and pathology. The L-arginine/NO pathway, particularly NO as an endothelial-derived relaxing factor, has also
been an area of keen interest however is not
clear how the balance between
NO and Ang II, rather than the absolute concentration of either, is what determines
pathophysiology. The reasons for the imbalances between the substances are often unclear. An understanding of the relations between hypertension, endorgan damage, and the NO-Ang II axis leads one to believe that available therapeutic strategies capable of restoring the homeostatic balance of these vasoactive agents within the vessel wall would be effective in preventing or arresting end-organ disease (Schulman et al., 2006). Formation and accumulation of AGEs (advanced glycation end-products) is also believed to contribute to smooth muscle dysfunction, perhaps via fibrosis and remodelling (Semba et al., 2010). 3.4 Changes in intracellular signaling functions. Vascular intracellular signaling works differently in the isolated smooth muscle of young and old rats; intracellular second messenger secretion is altered due to age- related changes in the signals sent by the endothelial cells. Traffic of intracellular messengers is altered by the calcium-calmodulin II enzyme (Lundberg and Crow, 1999). The cGMP concentration falls with age, following the same pattern of NOS expression (Francis et al., 2010). Reduced relaxation during aging in rats may be due to a decreased activation of protein kinase G-1 (PKG-1) (Lin et al., 2001). Some authors have found that adenosine mediates NO-dependent relaxation as well as relaxation mediated by other substances in the aorta and coronary arteries and that aging and maturity reduces the response to adenosine. A decreased aortic response also involves a reduction of the optimal transduction signal to the adenosine receptor (Hinschen et al., 2001).
One of the key factors that regulate arterial tone is the activity of K+ channels in the VSMC; in particular, voltage-dependent and Ca(2+)-activated K+ (BKCa) channels. Aging induces a reduction in the density of the alpha-subunit of BKCa channels in coronary smooth muscle and increases the response to endothelial constrictor factors and potassium (Shi et al., 2013).
4. Changes in the extracellular vascular matrix with aging. The extracellular matrix of blood vessels is engrossed during aging. The extracellular matrix provides a structural framework essential for the functional properties of vessel walls. The three dimensional organization of the extracellular matrix molecules - elastin, collagens, proteoglycans and structural glycoproteins - synthesized during fetal development - is optimal for these functions. In uninjured arteries and veins, some proteases are constitutively expressed, but because of the control of their activation and/or their inhibition by inhibitors, they have a very low activity and the turn-over of elastic and collagen fibers is low. During aging and during the occurrence of vascular pathologies, the balance between proteases and their inhibitors is temporally destroyed through the induction of matrix metalloproteinase gene expression, the activation of zymogens or the secretion of enzymes by inflammatory cells. Smooth muscle cells, the most numerous cells in vascular walls, have a high ability to respond to injury through their ability to synthesize extracellular matrix molecules and protease inhibitors. However, the three dimensional organization of the newly synthesized extracellular matrix is never functionally optimal. In some pathological conditions, the injury overcomes the responsive capacity of smooth muscle cells and the quantity of extracellular matrix decreases. Care
should be taken to maintain the vascular extracellular matrix reserve and any therapeutic manipulation of the protease/inhibitor balance must be perfectly controlled, because an accumulation of abnormal extracellular matrix has adverse effects (Jacob, 2003). Many of the complications of hypertension, such as stroke, coronary heart disease, and aneurysm formation are themselves a direct result of the vascular damage induced by prolonged blood pressure elevations. One of the pathological hallmarks of hypertensive tissue injury is an increase in tissue fibrosis, which leads to reductions in tissue compliance and function. Fibrosis (or sclerosis) occurs as result of marked changes in the amount and composition of the extracellular matrix. This extracellular matrix is a complex mixture
fibronectins, and proteoglycans. Hypertension is known to be associated with increases in the synthesis of extracellular matrix proteins and changes in their degradation. These processes are mediated by several mediators, in particular the renin-angiotensin-aldosterone system (Sasamura et al., 2005).
5. Arterial stiffness during aging Aging causes structural changes in the arterial wall in large elastic arteries which include increased stiffening caused by a decrease in the elastin content of the arterial media and dominance of collagen content, associated to increased non-enzymatic cross-linkages between collagen structures (Nilsson, 2014). In the arterial wall vascular aging is characterized by a reduction in the elastin content, and by an increased content of collagen and its cross-linkages, leading to increased arterial stiffness and elevated central as well as brachial
blood pressure, accompanied by increased systolic blood pressure variability (Nilsson et al., 2013). The increased stiffness and impaired relaxation, is in line with reduced bioavailability of sarcoplasmic reticulum Ca2+-ATPase, deranged homeostasis of cytoskeleton proteins, and a post-transcriptional switch towards slow contractile protein isoforms of myosin (Bernhard and Laufer, 2008). While there appears to be a difference between aging and coronary atherosclerosisinduced cardiac fibrosis, these effects may well overlap. Arterial stiffening and its hemodynamic consequences can be easily and reliably measured and arterial stiffness and its consequences represent the great challenge of the twenty-first century for affluent countries (Palatini et al., 2011). Age-associated changes in the large arteries are complex and therefore, there are different parameters relating to vascular aging which can be measured. These include aortic and carotid stiffening; aortic and carotid lumen dilation; endothelial dysfunction (usually measured via brachial flow-mediated dilatation); and carotid intima-media thickness (Laurent, 2012). The predictive value of aortic stiffness for fatal and nonfatal cardiovascular events in various populations having different levels of cardiovascular risk such as general population, patients with hypertension, elderly subjects, patients with type-2 diabetes, and patients with end-stage renal disease has been demonstrated by many studies (Laurent et al., 2013). Arterial stiffness and wave reflection are now well accepted as the most important determinants of increasing systolic and pulse pressures in aging societies, thus affording a major contribution to stroke and myocardial infarction. A major reason for measuring arterial stiffness in hypertensive patients comes from the demonstration that arterial stiffness has a predictive value for
cardiovascular events, beyond classical cardiovascular risk factors. Aortic stiffening also gives direct evidence of target organ damage, and improves the determination of the overall cardiovascular risk of asymptomatic hypertensive subjects. In clinical practice, the measurement of aortic stiffness may avoid patients being mistakenly classified as at low or moderate risk, when they actually have an abnormally high aortic stiffness placing them within a higherrisk group (Laurent et al., 2012). Structural changes in large elastic arteries contribute to early vascular aging (EVA) in patients with increased arterial stiffness for their age and sex (Nilsson et al., 2008, 2009, 2013). EVA explains in part the etiology leading to increased cardiovascular risk in addition to atherosclerosis, plaque formation and plaque rupture. These morphological changes, linked to arterial stiffness can be measured in a quantitative way via carotid-femoral pulse wave velocity and can be used as a cardiovascular risk marker in clinical practice (Nilsson et al., 2013, 2014; Van Bortel et al., 2012). Arterial stiffness and wave reflection are now well accepted as the most important determinants of increasing systolic and pulse pressures in aging societies, thus affording a major contribution to stroke and myocardial infarction. A major reason for measuring arterial stiffness in hypertensive patients comes from the demonstration that arterial stiffness has a predictive value for cardiovascular events, beyond classical cardiovascular risk factors. Aortic stiffening also gives direct evidence of target organ damage, and improves the determination of the overall cardiovascular risk of asymptomatic hypertensive subjects (Nilsson et al., 2013).
6. Aging and hypertension.
Hypertension causes 7.1 million premature deaths per year worldwide and is responsible for 4.5% of the global burden of disease. This startling impact of hypertension on health worldwide in part reflects its high prevalence. (Bramlage and Hasford, 2009). According to a recent review of published literature, approximately a quarter of the adult population worldwide (26.4%) was hypertensive in 2000 and this is expected to increase to 29.2% by 2025 (Stokes, 2009). Isolated systolic hypertension is characterized by systolic blood pressure ≥ 140 mm Hg with diastolic blood pressure <90 mm Hg, and (consequently) high pulse pressure. Hypertension is a multifactorial disorder in which the mix of factors operative may vary according to age (Krousel-Wood et al., 2009; Uddin et al., 2003; García-Peña et al., 2001). Several models of hypertensive rats have been used to examine the influence of hypertension on the aging cardiovascular system. Numerous studies focus on comparing the differences in development and aging patterns between hypertensive and normal rats. Hypertensive rat vessels are stronger, more rigid and hyperactive than those in normal rats; therefore, they are capable of responding in a considerably wider range of tensions despite the high pressure to which the individuals may be exposed. This characteristic of the responses is enhanced when hypertension is corrected (Lundberg and Crow, 1999). Blood pressure in control rats diminishes, while in SHRs there is no significant change in blood pressure during aging (Küng and Lüscher, 1995; van der Loo et al., 2000). In metabolic syndrome (MS) rats, which show hypertension, arterial blood pressure diminishes during aging (Rubio-Ruiz et al., 2006).
An increase in the response to ET-1 was found with age in SHR (Montagnani et al., 2000). These changes are more pronounced in animals with cardiovascular dysfunctions such as hypertension (Santos and Joles, 2012). Alterations in ET-1 receptors exist in models of hypertension, insulin resistance, hypercholesterolemia and atherosclerosis (Bender et al., 2011). Lu et al. (1998) reported that aortas from SHRs have an increased number of ET-1 receptors in young and old animals. It has also been previously reported that insulin elevates the number of ET-1 receptors in aortic smooth muscle cells in normal and hyperinsulinemic rats in vitro and in vivo. Changes at the intracellular signaling pathway level of insulin and ET-1 have also been explored during aging. Both ET-1 and NA stimulated inositol phosphate formation decreased with age in SHRs. Age related decreases were consistently greater in SHRs than in WKYs. Thus, both age and rat strain modulated agonist stimulated inositol phosphate formation and this is not modified by hypertension or hyperlipidemia (Yang et al., 1996). It has been previously reported that arterial endothelium-dependent relaxation is diminished during aging in normotensive and hypertensive rats (Küng and Lüscher, 1995; Freitas, et al., 2003). These authors have proposed that the reduced response to Ach could be a consequence of an impairment of either the generation (synthesis or release) of relaxant factors or of the cellular response to them during aging. During the late stages of aging in SHR, there is an inhibition of the vascular relaxation pathway involving not only NO production by endothelial cells but also the bio-availability of NO and the smooth muscle response to NO (Seals et al., 2011).
7. Vascular remodeling during hypertension Vascular remodeling is a widely used term for different adaptive processes of the vessel wall structure during development, and aging. In addition, different types of vascular injuries can cause remodeling and maladaptive alterations primarily of the arterial vessel wall, which may result in disease processes. Following vascular injury, neointima formation occurs because of the accumulation of VSMCs. In pulmonary and arterial hypertension, the width of the tunica-media increases, which raises the vascular resistance and therefore raises blood pressure. The phenotype of SMCs is adaptable to environmental cues and varies between a contractile and a synthetic state. In addition, progenitor cells of SMCs from the circulation or the adventitia can be recruited to the neointima and differentiate into SMCs. Moreover, fibroblasts and vascular stem cells from the adventitia can migrate into the neointima and adopt a SMC phenotype. Endothelial cells sense stimuli that induce vascular remodeling, such as hemodynamic stress or hyperlipidemia, and transmit these signals to the medial SMCs or promote the inflammatory response. The phenotypes of SMCs and ECs, as well as the inflammatory activation of macrophages, are regulated by noncoding, small RNAs through posttranscriptional regulation of gene expression (Wei et al., 2013). Structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions, and the appearance of cells expressing smooth muscle-specific markers in normally
non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular transdifferentiation (Shimoda and Laurie, 2013). Atherosclerosis is accompanied by profound remodeling of the vascular wall driven by the inflammatory response to the subendothelial accumulation of modified lipoproteins. These maladaptive processes are mediated by various vascular cell types, including ECs and SMCs. In addition, an inflammatory response, characterized primarily by the recruitment of monocytes and macrophages, promotes vascular remodeling through the activation of SMCs (Wei et al., 2013). Most of the morbid events due to hypertension are related to alterations of the large arteries of the brain, the heart or the kidney. Aging, environmental and genetic factors are responsible for structural and functional changes of the arterial wall media (hypertrophy, extracellular matrix accumulation, calcium deposits) and of the vascular endothelium (decrease in the release of vasodilators and increased synthesis of vasoconstrictors), leading to a diminution of elasticity and increased stiffness. The alteration of large arteries elasticity has deleterious effects on the heart upstream being responsible for an inadequate increase in systolic pressure and a relative decrease in aortic diastolic pressure at any given value of mean arterial pressure (Lajemi et al., 1999). In addition, the greater atherosclerotic burden in the aged population is laden with a high incidence of acute cardiovascular events and is the major cause of mortality and disability in aged people. Advanced age is a marker of poor prognosis; 75% of all myocardial infarction-related deaths occur after the
age of 70 and the greater preexisting cardiovascular load of prior myocardial infarction and congestive heart failure. After myocardial infarction, these patients are highly prone to develop heart failure through adverse left ventricular remodeling, including greater infarct expansion, impaired infarct healing and, importantly, exaggerated and prolonged inflammatory response (Bernhard and Laufer, 2008). Aging may adversely affect left ventricular remodeling leading to progressive dilatation through modification of the inflammatory response after myocardial infarction (Valentina et al., 2011). Arterial remodeling also includes arterial calcification. The arterial calcification is one of the main complications associated with Chronic Kidney Disease (CKD). Calcification may occur in blood vessels, the myocardium and cardiac valves mostly as apatite calcium phosphate deposition. In the arterial vessel wall, calcification takes place in the intima or in the media. Medial calcification is the form classically associated with age, diabetes and CKD (Giachelli, 2009). The mechanisms leading to arterial remodeling and endothelial dysfunction during CKD involve other pathways, including activation of the RAS, ET-1, decreased Klotho expression, ADMA, inflammation and oxidative stress. Ang II exerts various effects at the level of the cardiovascular system, including a potent vasoconstrictor effect that increases vascular resistance, a remodeling effect with hypertrophy and fibrosis, and an inflammatory and pro-oxidant effect (Savoia et al., 2011; Touyz, 2005). In the HOPE (Heart Outcome and Prevention Evaluation) trials, renal insufficiency was associated with increased risk for cardiovascular events, and the ACEi (Angiotensin Converted Enzyme inhibitor) ramipril reduced the incidence of cardiovascular events in patients with
and without renal insufficiency (Mann et al., 2001). Even if these secondary analyses appear promising, trials specifically designed in CKD populations are still needed to properly assess the effect of RAS blockade on arterial remodeling and cardiovascular prognosis (Briet and Burns, 2012). Hypertension is also related to cognitive decline and dementia. Lowering blood pressure may reduce the risk of stroke-related cognitive decline or dementia. High blood pressure in middle age is a risk factor for dementia, but not when it is determined at old age. There are apparently critical periods of life during which hypertension has a stronger impact on the brain. Hypertension should therefore be assessed several decades before the onset of dementia. Duration of hypertension also seems to play an important role. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, more than 6000 patients with history of stroke or transient ischemic attack were treated with an ACEi with or without a diuretic and compared with a placebo. The risk of poststroke dementia was decreased by one third and the risk of post-stroke severe cognitive decline was almost halved. Blood pressure has also been related to brain damage regardless of stroke and therefore to poorer cognitive functioning and dementia. The Farmingham Heart Study showed that the cognitive functions and memory were related to midlife arterial pressure measured 12 to 14 years earlier being associated to worse performance and a more rapid decline in executive function and processing speed (Tzourio et al., 2014). The mechanisms mediating the relationship between hypertension and cognitive decline are not well known. Structural changes in small brain arteries, such as arteriolosclerosis and lipohyalinosis, are probably important mediators underlying the relationship between hypertension and white matter lesions.
Blood pressure could also interact with β-amyloid peptide deposition in small brain arteries (Tzourio et al., 2014). A wider pulse pressure is associated with increased risk of dementia and active treatment may disrupt the relationship between diastolic blood pressure and dementia. Future studies need to focus on exploring the ideal goal pressure for the elderly (Peters et al., 2013).
8. Aging, insulin resistance and hypertension. Diminished insulin sensitivity is a characteristic feature of various pathological conditions such as MS, type-2 diabetes and hypertension. Insulin resistance is associated with aging and contributes to vascular malfunction. The prevalence of type-2 diabetes increases with age and affects almost 20 % of people over age 65 (Kalyani et al., 2013) and there are twice as many hypertensive patients among diabetics subjects (Gunasekaran and Gannon, 2011). Aging and insulin resistance interact to increase vascular dysfunction and may alter the sympathetic or the vascular responses to insulin. We and other authors have shown that insulin levels, within and above the physiological ranges, increase vascular contractility by stimulating the production and release of ET-1 and may contribute to hypertension (Elgebaly et al., 2008). Contrary to the vasodilation caused in young adults, insulin caused vasoconstriction in healthy elderly individuals. The failure of the vasodilator action of insulin in the elderly may permit even modest insulin-induced sympathoexcitation to elicit vasoconstriction. The vasoconstrictor response to insulin may further potentiate insulin resistance in the elderly (Hausberg et al., 1997). The main alterations induced by hypertension and diabetes on the aging processes in the cardiovascular system are mentioned in Table 1.
Patients with essential hypertension are more prone than normotensive subjects to develop diabetes, and this propensity may reflect decreased ability of insulin to promote relaxation and glucose transport in vascular and skeletal muscle tissue. Although the etiology of skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of RAS (Henriksen, 2007). Ang II, acting through AT1 receptor, inhibits the actions of insulin by interfering with phosphatidylinositol 3 kinase (PI3K) and its downstream protein kinase B (Akt) signaling pathways. Ang II can act on AT1 receptors both in the vascular endothelium and in myocytes, with an enhancement of the intracellular production of ROS. Evidence from animal model and cultured skeletal muscle cell line studies indicates that Ang II can induce insulin resistance. Therefore, hypertension also leads to insulin resistance probably due to the stimulation of AT1 receptor, which interferes with the insulin signaling pathways and decreases NO cell production (Henriksen, 2007). The association of hypertension, dyslipidemias and hyperinsulinemia with insulin resistance is quite frequent in humans and experimental models. Specific clusters of MS components impact differentially on arterial stiffness measured by pulse wave velocity. The combinations of high triglycerides, elevated blood pressure and abdominal obesity are consistently associated with significantly stiffer arteries to an extent similar or greater than that observed in subjects with alteration in all the five MS components, even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus (Scuteri et al., 2014).
Models of diabetic and MS rats have been studied to analyze the role of these diseases in altering the aging cardiovascular system. Other authors, working with renal arteries of SHRs, have also found that only ETA receptors participate in their contraction in control animals while both ETA and ETB receptors participate in the response of the hypertensive adult and old rats (Seo and Lüscher, 1995).
9. Medicinal agents in hypertension during aging. Based on the age-dependent blood pressure targets currently recommended by the European Society of Hypertension/European Society of Cardiology guidelines (ESH/ESC), it is appropriate to differentiate between the “elderly” and the “very elderly”. The “elderly” comprises the group of patients aged 65 to 80 years while patients 80 years and older are considered as “very elderly” (Mancia et al., 2013). According to the stratification from the Framingham study on the risk of having cardiovascular disease at each decade of life, systemic arterial hypertension and age are major risk factors that are continuous, independent and consistent. People aged 70 years or more are considered to be at an elevated risk; there is a 10% risk of having coronary cardiopathy in the next 10 years in more than 95% of the population. A similar 10% risk in the next 10 years is present in only 33% of the population aged 50 to 59 and in a 66% in people aged 60 to 69 years. Although there have been several trials and meta analyses over the last 15 years regarding the reduction of stroke and cardiovascular events in the very elderly, there are few trials to establish the benefit to risk ratio of hypertension in
the very elderly (Thijs et al., 1992; Staessen et al., 1999); however, clinical trials convincingly demonstrate the benefits of treating both diastolic hypertension in persons up to age 80 years, and isolated systolic hypertension in persons over age 60. Reducing the elevated blood pressure results in a 27% to 36% decrease in overall cardiovascular mortality and reduces severe congestive heart failure, strokes and deaths from myocardial infarction (Fagard, 2002). Since 2001, a study in patients aged ≥ 80 years; the “Hypertension in the Very Elderly Trial” (HYVET) helped establish the benefits and risks of the antihypertensive
recommendations for treating the very elderly patients surged from this trial (Bulpitt et al., 2001, 2003 cita nueva ). Later, in another study by the HYVET group, treatment of hypertension based on indapamide (sustained release), with or without perindopril, in the very elderly, achieve a target blood pressure of 150/80 mm Hg and reduced risks of death from stroke, death from other cause, and heart failure. The evidence provided solved areas of clinical uncertainty about the relative benefits and risks of antihypertensive treatment in patients 80 years of age or older (Beckett et al., 2008). The 2007 guidelines on hypertension of the ESH/ESC and other guidelines recommend treating grade 1 hypertensive patients independently of age, however, all the trials showing the benefits of antihypertensive treatment in the elderly, have been conducted in patients with systolic blood pressures over 160 mm of Hg (grades 2 and 3). In a large number of randomized trials on antihypertensive treatment in the elderly there was a reduction in cardiovascular events through lowering of blood pressure (Beckett et al., 2008). The average systolic blood pressure
achieved never reached values <140mmHg (Zanchetti et al., 2009). Conversely, two recent Japanese trials of more- vs. less-intensive blood pressure lowering were unable to observe benefits by lowering average systolic blood pressure to 136 and 137mmHg rather than to 145 and 142mmHg (JATOS Study Group, 2008). On the other hand, a subgroup analysis of elderly patients in the FEVER study showed reduction of cardiovascular events by lowering systolic blood pressure just below 140 mmHg (compared with 145 mmHg) (Zhang et al., 2011). Recently, in the 2013 guidelines (ESH/ESC) after a prospective metaanalysis comparing the benefits of different antihypertensive regimens in patients younger or older than 65 years it was confirmed that there is no evidence of the different classes of drugs having different effects in the younger vs. the older patient, but it is recommended that in the in the patient, with hypertension, the diagnosis of hypertension should be confirmed, the causes of secondary hypertension should be detected, and cardiovascular risk and obstructive disease and concomitant clinical conditions should be assessed. In the treatment strategies, appropriate lifestyle changes are the cornerstone for the prevention of hypertension, but pharmacological therapy is very important since it is necessary to know the benefit to risk ratio and possible contraindications to the use of antihypertensive drugs (Turnbull et al., 2008). Vascular aging is viewed as a target process for intervention in order to achieve a healthier old age. Prevention of the mechanisms leading to endothelial dysfunction through lifestyle modifications or pharmacological interventions could markedly improve cardiovascular health in older people (El Assar et al., 2012). Implementing strategies to diagnose and treat NO
insufficiency may provide great benefit to the geriatric patient (Torregrossa et al., 2011). NO activates telomerase in ECs, delaying senescence (Vasa et al., 2000, Farsetti et al., 2009) and strategies aimed to increase endothelial NO bioavailability
could be considered as therapies to prevent endothelial cell
senescence associated with aging (Hayashi et al., 2006). So far, there are no genetic or molecular solutions to slow the progression of cardiovascular aging. Exercise decreases the progression of arterial stiffness and improves endothelial function in skeletal muscle (Vita and Keaney, 2000) promoting vasodilatation (Schiattarella et al., 2014). Exercise also lowers blood pressure and heart rate, thereby decreasing arterial wall distention, improves ejection volume and slows myocardial remodeling (Schiattarella et al., 2014). Vasodilator drugs such as ACEi or AT1-blockers and calcium channel blockers (Ting et al., 1993, 1995) reduce pulse wave reflection and thus the pressure pulse and they protect muscular arteries from endothelial dysfunction (Armentano et al., 2006) These drugs prevent ventricular remodeling due to pressure overload in hypertension and it is likely that they could also protect from overload during aging. These actions might explain the reduction in ventricular mass, the decreased incidence of cardiovascular events and the lack of cerebral and renal deterioration observed with these drugs. In recent years, drugs that reduce the rigidity of the aortic wall by breaking of molecular bonds such as alagebrium are being investigated. Alagebrium (formerly known as ALT-711) was a candidate drug developed by Alteon Corporation which was clinically tested with the purpose of breaking the crosslinks caused by AGEs, thereby reversing one of the main mechanisms of aging. Through this effect alagebrium was designed to reverse the stiffening of
blood vessel walls that contributes to hypertension and cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking. Alagebrium has proven effective in reducing systolic blood pressure and provides therapeutic benefit to patients with diastolic heart failure (Sell and Monnier, 2012). Whether this drug should be prescribed since an earlier age to prevent or retard cardiovascular remodeling during aging and therefore diminish the incidence of cardiovascular diseases and other organ remains unsolved. Induction of angiogenesis is a promising therapeutic approach for ischemic diseases. For this reason, understanding the basis of age-related impairment of angiogenesis and endothelial function has important implications for managing cardiovascular disease (Lähteenvuo and Rosenzweig, 2012). The impact of age on endothelial progenitor cell-mediated repair is also important and it would be necessary to identify therapeutic targets with potential for attenuating the age-related decline in vascular health via beneficial actions on endothelial progenitor cells (Williamson et al., 2012). There are also potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases with a focus on mitochondrial-targeted antioxidants, calorie restriction and exercise training (Dai et al., 2012).
9.1 Natural Compounds. Elderly study populations comply well with antihypertensive treatment, and blood pressure can be safely lowered with simple drug regimens; nevertheless, non pharmacological treatment including lifestyle changes and the use of natural compounds is recommended for initial treatment of mild diastolic hypertension and isolated systolic hypertension, and
as support treatment with medication (Morgenstern and Byyny, 1992; Frisoli et al., 2011). Nutrition and lifestyle play a vital role in prevention of hypertension particularly in the elderly and, therefore, there is a continuous search for dietary components having a positive effect on blood pressure (Rubio-Ruiz et al., 2013). Nutrient-gene interactions and epigenetics are a predominant factor in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Food and nutrients can prevent, control and treat hypertension through numerous vascular biology mechanisms. The use of a single and/or a multi-compound nutraceutical supplement including vitamins, antioxidants and minerals in the treatment of hypertension is based on scientifically controlled studies to complement the optimal dietary intake and other lifestyle modification (Houston, 2014). Some natural compounds have been found to possibly have potential beneficial
tetrahidrocurcumin lead to a decrease of blood pressure, peripheral vascular resistance, aortic stiffness and oxidative stress. It increases aortic eNOS expression, inhibits proliferative activity and expression of NF-B, the orchestrator of the inflammatory response (Rubio-Ruiz et al., 2013). It also prevents negative changes in blood vessel morphology that accompany hypertensive disease (Hlavačková et al., 2011). Hibiscus Sabdariffa crude extract (HSE) is a vasorelaxant compound, probably via action on calcium channels, acting as an inhibitor of ACE and activating eNOS. It is also a diuretic compound and has antioxidant effects. (Perez-Torres et al., 2013). Resveratrol is an inhibitor of NF-B activation and has free radical scavenger properties. It
also has anti aging properties, mimicking the effect of calorie restriction. It also prevents
Epigallocatechin-3-gallate, a component of tea (Camellia sinensis) acts on the microsomal enzyme 11b-hydroxysteroid deydrogenase type 1 (11b-HSD1) which plays an important etiological role in hypertension and other disorders including insulin resistance, type-2 diabetes, dyslipidemia and obesity (Hintzpeter et al., 2014). Glycine, a non-essential aminoacid that participates in metabolic balance and in aging has been proposed by basic and clinical trials. It favorably participates increasing the antioxidant reserve and prevents or delays protein glycation. Glycine activates specific receptors known as GlyR that are widely distributed in the organism and in the vascular endothelium (Díaz-Flores et al., 2013). Although natural compounds might be useful in the treatment of hypertension in the elderly population more studies are needed to determine the correct doses that might prove beneficial and to test potential side effects. Novel potential molecular targets for screening natural compounds for anti-aging activity, as well as the idea that anti-aging interventions represent a systemic approach that is effective against age-related diseases are currently being actively discussed and investigated (Argyropoulou et al., 2013).
9.2 Hormones. Cardiovascular risk is similar for older men and women, but lower in women during their fertile years. This age- and sex-related difference points to estrogen as a protective factor because menopause is marked by the loss of endogenous estrogen production. Experimental and
some clinical studies have attributed most of the protective effects of estrogen to its modulatory action on vascular endothelium. Estrogen promotes endothelial-derived NO production through increased expression and activity of eNOS, and modulates prostacyclin and TXA2 release. The TXA2 pathway is a key to regulating vascular tone in females. Despite all the experimental evidence, some clinical trials have reported no cardiovascular benefit from estrogen replacement therapy in older postmenopausal women. The "Timing Hypothesis," which states that estrogen-mediated vascular benefits occur only before the detrimental effects of aging are established in the vasculature, offers a possible explanation for these discrepancies. Nevertheless, a gap remains in current knowledge of cardiovascular aging mechanisms in women. Menopause and aging contribute jointly to vascular aging and estrogen (Novella et al., 2012). Testosterone interferes with vascular function by increasing the production of pro-inflammatory cytokines and arterial thickness. Experimental evidence indicates that testosterone modulates the synthesis and bioavailability of NO and, consequently, endothelial function, which is key for a healthy vasculature. Interestingly, aging itself is accompanied by endothelial and vascular smooth muscle dysfunction. Aging-associated decline of testosterone levels is accompanied by age-related diseases, such as metabolic and cardiovascular diseases, indicating that very low levels of androgens may contribute to cardiovascular dysfunction observed in these age-related disorders or, in other words, that testosterone may have beneficial effects in the cardiovascular system (Lopes et al., 2012).
9.3 Anti-oxidants. Aging is associated with a pro-oxidant state and a decline in endothelial function. Acute, enteral antioxidant treatment can reverse this decline in vascular function. Antioxidant consumption acutely restores endothelial function in the elderly while disrupting normal endotheliumdependent vasodilation in the young (Wray et al., 2012). A recent clinical trial has shown the acute reversal of endothelial dysfunction in the elderly after oral administration of an antioxidant cocktail (vitamin C + vitamin E + lipoic acid) (Wray et al., 2012). In one study, measurements of vitamin E in major organs and plasma of 3-year old rats were carried out. The largest increase, 70 times the normal, was localized in the aortic wall. This observation suggests the existence of adaptive mechanisms, conducive to protecting the organism from possible oxidative stress associated with aging (van der Loo et al., 2002). 9.4 Anti-inflammatory drugs. Aging is a state of low chronic inflammation and therefore antiinflammatory and antioxidant agents are particularly useful for vascular and metabolic disorders in the elderly. Aspirin has a potent antioxidant effect, diminishing lipoperoxidation levels, diminishing the production of superoxide anion in endothelial cells and inhibiting NOX in endothelial cells in normo and hypertensive rats (Lee et al., 2001). Treatment with aspirin can also diminish blood glucose in 25% and decrease CRP, total cholesterol total and triglycerides (Pignone and Williams, 2010). The effects of NSAIDs have been investigated in people with and without elevated blood pressure, and the effects were reviewed in a metaanalysis in 1994. An important question is whether there are differences between the various NSAIDs (Khatchadourian et al., 2014). Although the
mechanism by which blood pressure rises with NSAIDs is not known, it is probably through inhibition of prostaglandin synthesis (Egan and FitzGerald, 2006). Jung et al. (2010) have reported that a low-dose of aspirin increases NO produced by blood vessels, but the mechanism responsible for this effect is not fully understood. Doses of aspirin employed for cardiovascular diseases increase NOS enzymatic activity in endothelial cell homogenates and in platelets, and aspirin at high concentrations acetylates endothelial eNOS serine residues. Indomethacin has a beneficial effect on endothelium dependent relaxations in animal models of aging and in old patients. However, low-dose aspirin and selective COX-2 inhibitors have been shown to improve or worsen endothelial dysfunction in models of hypercholesterolemia and hypertension. Hennan et al. (2001) reported that a COX-2–specific inhibitor attenuates arachidonic acid–induced vasodilatation in canine coronary arteries, supporting a physiological role for COX-2 in vascular function. Although NSAIDs may have a hypertensive action, the mechanism for this effect is still unknown. Inhibition of prostaglandin action might participate or an increase in salt and water retention. NSAIDs also decrease the antihypertensive effect of some drugs, particularly of ACE inhibitors, diuretics and -blocker drugs. Populations with a higher risk of increasing blood pressure when receiving NSAIDs, and in which these drugs should be carefully administered, are the elderly, salt sensitive individuals and patients with renal dysfunction or hepatic diseases (Rubio-Ruiz and Guarner-Lans, 2012). Some effects of NSAIDs have been reported upon the vasculature but the
mechanisms responsible for these effects are not fully understood (Jung et al., 2010). In the older age human population, people frequently have multiple problems. A large number of people on drug treatment for hypertension have arthritis that requires medication for pain relief. Most of the agents used for pain relief inhibit COX.
9.5 Antihypertensive drugs. Hypertension is prevalent in the elderly and increases with advancing age. Hypertension in elderly people differs from that in younger individuals; it is predominantly systolic because of vascular stiffness and it is associated with reduced baro-reflex sensitivity, which increases blood pressure variability and vulnerability to hypotension during common daily activities (Lipsitz, 2013).
There is strong evidence that supports the use of antihypertensive treatment for effective and sustained blood pressure control in older patients to reduce the risk of vascular-related morbidity and mortality, particularly cerebrovascular accidents, including stroke (Volpe and Tocci, 2013). However, there are pharmacokinetic changes associated with aging that affect mainly the absorption,
Pharmacodynamic changes are observed particularly in the cardiovascular and neuroendocrine systems. The pharmacodynamic responses depend on the number and affinity of receptors, the mechanisms of signal transduction, cellular responses and in the homeostatic regulation.
As age increases other systems apart from the cardiovascular apparatus are progressively altered, modifying pharmacokinetic, pharmacodynamic and
toxicological properties of drugs. The chemical structure of drugs employed against arterial systemic hypertension can modify pharmacokinetic and pharmacodynamic properties. As an example, AT1 receptor antagonists, losartan and candesartan, are pro-drugs that require to be modified by the digestive tract to be transformed into their active principles. Losartan is turned into EXP-317 by the action of cytochrome P450. Candesartan, in contrast, is hydrolized. These mechanisms of absorption and bioavailability of pro-drugs need enzymatic systems whose efficiency depends on age and on other factors associated to drug absorption such as solubility, digestive tract motility, blood flow and pH. Another example of the influence of the chemical structure of this group of drugs includes their collateral benefic actions. Losartan, through its uricosuric activity, is therapeutically ideal in hypertension associated to urate deposits in joints as in the case of gout. The chemical structure of candesartan has a stronger affinity for AT1 receptors and a low dissociation coefficient since it interacts with four sites of the receptor (Buiyan et al., 2009). These characteristics of candesartan confer it with a higher antihypertensive efficacy, longer action duration and better security that allows it to be administered every 24
pharmacological effects as well as the magnitude of adverse effects in the elderly patients also depend on the relation between the chemical structure of the drug and changes in biological variables. The duration
pharmacological effect depends on physicochemical properties such as the drug`s chemical affinity coefficient for its receptors, the degree of reversibility of the interaction, its binding to plasma proteins, body mass, the rate of body water in the organism and renal and hepatic elimination mechanisms. All these
variables are altered during aging modifying therefore the efficacy and action security of antihypertensive drugs including diuretics, ACEi, calcium channel antagonists and alpha and beta adrenergic receptor blockers.
In elderly people, the use of antihypertensive drugs induces the development of adverse drug reactions (ADRs). The highest percentage of ADRs occurs in patients >61 years, who also receive other multiple therapies. The antihypertensive drugs that most frequently produce ADRs are furosemide and carvedilol, and the most frequently reported ADRs are hypotension and hyponatremia. Adverse drug events have been linked to preventable problems in elderly patients such as depression, constipation, falls, immobility, confusion, and hip fractures (Rende et al., 2013).
Usually, five major classes of antihypertensive agents are prescribed for treatment of hypertension in the elderly which include thiazide diuretics, loop diuretics, calcium channel blockers (CCBs), ACEi, angiotensin receptor antagonists and -blockers (Rubio-Ruiz et al., 2013). Diuretics are drugs capable of increasing the rate of urine ﬂow and sodium excretion and are used to adjust the volume and composition of body ﬂuids in a variety of clinical situations including hypertension, heart failure, renal failure, nephritic syndrome, and cirrhosis. Diuretics are commonly used in elderly patients, but recent outcome data have raised doubts about their long-term benefits.
The mechanism by which thiazide diuretics reduce blood pressure is not completely understood. It has been proposed that during long-term therapy, thiazides act by reducing total peripheral resistance probably through a direct vascular effect. Thiazides reduce water reabsorption in the distal convoluted
tubules and thereby diminish plasma volume and cardiac output (Bramlage, 2009; Raheja et al., 2012).
Of the diuretic drugs used to treat hypertension in the elderly, the loop diuretics, are the ones with most consequences. Treatment with furosemide, has been related to alterations of serum levels of sodium, potassium, and creatinine, particularly in patients with high risk for electrolyte imbalance in the presence of liquid loss. Previous studies have documented that it increases mortality particularly when the daily dose is 50 mg (Musini et al., 2012). Furthermore, high doses of furosemide (1-3 g daily) may be associated with ototoxicity (Dini et al., 2013; Sica et al., 2011). Torsemide is a loop diuretic of the pyridine-sulfonylurea class. Torsemide, and other loop diuretics such as furosemide, are indicated for the treatment of edema associated with congestive heart failure, renal disease, and hepatic disease. They also are indicated for the treatment of hypertension alone or in combination with other antihypertensive agents. However, this diuretic has not been extensively explored in elderly patients and its use is limited to patients with nephropathy with or without diabetic etiology and in cardiac failure. Its use for hypertension is limited (Preobrazhenskiĭ et al., 2011).
In the traditional Ayurvedic system of medicine, Pashanbhed (meaning ‘stone breaker’) is a well-known drug which is mainly used as a diuretic. The employment of aromaticus (leaves) as Pashanbhed was recently justified and supported since this drug proved to be the best diuretic agent having similar actions to loop diuretics, like furosemide (Verma et al., 2014).
hypertension. However, many studies have reported the variance of interindividual response to HCTZ. Recently, meta-analysis of published data to evaluate the pharmacogenetic associations of adducin-1 (ADD1) and ACE upon the variance of response to this drug has been conducted. ADD1 is an actinbinding protein that has been shown to play important roles in the stabilization of the membrane cortical cytoskeleton and cell-cell adhesions (Chan et al., 2014) and lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension (Zhang LN, 2013). Important correlations with certain polymorphisms were found (Choi et al., 2013).
CCBs represent a heterogeneous group of agents. They all block the transmembrane calcium influx in vascular and myocardial cells through L-type clacium channels. Non-dihydropyridinic CCBs (ie, verapamil) offer a mild protective effect on proteinuria in diabetic nephropathy, beyond their antihypertensive action (Pruijm et al., 2008).
ACEi include enalapril, which is a prodrug that is hydrolyzed to the active form enalaprilat and reduces the plasma levels of Ang II. Treatment of rats with either ACEi or an AT1 receptor antagonist improved endothelial dysfunction (mediated by the NO and the EDHF component) in aged blood vessels, in part by decreasing oxidative stress (Goto et al., 2000, Kansui et al., 2002, Mukai et al., 2002). Antihypertensive drugs such as ACEi or Ang II receptor antagonists also have antiinflammatory effects. RAS inhibitors have a better tolerability profile than diuretics (Borghi and Santi, 2012; Nakamura et al., 2010).
-blockers have the potential of reducing myocardial O2 consumption by decreasing sympathetic tone and myocardial contractility, resulting in decreases in heart rate and blood pressure (Priebe, 2009). Carvedinol is a non-selective blocker with vasodilatory effects that are due to its ability to concurrently block both - and -receptors; however, carvedilol may induce bradycardia (Rende et al., 2013). It is widely accepted that all patients with arterial systemic hypertension should receive one or more treatments. Hypertension in the elderly leads to the prescription of a pharmacological treatment which in the least probable case of uncomplicated hypertension has the goal of reaching a blood pressure of 130/88 mm Hg and the primary prevention of ischemic cardiopathy, chronic renal disease, cardiac insufficiency, type-2 diabetes, hemorrhage, cerebral thrombosis or cerebral vascular disease (Rosendorf, 2009). The most common form of systemic arterial hypertension in the eldery is the one associated to one or more of the above mentioned nosological entities. The pharmacological treatment of these patients usually involves ACEi, ARB, CCBs and thiazide diuretics as monotherapy or the combination of several of them. Most of the elderly patients require of the association of two or more antihypertensive drugs. The presence of stable angina of cardiac stroke antecedents in the patient justifies the use of beta adrenergic receptor antagonists such as metoprolol or carvedilol. In the presence of stroke, in hospitalized or stable patients, the use of beta adrenergic blockers with preponderant action upon type 1 beta receptors, without sympatomimetic activity and short action duration are indicated like esmolol. The use of aldosterone antagonists such as spironolactone and sprenone can also be of
benefit if there is a strict vigilance of serum creatinine and potassium levels, particularly in patients with renal insufficiency. However in patients with systemic arterial hypertension, cardiac insufficiency, type-2 diabetes or MS, beta adrenergic blockers are not recommended and the use long duration action dihydropiridinic CCB is of preference. The use of AT1 receptor blockers and of inhibitors of the angiotensin converting enzyme delays the progression of renal damage and the transition from microalbuminuria to proteinuria. The simultaneous administration of beta adrenergic blockers and CCB should be handled with great caution to prevent the induction of cardiac insufficiency, of miocardic ischemia through excessive reduction of arterial diastolic pressure and of bradicardia. Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug, and the value of strategies to combat the effect of adverse lifestyle behaviours on blood pressure. Novel drugs, including new pharmacological classes (such as vasopeptidase inhibitors and aldosterone synthase inhibitors) and new molecules from present pharmacological classes with additional properties in blood-pressure or metabolism pathways; and new procedures and devices have been proposed including stimulation of arterial baroreceptors and catheter-based renal denervation. Although several pharmacological targets have been discovered with
antihypertensive drugs has been more difficult and less productive than expected. The effectiveness and safety of new devices and procedures should be carefully assessed in patients with resistant hypertension, and in elderly patients (Laurent et al., 2012).
The question of the “right drug” in the very elderly has caused endless debate in various societies and guideline committees. One hundred and fortyseven randomized trials involving 464,000 patients have shown that all classes of blood pressure-lowering drugs have similar effects in reducing events and stroke for a given reduction in blood pressure (Law et al., 2009). Therefore, no drug has been consistently superior across all important outcomes (Opiyo et al., 2012). Only BBs (atenolol) and alpha-blockers (see and -blocker section) should not be first-choice drugs as they are not superior to any other drug class for any outcome. Another
antihypertensive therapies with each other and found that a similar blood pressure reduction resulted in equivalent risk reduction for the substances compared (Fretheim et al., 2012). A prospective meta-analysis comparing younger and older hypertensives (more than 65 years) treated with different antihypertensive drugs substantiated previous results and found similar drug-class efficacy in younger and older patients (Turnbull et al., 2008). Hence, all these investigations show limited evidence of pivotal differences between various drug classes; treatment success is dependent on which collateral outcome is preferred. The latest ESH/ESC guidelines (Mancia et al., 2013) recommend antihypertensive treatment classes that appeared beneficial in reducing cardiovascular risk in randomized clinical trials. All hypertensive agents are recommended, but diuretics and CCBs may be preferred in patients with isolated systolic hypertension (ISH). The ASH/ISH guidelines recommend different drugs for the initial therapy, depending on patients’ age, race, and
blood pressure levels. Former US guidelines (JNC7) favored thiazide-typediruetics when commencing antihypertensive therapy in patients without other compelling indications. JNC8 lately backs away from the JNC7 recommendation that thiazide-type diuretics should be initial therapy in most patients, suggesting ACEis, ARBs, CCBs, or thiazide-type diuretics are reasonable choices in nonblack. In black patients, thiazide-type diuretics and CCBs are recommended as first-line therapy for hypertension. They mention ACEis or ARBs for nonblack patients under the age of 60 and a CCB or thiazide in nonblack patients over the age of 60. The most recent Canadian guideline update strongly emphasizes ISH as a special entity rather than simply acknowledging “age” alone, and recommends thiazides, ARBs, and CCBs. In contrast, NICE 2011 is fairly rigid with regard to treatment recommendations and does not recommend different treatment approaches for patients below and above 80 years of age. Combined therapy can block counter-regulatory mechanisms and potentiate the antihypertensive efficacy beyond the additive response of each drug alone. The advantages of combination therapy are well documented: 1) Increased antihypertensive efficacy as a result of combining different mechanisms of action; 2) A lesser incidence of adverse effects because of the lower doses used and the possible compensatory responses; 3) Since fixed low-dose combinations are available, the treatment simplification may optimize compliance and, secondarily, enhance blood pressure control; and 4) Starting treatment with a two-drug combination may allow blood pressure goals to be achieved earlier than with only one antihypertensive drug. The TRINITY study included 2492 subjects aged 18-80 years including cases with hypertension and diabetes, CKD, or chronic cardiovascular disease. The long-term efficacy and
safety of treatment with a triple combination of olmesartan (OM) 40/amlodipine besylate (AML) 10/HCTZ 25 mg vs. the component dual-combination treatments (OM 40/AML 10 mg, OM 40/HCTZ 25 mg, and AML 10/ HCTZ 25 mg) were tested. Treatment with the triple-combination for 12 months resulted in greater blood pressure reductions and a greater proportion of participants achieving blood pressure goal of <130/80 mm Hg at week 12 compared with the dual-combination treatments (Kereiakes et al., 2012). Since the “Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension” (ACCOMPLISH) trial, the ACEi/CCB combination has shown substantial benefits in the overall population and in patients with of more than 70 years. These results were reflected 2 years later in the 2011 NICE recommendations (Kaiser et al., 2014). Since all antihypertensive agents can lower blood pressure in the elderly, therapy should be chosen based on its potential for side effects, drug interactions and effects on concomitant disease states (Steichen and Plouin, 2014).
10. Conclusions. Aging is associated to an impairment of blood vessel function, which is a very early and important condition leading to cardiovascular disease. The mechanisms underlying the age-related endothelial, smooth muscle and extracellular matrix vascular dysfunction were discussed. Hypertension is an age-dependent disorder, and almost half of the elderly human population is hypertensive. Several models of hypertensive rats have been used to examine
the influence of hypertension on the aging cardiovascular system. Insulin resistance is associated with aging and contributes to vascular malfunction. Therapeutics aimed to restore mechanisms involved in vascular and smooth muscle dysfunction could be potential targets for prevention and treatment of hypertension. Currently, non-pharmacological treatment is recommended for initial hypertension and as supporting treatment with medication.
Lifestyle modifications are suggested and natural compounds
could be useful. Hormone therapies could also be employed. Since all antihypertensive agents can lower blood pressure in the elderly, therapy should be chosen based on its potential for side effects, drug interactions and effects on concomitant disease states.
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Table 1. Manifestations of aging in the vascular system. 1) Increased blood pressure. 2) Reduced vasodilator response due to changes in the secretory function of endothelial cells. 3) Increased sensitivity of endothelial cells to oxidative stress. 4) Decreased number of endothelial cell replications and of circulating endothelial cells. 5) Increased proliferation of VSMC. 6) Change in cellular phenotype of
VSMC from contractile to
synthetizing. 7) Changes in sensitivity of VSMC to mediators secreted by the endothelial cells. 8) Increased arterial stiffness. 9) Arterial remodeling.