Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Future Cardiol. Author manuscript; available in PMC 2010 August 30.
Published in final edited form as:
PMCID: PMC2929677

Aging and the brain renin-angiotensin system

relevance to age-related decline in cardiac function


This article discusses evidence that impairments in control of autonomic outflow mediated by the brain renin-angiotensin system (RAS) contribute to the decline in baroreceptor reflex function and the development of insulin resistance that accompany hypertension and excess salt intake, especially during aging. Imbalances in the regulation of the sympathetic and parasympathetic limbs of the autonomic nervous system observed in older subjects underlie changes in heart-rate variability and play a role in the regulation of overall cardiac function. Age-related alterations in autonomic nervous system function may also explain the age-associated alterations in metabolism. Reduced heart-rate variability is linked to increased mortality in patients with cardiovascular disorders and, coupled with information that is known about local changes in the cardiac and brain RAS during aging, the evidence reveals potential mechanisms for the protective effects of systemic blockade of the RAS against age-related changes that impact the heart.

Executive summary

  • Disturbances in the brain renin-angiotensin system as a result of aging or conditions of excess salt contribute to imbalances in autonomic nervous system function leading to impairments in baroreceptor reflex control of heart rate and energy metabolism.
  • Cardiac structural and functional abnormalities, both systolic and diastolic, may result as a component of their etiology, the age-related hypertension and accompanying baroreflex, insulin resistance or bodyweight changes that are secondary to the impaired autonomic function resulting from alterations in the brain renin-angiotensin system.
  • Reductions in Ang-(1-7) in tissues such as brain or heart during the aging process or other conditions such as excess salt intake, rather than frank increases in Ang II, appear to contribute to pathophysiologic changes in cardiac structure and function.
Keywords: baroreceptor reflex, brain, cardiac function, diastolic function, insulin resistance, renin-angiotensin system, salt sensitivity

Manifestations of cardiovascular aging frequently include the development of systolic hypertension, central arterial stiffness and cardiac diastolic dysfunction. Aging is associated with marked changes in cardiac structure, such as cardiomyocyte loss, hypertrophy of remaining cells and the development of fibrosis [1,2]. Importantly, dietary salt excess has been shown to be an invariable determinant of the age-related changes in blood pressure and end-organ damage in many clinical and experimental studies. A large body of epidemiological and experimental evidence demonstrates a significant association between high salt intake and blood pressure as well as a rise in systolic and diastolic blood pressure with aging [3-5]. While these changes are presumed to be a major reason for the altered diastolic compliance of the senescent heart, age-related increases in arterial stiffness can further lead to vascular-ventricular uncoupling [6,7], which, when taken together, predispose to diastolic heart failure (DHF). Stimuli for this cardiovascular remodeling associated with aging and diastolic heart disease include hypertension, increases in bodyweight gain, insulin resistance and renal dysfunction [8]. A common feature associated with the conditions of excess salt or advanced age is impairment of the baroreceptor reflexes for control of heart rate. Reduced heart-rate variability accompanies the imbalance in the sympathetic and parasympathetic nervous system that contributes to reduced reflex function and both can be linked to the structural and humoral changes associated with aging. The role that the brain renin-angiotensin system (RAS) is thought to play in the changes responsible for cardiac aging is discussed below.

Brain RAS, baroreflex & autonomic dysfunction during aging

There is a close anatomical association in brain and periphery of the RAS with both sympathetic and parasympathetic limbs of the autonomic nervous system [9]. Long-term RAS blockade extends the lifespan and improves or prevents the age-related decline in cardiovascular and metabolic function in hypertensive rats as might be expected, but treatment of normotensive rats attenuates the age-related decline in cognitive function, the increase in bodyweight gain and decline in mitochondrial function, and preserves renal function [10-16]. Numerous studies, however, report a decrease in the plasma RAS components with increased age [17-19], which raises issues regarding whether RAS blockade of a variety of local tissue RAS (brain, kidney, heart, pancreas, adipose and adrenal) contributes to the improvements observed [20,21]. Little is known about the regulation of the local RAS, specifically, the levels of Ang II and Ang-(1-7), within each tissue during aging. There may be an overt elevation of components of the system, as reported for Ang II in the heart during aging [19], consistent with observations on the intrarenal RAS [14,16-18]. In experimental models, increases in gene expression of angiotensinogen, angiotensin-converting enzyme (ACE), Ang II type 1 (AT1) and Ang II type 2 (AT2) receptors have been identified in hearts from senescent rats, independent of circulating RAS [22,23]. Blockade of the RAS by either ACE inhibition or AT1-receptor blockers prevents the increase in urinary Ang II in several studies [14,16]. However, these treatments not only reduce the levels or actions of Ang II, but also cause an associated elevation in the levels or actions of Ang-(1-7), another active component of the RAS that has actions that oppose those of Ang II. These complex interactions are illustrated in Figure 1. Therefore, the exact mechanisms responsible for improvements in age-related dysfunctions with RAS blockade are not completely understood and recent studies reveal that maintenance of healthy levels of Ang-(1-7) may be part of the mechanisms of the cardiovascular protection.

Figure 1
Processing pathways and major components of the renin-angiotensin system

The nucleus of the solitary tract (nTS) in the dorsal medulla oblongata is a known site for the actions of Ang II to reduce the sensitivity of the baroreceptor reflex control of heart rate, a vagally mediated component of the reflex control of arterial pressure [24,25]. Endogenous Ang-(1-7) counterbalances the actions of Ang II on the baroreflex within the nTS as shown in Figure 2. In Sprague-Dawley (SD) rats, there is an increase in systolic blood pressure during aging that is associated with increased bodyweight gain, higher circulating insulin and leptin levels [26] and impairment of the baroreflex to levels similar to those seen in overt hypertension [27]. The facilitation of the reflex by endogenous Ang-(1-7) is absent in the older SD rats [27]. By contrast, the response to blockade of endogenous Ang II by an AT1-receptor antagonist is similar between older and younger SD rats [27]. Preliminary data suggest that expression and activity of the two Ang-(1-7)-forming enzymes (neprilysin and ACE2) are lower in brain medulla of older SD rats [27,28], which, if confirmed, would provide a mechanism for reduced endogenous Ang-(1-7) in older animals. Acute ACE2 inhibition in the nTS is associated with a reduction in baroreflex sensitivity for control of heart rate in young SD rats [29]. Thus, low levels of Ang-(1-7) in the nTS may contribute to the age-related imbalance in sympathetic and parasympathetic control of heart rate, and the possibility that its preservation in older animals contributes to the mechanism of action of ACE inhibitors or AT1-receptor blockers should be considered for the protective effects of these agents. The loss of baroreflex sensitivity may result in reduced heart-rate variability and increased blood pressure variability, and subsequent cardiac structural changes even in the absence of established hypertension, leading to cardiac function impairments.

Figure 2
Effect of endogenous angiotensin peptides on baroreflex function

Ang II receptors in brainstem nuclei parallel the distribution of the entire vagal sensory and motor pathways, and are not confined to the cardiopulmonary system [25,30,31], consistent with a widespread influence of the RAS on autonomic function [9,32]. It is not yet clear whether the other age-related changes in autonomic function that accompany the impaired baroreflex and that are associated with decreased heart-rate variability can be linked to changes in Ang-(1-7) in the medulla. However, these same brain areas are those involved in the control of appetite and body energy metabolism [33-37]. To better understand the specific role of the brain RAS in the aging process with respect to metabolic and cardiovascular function, our recent studies compared SD rats with transgenic rats that have a deficiency in brain angiotensinogen (ASrAogen). The ASrAogen transgenic rats have a GFAP promoter-linked angiotensinogen antisense sequence overexpressed in brain glia [38], thereby selectively targeting the main source of angiotensinogen and reducing cerebral levels of the prohormone to less than 10% of normal [38,39]. ASrAogen-deficient rats have slightly lower values of resting arterial pressure, but otherwise exhibit similar circulating levels of leptin, insulin and glucose values in early adulthood [26]. ASrAogen rats do not, however, exhibit increases in systolic pressure, insulin or leptin during aging [26], and have a longer lifespan [40,41]. In older ASrAogen rats, actions of Ang-(1-7) to facilitate baroreceptor reflex control of heart persist [42], indicating that both metabolic function and other indices of autonomic health are maintained in these animals. In fact, circulating levels of Ang-(1-7) are significantly higher in older ASrAogen rats than age-matched SD animals [18], and it is known that long-term systemic infusions of Ang-(1-7) improve baroreflex function [43]. All of the above features of the older ASrAogen animals are comparable with rats who have lifetime RAS blockade [10,13]. Surprisingly few studies have, however, assessed levels of angiotensin peptides or other RAS components in the brain during aging. The concept that the brain RAS is elevated with advanced age, and that blockade of the brain RAS specifically accounts for a part of the protective mechanisms of systemic RAS blockade, is currently under investigation. In fact, a recent study in hypertensive human subjects suggests that ACE inhibitors that cross the blood-brain barrier are more likely to preserve cognitive function in the elderly than other antihypertensive agents [44]. Whether ACE inhibitors with these characteristics would exhibit greater protection for cardiac and other cardiovascular and metabolic function during aging is an intriguing possibility that has not yet been established.

Brain RAS, cardiac aging & salt excess

Many interventional trials confirm that salt reduction successfully decreases arterial pressure not only in hypertensive, but also in normotensive subjects [45-47]. Since the increase in systolic blood pressure and reduced compliance of large arteries are frequent observations in cardiovascular aging, it is without surprise that left ventricular hypertrophy and fibrosis, and impairments in ventricular performance and coronary hemodynamics, are common findings in aging [48,49]. Importantly, studies from our laboratory provide evidence that in normotensive Wistar-Kyoto (WKY) rats fed a high salt diet from 20 to 60 weeks of age exhibit increases in arterial pressure and severely compromised coronary hemodynamics, promoting the development of heart disease [50]. These changes mimic age-related cardiovascular alterations in senescent WKY rats [51], providing strong evidence that dietary salt excess accelerates cardiovascular aging. Similar changes were evoked in both young adult and old spontaneously hypertensive rats (SHRs), a well-characterized model of essential hypertension in humans [52.53]. As seen in older WKY rats, salt-loaded SHRs manifest impaired left ventricular relaxation and preserved systolic function associated with enhanced fibrosis, a frequent observation in hypertensive and elderly patients. In addition, similar changes in fibrosis, function and coronary hemodynamics occur in the right ventricle of salt-loaded SHRs, a chamber that is not subjected to increased afterload resulting from high salt intake [53]. These findings strongly suggest that, besides affecting blood pressure, salt exerts additional nonhemodynamic cardiac effects. Indeed, several large epidemiological studies indicate that dietary salt excess is a strong and even independent contributor to increased cardiovascular risk and mortality [54,55]. Consistently, increased salt intake appears to be a critical independent predictor of left ventricular enlargement in patients with essential hypertension [56.57]. Moreover, in hypertensive patients challenged with high sodium intake, early abnormalities in left ventricular diastolic function are seen in sodium-sensitive but not in sodium-resistant subjects, despite similarities in basal blood pressure between the two groups [58].

Various nonhemodynamic mechanisms have been suggested to explain detrimental cardiovascular effects of salt excess. Thus, the function of the sympathetic nervous system, the interaction between different vasoactive hormones and growth factors and even the direct effects of sodium per se have been extensively studied in various experimental models of salt-sensitive hypertension [59-63]. In particular, the pathophysiological role of the RAS in salt-sensitive hypertension has been increasingly appreciated in recent years. Despite the fact that in response to high sodium intake a suppression of circulating RAS should occur [59,62,63], by contrast, an inadequate suppression or even paradoxal activation of local tissue RAS has been described. In fact, recent findings suggest a suppression of cardiac Ang-(1-7) in the face of elevated or maintained levels of Ang II resulting from decreases in ACE2 expression [64]. This imbalance in the two peptides may favor actions of Ang II locally within the heart. Long-term treatments with Ang-(1-7) protect the heart from global ischemia in situations of low nitric oxide hypertension and diabetes in normotension and hypertension, and endogenous Ang-(1-7) may contribute to the protection observed with RAS blockade [65-67]. The common theme for healthy cardiac function may, therefore, include preservation of Ang-(1-7), similar to what was previously mentioned with respect to the brain RAS during aging.

The mechanisms of high salt-induced impairments in cardiac function also include actions within the CNS. Chronic dietary salt intake results in sympathetic hyperactivity and pressor responses in salt-sensitive strains mediated through a brain ouabain-like substance and RAS [68-70]. Indeed, a high salt diet increased ACE mRNA and activity in the hypothalamus and pons of Dahl-sensitive rats [71], as well as AT1-receptor binding in the paraventricular nucleus, median preoptic nucleus, and suprachismatic nucleus [72]. By contrast, chronic AT1-receptor blockers given in the cerebral ventricles [68,69], median preoptic nucleus [73] or rostral ventrolateral medulla [74] prevented sympathoexcitation and hypertension in salt-sensitive strains. Further implicating the brain in the generation of the salt sensitivity is the additional finding that the ASrAogen rats are protected from the hypertension induced by centrally administered ouabain [39]. There is a large body of evidence suggesting that salt excess activates local cardiac [75-78] and renal [63] tissue RAS as well. Thus, it appears that brain RAS, in concert with activated local tissue RAS in peripheral organs, could account, at least in part, for blood pressure increases as well as target-organ damage in salt-sensitive hypertension. Therefore, we speculate that the inappropriate activity of the local tissue (brain, heart and kidney) RAS, especially with respect to the balance between Ang II and Ang-(1-7), relative to the level of salt intake may account for the blood pressure rise and the cardiovascular and renal functional and structural changes in the elderly that are regularly considered as the ‘physiological manifestation of aging’. An intriguing aspect of this concept is further compounded by data demonstrating that the neuron-specific expression of human angiotensinogen increased preference for salt in transgenic mice [79]. Clearly, further studies are warranted to confirm this attractive hypothesis.

Brain RAS, cardiac aging & diastolic dysfunction

Diastolic dysfunction, another common correlate of aging that has profound implications on functional abilities late in life, may also be linked, in part, to the brain RAS. In brief, diastolic dysfunction consists of abnormal myocardial relaxation and increased chamber stiffness induced by alterations in the cardiac calcium regulatory proteins and the extracellular matrix, respectively [80]. The age-related cellular and molecular alterations that contribute to diastolic impairment may represent adaptive, physiologic dysfunction (e.g., secondary to aortic stenosis or long-standing hypertension) or the other end of the clinical disease spectrum, DHF. Importantly, diastolic dysfunction is a mechanical abnormality (not a clinical syndrome) that occurs during diastole, which may or may not result in symptoms. By contrast, DHF is characterized by high left ventricular end-diastolic pressures due to abnormalities in left ventricular filling and neurohormonal regulation, which when taken together lead to pulmonary congestion, exercise intolerance and decreased life expectancy.

Indeed, diastolic dysfunction may antedate DHF since 11-15% of patients with asymptomatic diastolic dysfunction develop frank symptoms of heart failure within 5 years [81]. However, while numerous therapeutic and device strategies have been successfully instituted for the management of systolic heart failure [82], current treatment to prevent the worsening of diastolic dysfunction and/or reducing mortality has been empiric. This is partly owing to the fact that therapeutic studies with heart failure patients excluded elderly patients and patients with diastolic dysfunction with preserved systolic function. Another reason for the paucity of randomized treatment trials specifically addressing this syndrome is that we do not have a clear idea of the pathogenesis underscoring the disease process.

Aging is associated with marked changes in cardiac structure leading to the altered diastolic compliance observed in the senescent heart [6,7], yielding a predisposition to DHF. Hypertension, increases in bodyweight gain, insulin resistance and renal dysfunction are factors contributing to remodeling associated with aging and diastolic heart disease [8]. As mentioned above, increases in cardiac tissue components of the RAS occur in older rats [19,22,23]. Moreover, in patients with left ventricular hypertrophy, subsystemic doses of intracoronary ACE inhibitors improve left ventricular filling, distensibility and regional relaxation [83]. Longer-term oral treatment with ACE inhibitors and AT1-receptor blockers improve measures of diastolic function and functional capacity in hypertensive patients with left ventricular hypertrophy [84-86]. Although it is not entirely clear whether these effects translate into better clinical outcomes in older patients with heart failure with preserved systolic function, also known as DHF, findings from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved trial [87] indicate that treatment with the AT1-receptor blocker, candesartan reduces hospital admission for worsening heart failure. Certainly, findings from the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial of more than 4000 patients older than 60 years of age should provide more conclusive information regarding the primary end point of death [88].

Besides the local cardiac RAS, findings from animal studies suggest that activation of the brain RAS may also contribute to age-related left ventricular remodeling, diastolic dysfunction and heart failure. First, in studies involving heart failure due to myocardial infarction, heart-brain signaling via neurohumoral mechanisms has been shown to be an important determinant of left ventricular function and remodeling. Specifically, blockade of AT1 receptors in the brain of rats subjected to coronary ligation reverses the sympathetic hyperactivity associated with heart failure [89]. Furthermore, chronic AT1-receptor blockade or attenuation of brain ouabain-like activity (which also contributes to sympathetic hyperactivity associated with heart failure) substantially inhibits the development of left ventricular dilation and dysfunction in rats after myocardial infarction [90]. Consistent with these studies, Wang et al. demonstrated that the transgenic rats with low brain RAS (ASrAogen) due to suppression of the glial angiotensinogen gene, were protected from sympathetically induced left ventricular dysfunction and the increased fibrosis accompanying the remodeling after myocardial infraction [91]. Overall, these data suggest that the brain RAS, probably acting through the sympathetic nervous system, plays a substantial role in ventricular remodeling and myocardial dysfunction associated with ischemic heart failure. Lower activity of the brain RAS may protect the heart in pathological conditions normally associated with increased fibrosis, leading to the development of diastolic dysfunction.

In fact, to more specifically assess the role of Ang II locally produced in the brain in cardiac aging, we recently compared diastolic function among three groups of age-matched (12 months of age) rats with varying degrees of RAS activation, including [41]:

  • Elevated peripheral and brain Ang II of the transgenic (mRen2)27 rat with overexpression of the mouse renin gene:
  • Reduced brain and normal peripheral Ang II of the ASrAogen rat with low glial angiotensinogen:
  • Normal brain and peripheral Ang II of the Hannover SD rat, the parent strain of both transgenics.

In brief, chronic overactivity of peripheral and brain RAS of the aging transgenic (mRen2) 27 rat was associated with hypertension (systolic blood pressure of 155 mmHg), increased cardiac fibrosis and reduced levels of the calcium regulatory protein, SERCA2, and was accompanied by accelerated systolic and diastolic dysfunction. By contrast, the age-matched ASrAogen rat with low brain RAS and normal peripheral Ang II exhibited low resting systolic blood pressure (107 mmHg), minimal cardiac fibrosis, relatively conserved SERCA2 content and preserved diastolic function when compared with the (mRen2)27 and the SD parent strain, manifesting mild hypertension (systolic blood pressure of 145 mmHg) and reduced exercise tolerance at this age. Taken together, these data support the concept that overactive brain RAS exacerbates diastolic dysfunction of aging, and that low brain RAS expression and its consequences may be protective against hypertension and DHF. Moreover, the ASrAogen model provides a valuable experimental tool for elucidating the potential role of central RAS blockade in the attenuation of cardiac aging.

Future perspective

Ongoing studies are designed to understand the precise neural pathways involved in the effects of the brain RAS on the age-related changes in autonomic function. Determining whether the same pathways mediate regulation of blood pressure and metabolism is warranted, given that data support the dissociation of the two in overall development of age-related pathologies. The preliminary studies cited above provide intriguing insights into factors that regulate expression of the prohypertensive, vascular injury components of the RAS leading to generation of Ang II in comparison with the vasculo-protective arm leading to Ang-(1-7) formation. Certainly, the recent observations that regulation of the balance between ACE and ACE2 may play a key role in the preservation of cardiovascular health provides rationale for the basis of future research into therapies to increase expression of ACE2, especially during aging, salt excess, cardiac failure or hypertension. We already recognize that systemic inhibition of the RAS achieves a shift in the balance of the system from Ang II to Ang-(1-7), with both the decline in Ang II and the increase in Ang-(1-7) accounting for cardio- and renoprotection during aging and development of cardiovascular diseases. In the future, we hope to provide a better understanding of the role of the brain RAS and control of autonomic system function as contributors to the development of age-related and other cardiovascular pathologies, and whether specific blockade of the brain RAS accounts for a major component of the improvements observed with systemic RAS blockade.


Financial & competing interests disclosure

This work was supported, in part, by grants from NIH P01 HL-51952 (D Diz), Dennis Jahnigen Career Development Award, NIH K08-AG02674 and Paul Beeson Award (L Groban) and AHA 0765308U and WFUSM Venture Fund (J Varagic). Partial support from Unifi. Inc., Greensboro, NC, USA, and Farley-Hudson Foundation, Jacksonville, NC, USA, is also appreciated. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Contributor Information

Professor Debra I Diz, Wake Forest University School of Medicine, The Hypertension & Vascular Research Center, Medical Center Boulevard, Winston-Salem, NC 27157-1032, USA, Tel.: +1 336 716 2150; Fax: +1 336 716 2456; ude.cmbufw@zidd.

Research Assistant Professor Jasmina Varagic, Wake Forest University School of Medicine, The Hypertension & Vascular Research Center, Medical Center Boulevard, Winston-Salem, NC 27157-1032, USA, Tel.: +1 336 716 2738; Fax: +1 336 716 2456; ude.cmbufw@cigaravj.

Associate Professor Leanne Groban, Wake Forest University School of Medicine, Department of Anesthesiology, Medical Center Boulevard, Winston-Salem, NC 27157-1032, USA, Tel.: +1 336 716 1187; Fax: +1 336 716 8190; ude.cmbufw@naborgl..


Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

1. Kitzman D, Scholz D, Hagen P, et al. Age-related changes in normal human hearts during the first 10 decades of life. Part II (maturity): a qualitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin. Proc. 1988;63:137–146. [PubMed]
2. Burlew B. Diastolic dysfunction in the elderly - the interstitial issue. Am. J. Geriatr. Cardiol. 2004;13:29–38. [PubMed]
3. Elliott P, Stamler J, Nichols R, et al. INTERSALT revisited: further analysis of 24 hour sodium excretion and blood pressure within and across populations: INTERSALT Cooperative Research Group. Br. Med. J. 1996;312(1249):1253. [PMC free article] [PubMed]
4. Stamler J. The INTERSALT study: background, methods, findings, and implications. Am. J. Clin. Nutr. 1997;65(Suppl.):626–642. [PubMed]
5. Denton D, Weisinger R, Mundy NI, et al. The effect of increased salt intake on blood pressure of chimpanzees. Nat. Med. 1995;1:1009–1016. [PubMed]
6. Chen C, Nakayama M, Nevo E, et al. Coupled systolic-ventricular and vascular stiffness with age: implications for pressure regulation and cardiac reserve in the elderly. J. Am. Coll. Cardiol. 1998;32:1221–1227. [PubMed]
7. Zieman S, Melenovsky V, Kass D. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler. Thromb. Vasc. Biol. 2005;25(5):932–943. [PubMed] Excellent review of the structural, cellular and genetic contributors to arterial stiffness, including the roles of the extracellular matrix and inflammatory molecules that also affect diastolic function. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt and changes in neurohormonal regulation are discussed.
8. Maurer M, Burkhoff D. Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction. J. Am. Coll. Cardiol. 2007;49(9):972–981. [PubMed] Retrospective analysis of the Cardiovascular Health Study examined the association between left ventricular structure and heart failure with normal ejection fraction among 5800 study participants. Subjects with heart failure with normal ejection fraction (HFNEF) were older, more obese and more often African-American, and had a higher prevalence of diabetes, coronary heart disease, anemia and chronic renal disease. Besides the comorbidites, left ventricular diastolic diameter was increased in HFNEF subjects.
9. Diz DI, Averill DB. Angiotensin II/autonomic interactions. In: Robertson D, Biaggioni I, Burnstock G, Law PA, editors. Primer on the Autonomic Nervous System. Elsevier Academic Press; CA, USA: 2004. pp. 168–171.
10. Basso N, Paglia N, Stella I, et al. Protective effect of the inhibition of the renin-angiotensin system on aging. Regul. Pept. 2005;128:247–252. [PubMed]
11. Ferder L, Inserra F, Romano L, Ercole L, Pszenny V. Effects of angiotensin-converting enzyme inhibition on mitochondrial number in the aging mouse. Am. J. Physiol. 1993;34:C15–C18. [PubMed]
12. de Cavanagh EMV, Piotrkowski B, Basso N, et al. Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. FASEB J. 2003;17(9):1096–1098. [PubMed]
13. Linz W, Jessen T, Becker RHA, Scholkens BA, Wiemer G. Long-term ACE inhibition doubles lifespan of hypertensive rats. Circulation. 1997;96:3164–3172. [PubMed]
14. Kasper SO, Basso N, Kurnjek ML, et al. Divergent regulation of circulating and intra-renal renin-angiotensin systems in response to long-term blockade. Am. J. Nephrol. 2005;25(4):335–341. [PubMed]
15. Carter CS, Cesari M, Ambrosius WT, et al. Angiotensin-converting enzyme inhibition, body composition, and physical performance in aged rats. J. Gerontol. A Biol. Sci. Med. Sci. 2004;59(5):416–423. [PubMed]
16. Gilliam-Davis S, Payne VS, Kasper SO, et al. Long-term AT1 receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats. Am. J. Physiol. 2007;293(3):H1327–H1333. [PubMed]
17. Anderson S. Ageing and the renin-angiotensin system. Nephrol. Dial. Transplant. 1997;12(6):1093–1094. [PubMed]
18. Oden SD, Ganten D, Ferrario CM, Chappell MC, Diz DI. Rats with low brain angiotensinogen maintain normal levels of insulin and components of the circulating and intra-renal renin-angiotensin systems during aging. FASEB J. 2004;18(4):A738.
19. Groban L, Pailes NA, Bennett CDL, et al. Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. J. Gerontol. A Biol. Sci. Med. Sci. 2006;61(1):28–35. [PubMed]
20. Chappell MC, Diz DI, Gallagher PE. The renin-angiotensin system and the exocrine pancreas. JOP. 2001;2(1):33–39. [PubMed]
21. Bader M, Peters J, Baltatu O, et al. Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research. J. Mol. Med. 2001;79(2-3):76–102. [PubMed]
22. Heymes C, Swynghedauw B, Chevalier B. Activation of angiotensin and angiotensin-converting enzyme gene expression in the left ventricle of senescent rats. Circulation. 1994;90:1328–1333. [PubMed]
23. Heymes C, Silvestre J-S, Llorens-Cortes C, et al. Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology. 1998;139:2579–2587. [PubMed]
24. Averill DB, Diz DI. Angiotensin peptides and baroreflex control of sympathetic outflow: pathways and mechanisms of the medulla oblongata. Brain Res. Bull. 2001;51(2):119–128. [PubMed]
25. Diz DI, Jessup JA, Westwood BM, et al. Angiotensin peptides as neurotransmitters/neuromodulators in the dorsomedial medulla. Clin. Exper. Pharmacol. Physiol. 2001;29:473–482. [PubMed]
26. Kasper SO, Carter CS, Ferrario CM, et al. Growth and metabolism disturbances in transgenic rats with altered renin-angiotensin system expression. Physiol. Genomics. 2005;23:311–317. [PubMed]
27. Sakima A, Averill DB, Gallagher PE, et al. Impaired heart rate baroreflex in older rats. Role of endogenous angiotensin-(1-7) at the nucleus tractus solitarii. Hypertension. 2005;46:333–340. [PubMed]
28. Gegick S, Garcia-Espinosa MA, Gallagher PE, et al. Reduced formation of Ang-(1-7) by ACE2 in dorsal medulla oblongata of Sprague-Dawley (SD) and ASrAogen rats during aging. FASEB J. 2006;20:A1209.
29. Diz DI, Garcia-Espinosa MA, Gegick S, et al. Solitary tract nucleus ACE2 inhibitor MLN4760 injections reduce baroreceptor reflex sensitivity for heart rate control. Exp. Physiol. 2008 In Press. [PMC free article] [PubMed]
30. Diz DI, Barnes KL, Ferrario CM. Contribution of the vagus nerve to angiotensin II binding in the canine medulla. Brain Res. Bull. 1986;17:497–505. [PubMed]
31. Diz DI, Block CH, Barnes KL, Ferrario CM. Correlation between angiotensin II binding sites and substance P in the canine brain stem. J. Hypertens. 1986;4(Suppl. 6):S468–S471. [PubMed]
32. Diz DI. Commentary: angiotensin II receptors in central nervous system physiology. In: Husain A, Graham R, editors. Drugs, Enzymes and Receptors of the Renin-Angiotensin System: Celebrating a Century of Discovery. Harwood Academic Publishers; Amsterdam, The Netherlands: 1999. pp. 45–51.
33. Giza BK, Scott TR, Vanderweele DA. Administration of satiety factors and gustatory responsiveness in the nucleus tractus solitarius of the rat. Brain Res. Bull. 1992;28(4):637–639. [PubMed]
34. Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology. 1997;138(2):839–842. [PubMed]
35. Diz DI, Barnes KL, Ferrario CM. Functional characteristics of neuropeptides in the dorsal medulla oblongata and vagus nerve. Fed. Proc. 1987;46:30–35. [PubMed]
36. Berthoud HR. A new role for leptin as a direct satiety signal from the stomach. Am. J. Physiol. 2005;288:R796–R797. [PubMed]
37. Schwartz GJ, Moran TH. Leptin and neuropeptide Y have opposing modulatory effects on nucleus of the solitary tract neurophysiological responses to gastric loads: implications for the control of food intake. Endocrinology. 2002;143(10):3779–3784. [PubMed]
38. Schinke M, Baltatu O, Bohm M, et al. Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen. Proc. Natl Acad. Sci. USA. 1999;96(7):3975–3980. [PubMed]
39. Huang BS, Ganten D, Leenen FH. Responses to central Na+ and ouabain are attenuated in transgenic rats deficient in brain angiotensinogen. Hypertension. 2001;37(2 Part 2):683–686. [PubMed]
40. Diz DI, Kasper SO, Sakima A, Ferrario CM. Aging and the brain renin-angiotensin system: insights from studies in transgenic rats. Cleve. Clin. J. Med. 2007;74(Suppl. 1):S95–S98. [PubMed]
41. Groban L, Ferrario C, Ganten D, Diz D. Transgenic rats with low brain-renin-angiotensin system activity due to glial deficiency are protected against heart failure late in life. J. Card. Fail. 2007;13(6):S83.
42. Arnold AC, Sakima A, Ganten D, Ferrario CM, Diz DI. Modulation of reflex function by endogenous angiotensins in older transgenic rats with low glial angiotensinogen. Hypertension. 2008 Epub ahead of print. [PMC free article] [PubMed]
43. Benter IF, Diz DI, Ferrario CM. Pressor and reflex sensitivity is altered in spontaneously hypertensive rats treated with angiotensin-(1-7) Hypertension. 1995;26:1138–1144. [PubMed]
44. Sink KM, Leng X, Williamson J, et al. Centrally active ACE inhibitors may slow cognitive decline: the Cardiovascular Health Study. J. Am. Geriatr. Soc. 2007;55:S14.
45. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE): TONE Collaborative Research Group. JAMA. 1998;279:839–846. [PubMed] Has an important public health implication showing that dietary salt reduction decreased the need for antihypertensive therapy in older patients.
46. Sacks FM, Svetkey LP, Vollmer WM, et al. DASH-Sodium Collaborative Research Group Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N. Engl. J. Med. 2001;344:3–10. [PubMed]
47. Katovich MJ, Soltis EE, Field FP. Effects of NaCl on vascular responsiveness in male rats. Comp. Biochem. Physiol. 1984;78:369–372. [PubMed]
48. Susic D, Nunez E, Hosoya K, Frohlich ED. Coronary hemodynamics in aging spontaneously hypertensive and normotensive Wistar-Kyoto rats. J. Hypertens. 1998;16:231–237. [PubMed]
49. Groban L. Diastolic dysfunctioin in the older heart. J. Cardiothorac. Vasc. Anesth. 2005;19:228–236. [PubMed]
50. Varagic J, Sisic D, Frohlich ED. Prolonged salt excess accelerates cardiovascular aging in normal WKY; Presented at: XIVth Annual National Scientific Sessions of The Consortium for Southeastern Hypertension Control in Conjunction with the XVIIth Scientific Sessions of the Inter-American Society of Hypertension; Miami. FL, USA. 6-10 May (2007).
51. Susic D, Varagic J, Frohlich ED. Isolated systolic hypertension in elderly WKY is reversed with l-arginine and ACE inhibition. Hypertension. 2001;38:1422–1426. [PubMed]
52. Ahn J, Varagic J, Slama M, Susic D, Frohlich ED. Cardiac structural and functional responses to salt loading in SHR. Am. J. Physiol. 2004;287:H767–H772. [PubMed]
53. Varagic J, Frohlich ED, Diez J, et al. Myocardial fibrosis, impaired coronary hemodynamics, and biventricular dysfunction in salt-loaded SHR. Am. J. Physiol. 2006;290:H1503–H1509. [PubMed]
54. He J, Ogden LG, Vupputuri S, et al. Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults. JAMA. 1999;282:2027–2034. [PubMed]
55. Tuomilehto J, Jousilahti P, Rastenyte D, et al. Urinary sodium excretion and cardiovascular mortality in Finland: a prospective study. Lancet. 2001;357:848–851. [PubMed]
56. du Cailar G, Ribstein J, Grolleau R, Mimran A. Influence of sodium intake on left ventricular structure in untreated essential hypertensives. J. Hypertens. 1989;7:S258–S259. [PubMed]
57. de la Sierra A, Lluch MM, Pare JC, et al. Increased left ventricular mass in salt-sensitive hypertensive patients. J. Hum. Hypertens. 1996;10:795–799. [PubMed]
58. Musiari L, Ceriati R, Taliani U, Montesi M, Novarini A. Early abnormalities in left ventricular diastolic function of sodium-sensitive hypertensive patients. J. Hum. Hypertens. 1999;13:711–716. [PubMed]
59. Yu HC, Burrell LM, Black MJ, et al. Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation. 1998;98:2621–2628. [PubMed]
60. Yoshida J, Yamamota K, Mano T, et al. Angiotensin II type I and endothelin type A receptor antagonists modulate the extracellular matrix regulatory system differently in diastolic heart failure. J. Hypertens. 2003;21:437–444. [PubMed]
61. Leenen FHH, Yuan B. Dietary-sodium-induced cardiac remodeling in spontaneously hypertensive rat versus Wistar-Kyoto rat. J. Hypertens. 1998;16:885–892. [PubMed]
62. Gu JW, Amand V, Shek EW, et al. Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells. Hypertension. 1998;31:1083–1087. [PubMed]
63. Nishiyama A, Yoshizumi M, Rahman M, et al. Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats. Kidney Intl. 2004;65:972–981. [PMC free article] [PubMed]
64. Varagic J, Brosnihan B, Groban L, Gallagher PE, Ferrario CM. Decreased expression of cardiac ACE2 is associated with salt-induced cardiac remodeling and dysfunction. Hypertension. 2007;50:E150.
65. Benter IF, Yousif MH, Cojocel C, Al-Maghrebi M, Diz DI. Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction. Am. J. Physiol. 2007;292(1):H666–H672. [PubMed]
66. Benter IF, Yousif MHM, Anim JT, Cojocel C, Diz DI. Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with l-NAME. Am. J. Physiol. Heart Circ. Physiol. 2006;290(2):H684–H691. [PubMed]
67. Benter IF, Yousif MHM, Dhaunsi GS, et al. Angiotensin-(1-7) prevents sctivation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am. J. Nephrol. 2008;28:25–33. [PubMed]
68. Huang BS, Leenen FS. Brain ‘ouabain’ and angiotensin II in salt-sensitive hypertension in spontaneously hypertensive rats. Hypertension. 1996;28:1005–1012. [PubMed]
69. Huang BS, Leenen FS. Both brain angiotensin II and ‘ouabain’ contribute to sympathoexcitation and hypertension in Dahl S rats on high salt intake. Hypertension. 1998;32:1028–1033. [PubMed]
70. Van Huysse JW, Hou X. Pressor response to CSF sodium in mice: mediation by a ouabaine-like substance and renin-angiotensin system in the brain. Brain Res. 2004;1021:219–231. [PubMed]
71. Song K, Allen AM, Paxinos G, Mendelsohn FA. Mapping of angiotensin II receptor subtype heterogeneity in rat brain. J. Comp. Neurol. 1992;316(4):467–484. [PubMed]
72. Wang JM, Veerasingham SJ, Tan J, Leenan FS. Effects of high salt intake on brain AT1 receptor densities in Dahl rats. Am. J. Physiol. 2003;285:H1949–H1955. [PubMed]
73. Budzikowski AS, Leenen FH. Ang II in median preoptic nucleus and pressor responses to CSF sodium and high sodium intake in SHR. Am. J. Physiol. 2001;281(3):H1210–H1216. [PubMed]
74. Ito S, Hiratsuka K, Tsukamoto K, Kanmatsuse K, Sved AF. Ventrolateral medulla AT1 receptors support arterial pressure in Dahl salt-sensitive rats. Hypertension. 2003;41:744–750. [PubMed] Demonstrates that high salt intake increased extra-adrenal aldosterone production in the heart of stroke-prone spontaneously hypertensive rats.
75. Takeda Y, Yoneda T, Demura M, et al. Effects of high sodium intake on cardiovascular aldosterone synthesis in stroke-prone spontaneously hypertensive rats. J. Hypertens. 2001;19:635–639. [PubMed]
76. Kreutz R, Fernandez-Alfonso MS, Liu Y, Ganten D, Paul M. Induction of cardiac angiotensin I-converting enzyme with dietary NaCl-loading in genetically hypertensive and normotensive rats. J. Mol. Med. 1995;73:243–248. [PubMed]
77. Zhu Z, Zhu S, Wu Z, et al. Effect of sodium on blood pressure, cardiac hypertrophy, and angiotensin receptor expression in rats. Am. J. Hypertens. 2004;17:21–24. [PubMed]
78. Hodge G, Ye VS, Duggan KA. Dysregulation of angiotensin II synthesis is associated with salt sensitivity in the spontaneous hypertensive rat. Acta Physiol. Scand. 2002;(174):209–215. [PubMed]
79. Morimoto S, Cassell MD, Sigmund CD. Neuron-specific expression of human angiotensinogen in brain causes increased salt appetite. Physiol. Genomics. 2002;9(2):113–120. [PubMed] Demonstrates that neuron-specific anglotensinogen plays an essential role in the regulation of salt appetite.
80. Zile M, Brutsaert D. New concepts in diastolic dysfunction and diastolic heart failure: diagnosis, prognosis, and measurements of diastolic function. (Part I) Circulation. 2002;105:1387–1393. [PubMed] Focuses on the criteria used to diagnose diastolic heart failure, the effects of diastolic heart failure on prognosis and measurements used to assess diastolic function.
81. Aurigemma G, Gottdiener J, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the Cardiovascular Health Study. J. Am. Coll. Cardiol. 2001;37:1042–1048. [PubMed]
82. Hunt S, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to update the 2001 guidelines for the evaluation and management of heart failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:E154–E235. [PubMed]
83. Kyriakidis M, Triposkiadis F. Effects of cardiac versus circulatory angiotensin-converting enzyme inhibition on left ventricular diastolic function and coronary blood flow in hypertrophic obstructive cardiomyopathy. Circulation. 1998;97(14):1342–1347. [PubMed]
84. Wachtell K, Bella J. Change in diastolic left ventricular filling after one year of antihypertensive treatment: the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study. Circulation. 2002;105:1071–1076. [PubMed]
85. Grandi A, Laurita E. Angiotensin-converting enzyme inhibitors influence left ventricular mass and function independently of the antihypertensive effect. J. Cardiovasc. Pharmacol. 2006;48(5):207–211. [PubMed]
86. Mattioli A, Zennaro M. Regression of left ventricular hypertrophy and improvement of diastolic function in hypertensive patients treated with telmisartan. Int. J. Cardiol. 2004;97(3):383–388. [PubMed]
87. Yusuf S, Pfeffer M, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left ventricular ejection fraction: the CHARM-Preserved trial. Lancet. 2003;362:777–781. [PubMed]
88. Carson P, Massie B, McKelvie R, et al. The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial: rationale and design. J. Card. Fail. 2005;11:576–585. [PubMed]
89. Zhang Z, Huang B. Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 1999;276:H1608–H1615. [PubMed]
90. Leenen F, Yuan B. Brain ‘ouabain’ and angiotensin II contribute to cardiac dysfunction after myocardial infarction. Am. J. Physiol. 1999;277:H1786–H1792. [PubMed]
91. Wang H, Huang B, Ganten D. Prevention of sympathetic and cardiac dysfunction after myocardial infarction in transgenic rats deficient in brain angiotensinogen. Circ. Res. 2004;94:843–849. [PubMed]