Abstract-Age-related baroreflex reductions in function may originate from central neural dysregulation as well as vascular structural/functional changes. We determined the role of 2 angiotensin (Ang) peptides at the nucleus tractus solitarii in age-related baroreflex impairment. Baroreflex sensitivity control of heart rate in response to increases in blood pressure was tested in younger (3 to 5 months) and older (16 to 20 months) anesthetized male Sprague-Dawley rats before and after bilateral solitary tract injections of the Ang II type 1 (AT 1 ) receptor antagonist candesartan (24 pmol) or the Ang-(1-7) antagonist (D-Ala 7 )-Ang-(1-7) (144 fmol or 24 pmol). Basal reflex sensitivity of older rats was significantly lower than younger rats. In younger rats, the reflex was facilitated by bilateral candesartan injections and attenuated by bilateral (D-Ala 7 )-Ang-(1-7) injections. In older rats, the reflex was facilitated by AT 1 blockade; however, (D-Ala 7 )-Ang-(1-7) injected into the solitary tract nucleus had no effect. Neprilysin mRNA in the medulla was lower in older rats compared with younger rats, whereas angiotensin-converting enzyme (ACE), ACE2, and mas receptor mRNA levels of older rats did not differ from values of younger rats. Thus, opposing actions of endogenous Ang II and Ang-(1-7) in the solitary tract nucleus contribute to baroreflex function in response to increases in mean arterial pressure of younger rats. The attenuated counterbalancing effect of Ang-(1-7) on baroreflex function is lost in older rats, which may be attributable to diminished production of the peptide from neprilysin.

Transgenic rats with targeted decreased glial expression of angiotensinogen (ASrAogen rats) did not show an increase in systolic pressure compared with Sprague-Dawley (SD) rats during aging (15-69 wk of age). ASrAogen animals had lower body weights throughout the study, similar to reports for animals with systemic knockout of angiotensinogen or treated long term with renin-angiotensin system (RAS) blockers. Further characterization of indexes of growth and metabolism in ASrAogen rats compared with (mRen2)27 and SD rats, which express elevated versus normal brain and tissue angiotensin II levels, respectively, revealed that serum leptin was 100-200% higher in SD and (mRen2)27 rats at 46 wk and 69 wk of age. Consistent with low serum leptin, ASrAogen rats had higher food intake (73%) compared with SD or (mRen2)27 rats. (mRen2)27 rats had higher resting insulin levels than ASrAogen rats at all ages. Insulin levels were constant during aging in ASrAogen rats, whereas an increase occurred in SD rats, leading to higher insulin levels at 46 and 69 wk of age compared with ASrAogen rats. IGF-1 was comparable among strains at all ages, but (mRen2)27 rats had longer and ASrAogen rats had shorter tail lengths versus SD rats at 15 wk of age. In conclusion, reduced expression of glial angiotensinogen blunts the age-dependent rise in insulin levels and weight gain, findings that mimic the effects of long-term systemic blockade of the RAS or systemic knockout of angiotensinogen. These data implicate glial angiotensinogen in the regulation of body metabolism as well as hormonal mechanisms regulating blood pressure.

Sakima A, Averill DB, Kasper SO, Jackson LR, Ganten D, Ferrario CM, Gallagher PE, Diz DI. Baroreceptor reflex regulation in anesthetized transgenic rats with low glia-derived angiotensinogen. Am J Physiol Heart Circ Physiol 292: H1412-H1419, 2007. First published November 3, 2006; doi:10.1152/ajpheart.00984.2006.-Endogenous angiotensin (ANG) II and ANG-(1-7) act at the nucleus tractus solitarius (NTS) to differentially modulate neural control of the circulation. The role of these peptides endogenous to NTS on cardiovascular reflex function was investigated in transgenic rats with low brain angiotensinogen (Aogen) due to glial overexpression of an antisense to Aogen (ASrAOGEN) and in Sprague-Dawley (SD) rats. Arterial baroreceptor reflex sensitivity (BRS) for control of heart rate (HR) in response to increases in mean arterial pressure (MAP) was tested before and after bilateral microinjection of the angiotensin type 1 (AT 1) receptor blocker candesartan or the ANG-(1-7) receptor blocker (D-Ala 7 )-ANG-(1-7) into the NTS of urethane-chloraloseanesthetized ASrAOGEN and SD rats. Baseline MAP was higher in ASrAOGEN than in SD rats under anesthesia (P Ͻ 0.01). Injection of candesartan or (D-Ala 7 )-ANG-(1-7) decreased MAP (P Ͻ 0.01) and HR (P Ͻ 0.05) in ASrAOGEN, but not SD, rats. The BRS at baseline was similar in ASrAOGEN and SD rats. Candesartan increased BRS by 41% in SD rats (P Ͻ 0.01) but was without effect in ASrAOGEN rats. In contrast, the reduction in BRS after (D-Ala 7 )-ANG-(1-7) administration was comparable in SD (31%) and ASrAOGEN rats (34%). These findings indicate that the absence of glia-derived Aogen is associated with 1) an increase in MAP under anesthesia mediated via AT 1 and ANG-(1-7) receptors within the NTS, 2) the absence of an endogenous ANG II contribution to tonic inhibition of BRS, and 3) a continued contribution of endogenous ANG-(1-7) to tonic enhancement of BRS.baroreceptors; solitary tract nucleus; brain renin-angiotensin system; transgenic rats ENDOGENOUS ANGIOTENSIN (ANG) II contributes to cardiovascular and autonomic reflex function (1,8,17,21,52). ANG II receptors have been identified in the nucleus tractus solitarius (NTS), where baroreceptor and chemoreceptor afferents terminate and ANG II, of endogenous or exogenous origin, is known to attenuate baroreflex function (1,8,11,14,24,30,40,46). ANG-(1-7) is also present in the brain, in the hypothalamus and medulla oblongata, at concentrations equivalent to or greater than ANG II (12). ANG-(1-7), from endogenous or exogenous sources, enhances baroreflex control of heart rate (HR), resulting in actions opposite to those of ANG II (1, 6, 9, 13, 21, 44, 52).Transgenic animals are useful for investigation of the functional role of the brain renin-angiotensin system (RAS) in cardiovascular regulation and fluid homeostasis. In fact, glial and neuronal overexpression of renin and angiotensinogen produces different patterns of alterations in resting arterial pressure and baroreceptor reflex function. Morimoto et al. (42,43) recently demonst...

Gilliam-Davis S, Payne VS, Kasper SO, Tommasi EN, Robbins ME, Diz DI. Long-term AT1 receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats. Am J Physiol Heart Circ Physiol 293: H1327-H1333, 2007. First published July 6, 2007; doi:10.1152 doi:10. /ajpheart.00457.2007 rats exhibit proteinuria and insulin resistance in the absence of hypertension as they age. We determined the effects of long-term (1 yr) treatment with the angiotensin (ANG) II type 1 (AT1) receptor blocker L-158,809 on plasma and urinary ANG peptide levels, systolic blood pressure (SBP), and indexes of glucose metabolism in 15-mo-old male F344 rats. Young rats at 3 mo of age (n ϭ 8) were compared with two separate groups of older rats: one control group (n ϭ 7) and one group treated with L-158,809 (n ϭ 6) orally (20 mg/l) for 1 yr. SBP was not different between control and treated rats but was higher in young rats. Serum leptin, insulin, and glucose levels were comparable between treated and young rats, whereas controls had higher glucose and leptin with a similar trend for insulin. Plasma ANG I and ANG II were higher in treated than untreated young or older rats, as evidence of effective AT1 receptor blockade. Urinary ANG II and ANG-(1-7) were higher in controls compared with young animals, and treated rats failed to show age-related increases. Protein excretion was markedly lower in treated and young rats compared with control rats (young: 8 Ϯ 2 mg/day vs. control: 129 Ϯ 51 mg/day vs. treated: 9 Ϯ 3 mg/day, P Ͻ 0.05). Long-term AT1 receptor blockade improves metabolic parameters and provides renoprotection. Differential regulation of systemic and intrarenal (urinary) ANG systems occurs during blockade, and suppression of the intrarenal system may contribute to reduced proteinuria. Thus, insulin resistance, renal injury, and activation of the intrarenal ANG system during early aging in normotensive animals can be averted by renin-ANG system blockade.angiotensin type 1 receptor blockade; glucose metabolosim; aging MANY NORMOTENSIVE RAT STRAINS exhibit increases in systolic blood pressure (SBP) (42), insulin resistance, body weight (13,30,31,41), and serum leptin (30, 39) as they age. Similar changes occur in the aging human population, and a clustering of these factors is consistent with the metabolic syndrome (MetS) (22, 41a). MetS, a collection of cardiovascular risk factors, is an intermediate state between normal metabolism and Type 2 diabetes (22,43). Clinical trials have shown that renin-angiotensin (ANG) system (RAS) blockade, either by ANG-converting enzyme (ACE) inhibitors (4, 57) or ANG II type 1 (AT 1 ) receptor blockers (17, 27), may substantially lower the risk for Type 2 diabetes in hypertensive subjects. However, the exact mechanism underlying this effect is unknown. Moreover, long-term ACE inhibition or AT 1 receptor blockade in rodents protects against most of these age-related changes, including the increase in blood pressure (5, 18), weight gain (11), and decline in cognitive, mitochondrial,...

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