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Angiotensin-(1-12) [ANG(1-12)] is a newly identified peptide detected in a variety of rat tissues, including the brain. To determine whether brain ANG-(1-12) participates in blood pressure regulation, we treated male adult (mRen2)27 hypertensive rats (24-28 wk of age) with Anti-ANG-(1-12) IgG or Preimmune IgG via an intracerebroventricular cannula for 14 days. Immunoneutralization of brain ANG-(1-12) lowered systolic blood pressure (-43 [+ or -] 8 mmHg on day 3 and -26 [+ or -] 7 mmHg on day 10 from baseline, P < 0.05). Water intake was lower on intracereroventricular day 6 in the Anti-ANG-(1-12) IgG group, accompanied by higher plasma osmolality on day 13, but there were no differences in urine volume, food intake, or body weight during the 2-wk treatment. In Preimmune IgG-treated animals, there were no significant changes in these variables over the 2-wk period. The antihypertensive effects produced by endogenous neutralization of brain ANG-(1-12) suggest that ANG-(1-12) is functionally active in brain pathways regulating blood pressure. hypertension; transgenic rats; renin-angiotensin system; brain; sympathetic nerve; antibody

Clinical trials revealed that estrogen may result in cardiovascular risk in patients with coronary heart disease, despite earlier studies demonstrating that estrogen provided cardiovascular protection. It is possible that the preexisting condition of hypertension and the ability of estrogen to activate the renin-angiotensin system could confound its beneficial effects. Our hypothesis is that the attenuation of estrogen to agonist-induced vasoconstrictor responses through the activation of nitric oxide (NO) synthase (NOS) is impaired by hypertension. We investigated the effects of 17[beta]-estradiol ([E.sub.2]) replacement in normotensive Sprague-Dawley (SD) and (mRen2)27 hypertensive transgenic (TG) rats on contractile responses to three vasoconstrictors, angiotensin II (ANG II), serotonin (5-HT), and phenylephrine (PE), and on the modulatory role of vascular NO to these responses. The aorta was isolated from ovariectomized SD and TG rats treated chronically with 5 mg [E.sub.2] or placebo (P). The isometric tension of the aortic rings was measured in organ chambers, and endothelial NOS (eNOS) in the rat aorta was detected using Western blot analysis. [E.sub.2] treatment increased eNOS expression in the SD and TG aorta and reduced ANG II- and 5-HT- but not PE-induced contractions in SD and TG rats. The inhibition of NOS with [N.sup.[omega]]-nitro-L-arginine methyl ester enhanced ANG II-, 5-HT-, and PE-induced contractions in P-treated and ANG II and PE responses in [E.sub.2]-treated SD and TG rats. Only the responses to 5-HT were augmented in hypertensive rats. In conclusion, this study shows that the preexisting condition of hypertension augmented the vascular responsiveness of 5-HT, whereas the attenuation of estrogen by ANG II and 5-HT vascular responses was not impaired by hypertension. The adrenergic agonist was unresponsive to estrogen treatment. The contribution of NO as a factor contributing to the relative refractoriness of the vascular responses is dependent on the nature of the vasoconstrictor and/or the presence of estrogen. angiotensin II; serotonin; phenylephrine

Angiotensin-converting enzyme-2 (ACE2) converts angiotensin II (ANG II) to angiotensin-(1-7) [ANG-(1-7)], and this enzyme may serve as a key regulatory juncture in various tissues. Although the heart expresses ACE2, the extent that the enzyme participates in the cardiac processing of ANG II and ANG-(1-7) is equivocal. Therefore, we utilized the Langendorff preparation to characterize the ACE2 pathway in isolated hearts from male normotensive Sprague-Dawley [[Tg.sup.(-)]] and hypertensive [mRen2]27 [[Tg.sup.(+)]] rats. During a 60-rain recirculation period with 10 nM ANG II, the presence of ANG-(1-7) was assessed in the cardiac effluent. ANG-(1-7) generation from ANG II was similar in both the normal and hypertensive hearts [[Tg.sup(-)]: 510 [+ or -] 55 pM, n = 20 vs. [Tg.sup.(+)]: 497 [+ or -] 63 pM, n = 14] with peak levels occurring at 30 rain after administration of the peptide. ACE2 inhibition (MLN-4760, 1 [micro]M) significantly reduced ANG-(1-7) production by 83% (57 [+ or -] 19 pM, P < 0.01, n = 7) in the [Tg.sup.(-)] rats, whereas the inhibitor had no significant effect in the [Tg.sup.(-)] rats (285 [+ or -] 53 pM, P > 0.05, n = 10). ACE2 activity was found in the effluent of perfused [Tg.sup.(-)] and [Tg.sup.(+)] hearts, and it was highly associated with ACE2 protein expression (r = 0.78). This study is the first demonstration for a direct role of ACE2 in the metabolism of cardiac ANG II in the hypertrophic heart of hypertensive rats. We conclude that predominant expression of cardiac ACE2 activity in the [Tg.sup.(+)] may be a compensatory response to the extensive cardiac remodeling in this strain. angiotensin II; hypertension; isolated heart doi:10.1152/ajpheart.01198.2006.

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 (A[T.sub.1]) receptor blocker candesartan or the ANG-(1-7) receptor blocker (D-[Ala.sup.7])-ANG-(1-7) into the NTS of urethane-chloralose-anesthetized ASrAOGEN and SD rats. Baseline MAP was higher in ASrAOGEN than in SD rats under anesthesia (P < 0.01). Injection of candesartan or (D-[Ala.sup.7])-ANG-(1-7) decreased MAP (P < 0.01) and HR (P < 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 < 0.01) but was without effect in ASrAOGEN rats. In contrast, the reduction in BRS after (D-[Ala.sup.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 A[T.sub1] 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