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Angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice.

ABSTRACT: Angiotensin-converting enzyme 2 (ACE2), a new component of the brain renin-angiotensin system, has been suggested to participate in the central regulation of blood pressure (BP). To clarify the relationship between ACE2 and other brain renin-angiotensin system components, we hypothesized that central angiotensin II type 1 receptors reduce ACE2 expression/activity in hypertensive mice, thereby impairing baroreflex function and promoting hypertension. To test this hypothesis, chronically hypertensive mice (RA) with elevated angiotensin II levels were treated with losartan (angiotensin II type 1 receptor blocker) or PD123319 (angiotensin II type 2 antagonist; 10 mg/kg per day, SC) for 2 weeks. Baseline spontaneous baroreflex sensitivity and brain ACE2 activity were dramatically decreased in RA compared with nontransgenic mice, whereas peripheral ACE2 activity/expression remained unaffected. Losartan, but not PD123319, increased central ACE2 activity, spontaneous baroreflex sensitivity, and normalized BP in RA mice. To confirm the critical role of central ACE2 in BP regulation, we generated a triple-transgenic model with brain ACE2 overexpression on a hypertensive RA background. Triple-transgenic-model mice exhibit lower BP and blunted water intake versus RA, suggesting lower brain angiotensin II levels. Moreover, the impaired spontaneous baroreflex sensitivity, parasympathetic tone, and increased sympathetic drive, observed in RA, were normalized in triple-transgenic-model mice. These data suggest that angiotensin II type 1 receptors inhibit ACE2 activity in RA mice brain, thus contributing to the maintenance of hypertension. In addition, overexpression of ACE2 in the brain reduces hypertension by improving arterial baroreflex and autonomic function. Together, our data suggest that angiotensin II type 1 receptor-mediated ACE2 inhibition impairs baroreflex function and support a critical role for ACE2 in the central regulation of BP and the development of hypertension.

SUBMITTER: Xia H

PROVIDER: S-EPMC2695598 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice.

Xia Huijing H Feng Yumei Y Obr Teresa D TD Hickman Peter J PJ Lazartigues Eric E

Hypertension (Dallas, Tex. : 1979) 20090105 2

Angiotensin-converting enzyme 2 (ACE2), a new component of the brain renin-angiotensin system, has been suggested to participate in the central regulation of blood pressure (BP). To clarify the relationship between ACE2 and other brain renin-angiotensin system components, we hypothesized that central angiotensin II type 1 receptors reduce ACE2 expression/activity in hypertensive mice, thereby impairing baroreflex function and promoting hypertension. To test this hypothesis, chronically hypertens ...[more]

PMID: 19124678

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Project description:Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1-7), and it was reduced in Mas knockout mice. These effects were associated with reduction in reactive oxygen species production. In addition, Ang II-induced reactive oxygen species production in human aortic endothelial cells was attenuated by preincubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that angiotensin-converting enzyme 2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.

Project description:IntroductionThis meta-analysis aimed to summarize the available evidence to compare angiotensin-converting enzyme (ACE) inhibitors with angiotensin II receptor blockers (ARBs) on improving insulin sensitivity in hypertensive patients.MethodsRandomized controlled trials (RCTs) comparing ACE inhibitors versus ARBs published with outcomes on homeostasis model assessment of IR (HOMA-IR), glucose infusion rate (GIR), the quantitative insulin sensitivity check index (QUICKI), insulin sensitivity index (ISI) composite, fasting plasma glucose (FPG), fasting plasma insulin (FPI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were searched through 5 databases. Data were searched from their inception to July 5, 2020. Stata 14.0 was used to perform the meta-analysis.ResultsEleven RCTs (n = 1015) were included in this meta-analysis. Pooled analysis of studies showed no significant difference in HOMA-IR between ARBs and ACE inhibitors (WMD = -0.09, 95% CI: -0.69 to 0.50, P = 0.755); however, subgroup analysis of therapeutic duration showed a significant difference in HOMA-IR between ARBs and ACE inhibitors among the long-term intervention subgroup (>12 weeks) (WMD = 0.41, 95% CI: 0.06 to 0.76, P = 0.022) and hypertensive patients with diabetes mellitus subgroup (WMD = 0.55, 95% CI: 0.49 to 0.61, P < 0.001); results showed no significant difference between ARBs and ACE inhibitors on QUICKI score (WMD = -0.00, 95% CI: -0.03 to 0.03, P = 0.953) in hypertensive patients; however, the efficacy of ACE inhibitors on improving GIR and ISI composite was significantly better than that of ARBs (WMD = -1.09, 95% CI: -1.34 to -0.85, P < 0.001; WMD = -0.80, 95% CI: -1.24 to -0.36, P < 0.001, respectively). Furthermore, no significant differences were noted on FPG (WMD = 0.72, 95% CI: -1.39 to 2.83, P = 0.505), FPI (WMD = -0.48, 95% CI: -1.60 to 0.64, P = 0.398), SBP (WMD = -0.65, 95% CI: -1.76 to 0.46, P = 0.254), and DBP (WMD = -0.30, 95% CI: -1.70 to 1.10, P = 0.675) between ARBs and ACE inhibitors.ConclusionResults from this meta-analysis showed that ACE inhibitors resulted in more effective improvement of HOMA-IR compared with ARBs among the long-term intervention and hypertensive patients with DM subgroup; furthermore, the efficacy of ACE inhibitors on improving GIR and ISI composite was significantly better than that of ARBs in hypertensive patients. However, ARBs had no significant difference in QUICKI score, FPG, FPI, SBP, and DBP compared with ACE inhibitors. Larger and better-designed studies are needed to further verify this conclusion.

Dataset Information

Angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice.

Publications

Angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice.

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