Feedback regulation of angiotensin converting enzyme activity and mRNA levels by angiotensin II

H. Schunkert, J. R. Ingelfinger, A. T. Hirsch, Y. Pinto, W. J. Remme, H. Jacob, V. J. Dzau

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137 Scopus citations

Abstract

Although renin and angiotensinogen are known to be subject to feedback regulation, the effects of angiotensin II (Ang II) on the regulation of angiotensin converting enzyme (ACE) gene expression and enzymatic activity have not yet been studied. Therefore, the effects of exogenous Ang II infusion and ACE inhibition on ACE mRNA expression were examined. Ang II was infused intravenously in male Sprague-Dawley rats for 3 days at 100 (low dose), 300 (medium dose), or 1,000 (high dose) ng/kg per minute (n=8 for each group). Compared with control (vehicle infusion, n=8), Ang II infusion increased plasma Ang II concentration (62, 101, 126 [p<0.05], and 187 [p<0.05] fmol/ml) and mean arterial blood pressure (106, 119 [p<0.05], 134 [p<0.05], and 125 mm Hg for control, low, medium, and high doses, respectively). Ang II infusion decreased ACE mRNA levels in the lung (57%, 52%, and 51%; p<0.05 for each) and testis (49%, 63%, and 53% of control for low, medium, and high doses, respectively; p<0.05 for each), two major sites of ACE synthesis. There was, albeit less pronounced, a parallel decrease in pulmonary ACE activity (4.38, 3.92, 3.07 [p<0.05], and 3.48 [p<0.05] nM/mg per minute for control, medium, and high doses, respectively). In contrast, serum (54, 50, 48, and 38 [p<0.05] nM/ml per minute) and testicular (2.63, 2.08 [p<0.05], 2.24, and 2.18 nM/mg per minute for control, low, medium, and high doses, respectively) ACE activities displayed only minimal change in animals infused with Ang II. The effects of blockade of Ang II production were studied after 3 days of ACE inhibition by quinapril (10 mg/kg per day) in drinking water. Mean arterial blood pressure decreased significantly (111 versus 99 mm Hg, p<0.05). Quinapril treatment suppressed serum (43% of control, p<0.05) and pulmonary (66% of control, p<0.001) ACE activities. However, ACE mRNA level was induced in the lung (140% of control, p<0.05). Testicular ACE activity was not significantly inhibited by quinapril (88% of control), and no significant difference was seen in the testicular mRNA levels between the two groups (98% of control). To study the effects of discontinuation of ACE inhibition on the regulation of serum ACE activity, additional rats were treated with quinapril (10 mg/kg per day for 3 days, followed by a single gavage of 10 mg/kg). Serum ACE activity was measured 6, 24, 48, 96, and 168 hours after withdrawal of treatment. Serum ACE activity was inhibited at 6 hours after gavage. However, serum ACE activity exceeded baseline values significantly at 48 hours (193% of baseline, p<0.05) and 96 hours (146% of baseline, p<0.05) after discontinuation of ACE inhibition. These studies suggest that pulmonary ACE expression is subject to negative feedback by Ang II. Furthermore, our data are consistent with previous reports that ACE inhibitors do not penetrate into the testis in vivo.

Original languageEnglish (US)
Pages (from-to)312-318
Number of pages7
JournalCirculation research
Volume72
Issue number2
DOIs
StatePublished - 1993

Keywords

  • angiotensin II
  • angiotensin converting enzyme
  • angiotensin converting enzyme inhibitor
  • feedback regulation
  • gene expression

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