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

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Augmented Short- and Long-Term Hemodynamic and Hormonal Effects of an Angiotensin Receptor Blocker Added to Angiotensin Converting Enzyme Inhibitor Therapy in Patients With Heart Failure

“…11,26 Renin is activated during long-term ACE inhibitor therapy, and AngI levels are elevated. 6,7 The increased substrate levels may therefore be adequate to overcome the competitive inhibition of the converting enzyme, especially during the intervals between dosing. In addition, tissue levels of AngII could persist even if circulating levels of the hormone are suppressed by the drug.…”

“…5 ACE inhibitors are also competitive inhibitors whose blockade could be overridden by increased AngI levels that result from the loss of feedback inhibition of renin activity. 6,7 Even if circulating AngII levels are reduced, the ability of different ACE inhibitors to suppress various tissue levels of AngII remains unclear. 8 Furthermore, there is growing evidence that alternative pathways of conversion of AngI to AngII, including a chymase pathway, may restore circulating or tissue levels despite ACE inhibition.…”

Structural remodeling in hypertensive heart disease and the role of hormones.

“…27 Moreover, TACE in these latter models was not subject to feedback regulation by Ang II, as is the case for endothelial ACE. 70 Myocardial ACE activity, measured by the conversion of Ang I to Ang II in isolated perfused rat heart, is increased after suprarenal aortic banding. 71 This may be related to increased TACE that accompanies the perivascular fibrosis of intramyocardial coronary arteries in both ventricles with RAAS activation.…”

Protection against ischemia/reperfusion injury and myocardial dysfunction by antisense-oligodeoxynucleotide directed at angiotensin-converting enzyme mRNA

“…Notably, chronic use of chemical ACE inhibitors can also increase ACE mRNA level in heart, lung, duodenum, and aorta by feedback regulation. 30,34,35 We found that ACE mRNA expression measured by RT-PCR did not increase in the myocardium immediately after ischemia/reperfusion. Pretreatment with captopril also did not affect the level of ACE mRNA in myocardium.…”