Endothelial Metabolism of Angiotensin II to Angiotensin III, not Angiotensin (1–7), Augments the Vasorelaxation Response in Adrenal Cortical Arteries

Abstract

Hyperaldosteronism is linked to the development and progression of several different cardiovascular diseases. Angiotensin (Ang) II increases aldosterone secretion and adrenal blood flow. Ang II peptide fragments are produced by various peptidases, and these Angs have diverse and vital physiologic roles. Due to the uncharacteristic vasorelaxation of adrenal arteries by Ang II, we tested the hypothesis that Ang II metabolism contributes to its relaxant activity in adrenal arteries. Metabolism of Angs by bovine adrenal cortical arteries and isolated bovine adrenal vascular cells was measured by liquid chromatography-mass spectrometry. The primary Ang metabolites of adrenal arteries are Ang III and Ang (1-7), with Ang IV produced to a lesser extent. Bovine microvascular endothelial cells produced a similar metabolic profile to adrenal arteries, whereas bovine adrenal artery smooth muscle cells exhibited less metabolism. In preconstricted adrenal arteries, Ang II caused relaxation in picomolar concentrations and constrictions at 10nM. Ang-converting enzyme 2 inhibition augmented this relaxation response, whereas aminopeptidase inhibition did not. Ang III was equipotent to Ang II in relaxing adrenal arteries. Ang IV did not cause relaxation. Nitric oxide synthase inhibition enhanced Ang II-induced constriction of adrenal arteries. Aminopeptidase inhibition increased the concentration range for Ang II-induced constriction of adrenal arteries. Ang III and Ang IV did not change the basal tone but caused constriction of adrenal arteries with nitric oxide synthase inhibition. These data indicate that Ang II metabolism modulates the vascular effects of Ang II in the adrenal vasculature.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…ANG (1-7) concentration in human, mouse, and rat plasma were quite low and averaged 4 -80 fmol/ml (140,1165). However, it is important to remember that ANG II stimulation or infusion has indirect effects on cells and animals via its metabolites including ANG (1-7), ANG III, and ANG IV, which are regulated cell/tissue specifically (140,509).…”

Angiotensin II Contributes to the Pathophysiology of Heart Failure

“…It maintains blood pressure and fluid balance in the body. It is formed from its original precursor, angiotensinogen, by a series of two enzymatic cleavages [3,14]. When renal blood flow is lower than usual, the plasma sodium concentration is reduced, in the kidneys prorenin (an intracellular protein) will convert into renin, Renin is an enzyme created via pericytes in the vicinity of the afferent arterioles and juxtaglomerular apparatus cells.…”

“… ANG II, via AT1 receptors, carries out its functions, the central signalling mechanisms by which angiotensin affected on cardiovascular physiology and pathology [3,10,[14][15][16].…”

Synthesis of Alamandine Glycoside Analogues as New Drug Candidates to Antagonize the MrgD Receptor for Pain Relief

“…RAS also plays a vital role in atherogenesis [2], high blood pressure, and other pathological conditions [3]. Important vasoactive controls are mediated by the principal angiotensin receptors AT1 and AT2, which are agonized by the proteolytic cleavage products of Angiotensin I (Ang I), including Ang II, Ang III, Ang1-7, Ang1-9 and Ang IV [4] [5]. Angiotensin-Converting Enzymes 1 and 2 (ACE1, ACE2) and Neutral Endopeptidase (NEP) play important roles in these regulatory pathways [6].…”