This is the first study to demonstrate Ang II metabolism in intact arteries. Importantly, these studies were performed in small resistance-sized adrenal cortical arteries which are a primary site for the regulation of adrenal cortical blood flow (22
). The physiological implications for Ang II metabolism at this site are two-fold. First, because Ang II causes dynamic changes in vascular tone of these arteries (i.e. dilations at low concentrations and constrictions at high concentrations (15
)), subtle changes in Ang II concentrations by vascular metabolism could alter vascular resistance and therefore adrenal cortical blood flow. Secondly, Ang II metabolism would decrease Ang II concentrations and increase metabolite concentrations presented to the steroidogenic cells. This alteration in Ang II/metabolite ratios could alter aldosterone release and secondarily, blood volume and blood pressure.
In bovine adrenal cortical arteries, relaxations to Ang II were inhibited by the removal of the endothelium. However, it was not evident if the relaxations occur through Ang II metabolism to vasoactive peptides that activate relaxing factor release or through the direct action of Ang II. Ang II metabolism to Ang III, Ang IV and Ang (1-7) was demonstrated in endothelial cells from bovine adrenal arteries and human aorta and human umbilical veins (17
). The contribution of the smooth muscle to the Ang II metabolism has not been clarified, although ACE2 transcriptional expression has been demonstrated in human coronary, cerebral, pulmonary, renal and mesenteric arteries (24
). In the intact adrenal cortical arteries from this study, metabolism of Ang II to Ang (1-7) does not appear to contribute to the vascular relaxations to Ang II. This was evident because the Ang (1-7) receptor antagonist did not alter the relaxations to Ang II. In contrast, in rat carotid arteries, Ang II relaxations are partially dependent on Ang II metabolism to Ang (1-7) (25
). Thus, it appears that the role of angiotensin metabolites in Ang II relaxation vary with the vasculature and/or species.
Ang II relaxations were mediated by endothelial cell NO. This was demonstrated in the current study and a previous study of perfused bovine adrenal cortical arteries by the inhibition of the Ang II relaxations/dilations by L-NA (15
). As reviewed by Toda and colleagues (11
), the role of the endothelium and NO production in Ang II and Ang (1-7) relaxations has been also demonstrated in numerous arteries from various species. Thus, our results fit the paradigm of NO as the primary effector of Ang II relaxations. Similarly, adrenal cortical arterial relaxations to Ang (1-7) were mediated by endothelial NO production. Because the relaxations induced by Ang (1-7) were blocked by the Ang (1-7) receptor antagonist, we conclude that this receptor activates endothelial cell signaling cascades that culminate with NO release.
Relaxations to Ang III and Ang (1-7) were more than 1000 fold less potent that Ang II relaxations. Therefore, Ang II metabolism to these metabolites should not significantly contribute to Ang II relaxations. However, Ang II metabolism and the impact on adrenal arterial vascular tone may be more important during times of high Ang II. Under this scenario, Ang II vascular constriction would overcome Ang II relaxation. Because Ang III and Ang (1-7) did not cause vascular constriction in the adrenal arteries, their relaxing properties could counterbalance Ang II constrictions. Alternatively, high concentrations of Ang (1-7) infusion in humans reduced forearm blood flow (26
) and in rats reduced blood flow to the kidney, mesentery and skin (27
The consequence of cortical artery Ang II metabolism on the concentrations of Ang II and Ang II metabolites that reach the adrenal steroidogenic cells depends on the steroidogenic activity of the metabolites. In this regard, Ang III was equipotent to Ang II in stimulating aldosterone and corticosterone production in conscious rats and aldosterone production from rat adrenal cortical cells (18
). Alternatively, Ang IV and Ang (1-7) did not stimulate aldosterone production in bovine adrenal zona glomerulosa cells (16
). Since the primary Ang II metabolite from the cortical arteries was Ang (1-7), we predict that vascular Ang II metabolism would reduce Ang II stimulation of steroid hormone release.
The role of Ang (1-7) as an antihypertensive peptide has not been demonstrated. In the kidney, the effects of Ang (1-7) on natriuresis and diuresis have been mixed (28
). Therefore, other mechanisms must counteract the direct vasodilatory effects of Ang (1-7). Adrenal mechanisms including an increase in blood flow and the consequent increase in aldosterone release could compensate for the systemic vascular actions of Ang (1-7). Further studies will be required to address this possibility.