Treatment with angiotensin-converting enzyme inhibitors increases the angiotensin-(1-7) [Ang-(1-7)] and bradykinin concentrations in plasma and tissue. In this study we evaluated the interaction between these peptides by determining the effect of Ang-(1-7) on the hypotensive action of bradykinin in conscious rats. Administration of Ang-(1-7) (5 nmol) did not change mean arterial pressure or heart rate. However, the hypotensive effect of bradykinin, produced by an intravenous or intra-arterial route, was potentiated by Ang-(1-7) in a dose-dependent manner. The Ang-(1-7) doses necessary to transform the effect of a single dose of bradykinin into that produced by a double dose (potentiating unit) were 2 nmol i.v. and 5 nmol IA. The Ang-(1-7) dose used did not change either the pressor effect of Ang II or the hypotensive effect of sodium nitroprusside. The bradykinin-potentiating Ang-(1-7) activity was significantly attenuated by pretreatment with indomethacin (5 mg/kg IM, n = 4). In an additional group the bradykinin-potentiating activity of Ang-(1-7) was evaluated 30 minutes after treatment with the angiotensin-converting enzyme inhibitor enalaprilat (10 mg/kg i.v., n = 9). Under this condition the bradykinin-potentiating activity of Ang-(1-7) was substantially increased, resulting in a potentiating unit of approximately 0.2 nmol IV. Pretreatment with indomethacin (5 mg/kg IM, n = 7) also attenuated the bradykinin-potentiating activity of Ang-(1-7) in enalaprilat-treated rats. These results show that Ang-(1-7) is a bradykinin-potentiating peptide in vivo. Furthermore, the data obtained with indomethacin suggest that prostaglandins participate in the mechanism of the bradykinin potentiation by Ang-(1-7). More importantly, these data suggest that the interaction between Ang-(1-7) and bradykinin can contribute to the pharmacological effects of angiotensin-converting enzyme inhibitors.
In this study we evaluated the effect of angiotensin-(1-7) on the hypotensive action of bradykinin (BK) in normotensive rats, renal hypertensive rats (RHR), and spontaneously hypertensive rats (SHR). In addition, we evaluated the effect of angiotensin-converting enzyme (ACE) inhibition with enalaprilat treatment (10 mg/kg I.V.) on the BK-potentiating activity of Ang-(1-7). Renal hypertension was produced by aorta coarctation between the origin of renal arteries. Ang-(1-7) (0.3 pmol/min) or saline (0.9% NaCl, 5 microL/min) was infused intravenously in conscious male Wistar rats, adult SHR, or RHR. Intravenous bolus injections of BK (0.1 to 1.6 nmol in RHR and SHR; 0.625 to 5 nmol in Wistar rats) were made before and within 30 and 60 minutes of Ang-(1-7) infusion. Ang-(1-7) infusion did not change mean arterial pressure (MAP) of Wistar rats (MAP=97+/-3 mm Hg), RHR (MAP=173+/-3 mm Hg), or SHR (MAP=177+/-5 mm Hg). In Wistar rats, Ang-(1-7) increased the BK hypotensive effect by 24+/-6% within 60 minutes of infusion. No significant changes were observed at 30 minutes of infusion. In additional groups of rats, Ang-(1-7) (5 pmol/min, n=5) was infused alone or combined with its selective antagonist D-Ala7-Ang-(1-7) (A-779) (5 pmol/min, n=6). The bradykinin-potentiating activity of Ang-(1-7) was completely abolished by A-779. In SHR and RHR, Ang-(1-7) significantly increased the hypotensive effect of BK by 59+/-8% and 57+/-9.8%, respectively, within 60 minutes of infusion. No significant changes were observed with saline infusion. In Wistar rats, enalaprilat treatment increased the BK-potentiating activity of Ang-(1-7) transforming the effect of 0.3 pmol/min into that observed with a rate 16-fold higher (5 pmol/min). On the other hand, in SHR enalaprilat did not change the Ang-(1-7) effect, while it abolished the BK potentiation in RHR. Our data show that the BK-potentiating activity of Ang-(1-7) is preserved and even augmented in hypertensive rats. The finding that the BK-potentiating activity of Ang-(1-7) could be demonstrated at a very low infusion rate suggests that this angiotensin can act as an endogenous modulator of the vascular actions of kinins. ACE inhibition can influence differently the BK-potentiating activity of Ang-(1-7) in normotensive and hypertensive rats.
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