Angiotensin-(1-7) Potentiates the Hypotensive Effect of Bradykinin in Conscious Rats

Abstract

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.

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…This BK-potentiating effect of Ang-(1-7) may contribute for its cardiovascular effects in normotensive (Paula et al 1995, Oliveira et al 1999, Greco et al 2006 and hypertensive (Lima et al 1997, Fernandes et al 2001 rats. Several mechanisms have been proposed to explain the BK-potentiating activity of Ang-(1-7), including ACE inhibition since Ang-(1-7) is an ACE substrate (Li et al 1997, Tom et al 2001, allosteric changes in ACE (Erdos et al 2002), and Mas-mediated changes in the BK signaling (Paula et al 1995, Oliveira et al 1999, Fernandes et al 2001, Ferreira et al 2001. In addition, vascular Ang-(1-7) actions could involve modulation of vascular effects of Ang II (Roks et al 1999, Stegbauer et al 2004.…”

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

“…In addition, Ang-(1-7) amplifies the vasodilator actions of bradykinin (BK). 23 Additional evidence suggests that Ang-(1-7) reduces the release of norepinephrine acting through a BK/ nitric oxide-mediated mechanism that stimulates cGMP/ protein kinase G signaling. 24 Other experiments also point to an interrelationship between Ang-(1-7) and the prostaglandin-BK-nitric oxide system.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…To determine the interaction of Ang-(1-7) and NO, studies conducted from our group confirmed that the vasodilator response was mediated by NO-but it was discovered that inhibition of NO synthase in 2-kidney-1-clip (2K1C) hypertension induced in dogs resulted in a blunted vasodilatory response, suggesting that an impairment in the NO system may play a role in the pathology of hypertension (Nakamoto et al 1995). Moreover, Ang-(1-7) potentiated the vasodilatory effect of bradykinin administered to conscious rats, and this response was significantly attenuated by indomethacin, suggesting the involvement of prostaglandins (Paula et al 1995). This effect was later confirmed by us, and we showed that this effect of Ang-(1-7) to potentiate bradykinin-induced vasodilation was due to the ability of Ang-(1-7) to inhibit ACE activity and release NO (Li et al 1997), thereby decreasing the metabolism of bradykinin and further stimulating vasodilation.…”