Angiotensin-(1-7) Produces Hypotensive Responses in Anesthetized At1a Receptor Knockout Mice [Agtr1a(-/-)].
Angiotensin-(1-7) [Ang-(1-7)] produces arteriolar dilation and a hypotensive action, which may be mediated through nitric oxide, prostaglandin or bradykinin mechanisms. In rats, Ang-(1-7) produces a biphasic pressor/depressor action; the pressor component is blocked by AT1 antagonists while the depressor component is not blocked by either AT1 or AT2 antagonists. In this study, we determined whether Ang-(1-7) would produce cardiovascular effects in AT1a receptor knockout mice. Male Agtr1a(-/-) (n = 5) and control mice (n = 6) were anesthetized with ketamine:xylazine (71:7 mg/kg) and received femoral artery and jugular vein catheters. As previously reported, baseline blood pressure was lower (62 ± 5 mm Hg) in the Agtr1a(-/-) than in the controls (79 ± 6 mm Hg). Arterial blood pressure responses to Ang-(1-7) (0.15 - 1.5 μmol/kg) were determined. Ang-(1-7) produced a dose dependent pressor response in control animals with the peak response at the highest dose (15 ± 2 mm Hg). The pressor response was followed immediately by a depressor response ranging from -6 ± 1 at the lowest dose to -8 ± 1 mm Hg for the highest dose. AT1a receptor knockout mice showed no pressor response to Ang-(1-7) but did show an immediate depressor response ranging from -4 ± 1 to -6 ± 2 mm Hg. Similar reductions in blood pressure without pressor effects were observed in female knockout mice (-5 ± 2 mm Hg to -9 ± 2 mm Hg over the same dose range, n = 3). The results of this study indicate that the depressor response to Ang-(1-7) is not dependent on a preceding pressor response to this peptide. Furthermore, the depressor response is not mediated by an AT1a receptor, consistent with our previous reports of a non-AT1, non-AT2 receptor mediating the actions of Ang-(1-7) in the vasculature. (Support: HL51952; HL55082)