AT 2 receptor-mediated vasodilation in the mouse heart depends on AT 1A receptor activation

1 Angiotensin (Ang) II type 2 (AT"2) receptors are believed to counteract Ang II type 1 (AT"1) receptor-mediated effects. Here, we investigated AT"2 receptor-mediated effects on coronary and cardiac contractility in C57BL/6 mice. 2 Hearts were perfused according to Langendorff. Baseline coronary flow (CF) and left ventricular systolic pressure (LVSP) were 2.7±0.1 ml min -1 and 111±3 mmHg (n=50), respectively. 3 Ang II (n=14) concentration dependently decreased CF and LVSP, by maximally 41±4 and 25±3%, respectively (pEC"5"0s 7.41±0.12 and 7.65±0.12). The AT"1 receptor antagonist irbesartan (n=4) abolished all Ang II-induced changes, whereas the AT"2 receptor antagonist PD123319 (n=6) enhanced (P<0.05) the effect of Ang II on CF (to 59±1%) and LVSP (to 44±2%), without altering its potency. A similar enhancement was observed in the presence of nitric oxide (NO) synthase inhibitor N ω-nitro-L-arginine methyl ester HCl (L-NAME; n=4). On top of L-NAME, PD123319 no longer affected the response to Ang II (n=4). 4 The AT"2 receptor agonist CGP42112A (n=4) did not affect CF or LVSP, nor did CGP42112A (n=4) alter the constrictor response to the α"1- adrenoceptor agonist phenylephrine. Furthermore, Ang II exerted no effects in hearts of AT(1A) -/- mice (n=5), whereas its effects in hearts of AT(1A) +/+ wild-type control mice (n=7) were indistinguishable from those in hearts of C57BL/6 mice. 5 In conclusion, Ang II exerts opposite effects on coronary and cardiac contractility in the mouse heart via activation of AT(1A) and AT"2 receptors. AT"2 receptor-mediated effects depend on NO and occur only in conjunction with AT(1A) receptor activation.

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