Hypertension. 2005;45:960-966
Published online before print March 14, 2005,
doi: 10.1161/01.HYP.0000160325.59323.b8
(Hypertension. 2005;45:960.)
© 2005 American Heart Association, Inc.
Angiotensin-(1–7) Acts as a Vasodepressor Agent Via Angiotensin II Type 2 Receptors in Conscious Rats
Pia E. Walters;
Tracey A. Gaspari;
Robert E. Widdop
From the Department of Pharmacology, Monash University, Melbourne, Australia.
Correspondence to Associate Professor Robert Widdop, Department of Pharmacology, Monash University, Melbourne, VIC 3800, Australia. E-mail robert.widdop{at}med.monash.edu.au
Given that angiotensin-(1–7) (Ang-[1–7]) has been frequently reported to exert direct in vitro vascular effects but less often in vivo, we investigated whether a vasodepressor effect of Ang-(1–7) could be unmasked acutely in conscious spontaneously hypertensive rats (SHR) against a background of angiotensin II type 1 (AT1) receptor blockade. Mean arterial pressure (MAP) and heart rate were measured over a 5-day protocol in various groups of rats randomized to receive the following drug combinations: saline, AT1 receptor (AT1R) antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, Ang-(1–7) (5 pmol/min) alone, candesartan plus Ang-(1–7), and candesartan plus Ang-(1–7) and angiotensin II type 2 (AT2) receptor (AT2R) antagonist PD123319 (50 µg/kg per minute). In Wistar-Kyoto (WKY) rats, saline, Ang-(1–7), or candesartan alone caused no significant alteration in MAP, whereas Ang-(1–7) coadministered with candesartan caused a marked, sustained reduction in MAP. A similar unmasking of a vasodepressor response to Ang-(1–7) during AT1R blockade was observed in SHR. Moreover, the AT2R antagonist PD123319 markedly attenuated the enhanced depressor response evoked by the Ang-(1–7)/candesartan combination in SHR and WKY rats, whereas in other experiments, the putative Ang-(1–7) antagonist A-779 (5 and 50 pmol/min) did not attenuate this vasodepressor effect. In separate experiments, the bradykinin type 2 receptor antagonist HOE 140 (100 µg/kg IV) or the NO synthase inhibitor N
-nitro-L-arginine methyl ester (1 mg/kg IV) abolished the depressor effect of Ang-(1–7) in the presence of candesartan. Collectively, these results suggest that Ang-(1–7) evoked a depressor response during AT1R blockade via activation of AT2R, which involves the bradykinin–NO cascade.
Key Words: receptors, angiotensin • rats, spontaneously hypertensive
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