Published Online
on March 14, 2005

A more recent version of this article appeared on May 1, 2005

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Submitted on January 28, 2005
Revised on February 1, 2005

Angiotensin-(1-7) Acts as a Vasodepressor Agent Via Angiotensin II Type 2 Receptors in Conscious Rats

Pia E. Walters; Tracey A. Gaspari; and Robert E. Widdop^*

From the Department of Pharmacology, Monash University, Melbourne, Australia.

^* To whom correspondence should be addressed. E-mail: robert.widdop{at}med.monash.edu.au.

Abstract--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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