Angiotensin-(1-7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats.
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 microg/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 AT(2)R 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 microg/kg IV) or the NO synthase inhibitor Nomega-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.
Walters
Pia E
PE
Department of Pharmacology, Monash University, Melbourne, VIC, Australia.
Gaspari
Tracey A
TA
Widdop
Robert E
RE
D000803:Angiotensin I / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004338:Drug Combinations; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004338:Drug Combinations; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; C073402:PD 123319; D000803:Angiotensin I; C118790:angiotensin I (1-7); C081643:candesartan