AT 2 Receptor Stimulation Enhances Antihypertensive Effect of AT 1 Receptor Antagonist in Hypertensive Rats

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Abstract
—In the present study, we investigated the role of the angiotensin type 2 (AT 2 ) receptor in the regulation of blood pressure in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We tested the hypothesis that AT 2 receptor activation may contribute to the antihypertensive effects of angiotensin type 1 (AT 1 ) receptor antagonists. Mean arterial pressure (MAP) and heart rate were measured over a 4-day protocol in various groups of rats that received the following drug combinations: the AT 1 receptor antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, the AT 2 receptor agonist CGP42112 (1 μg/kg per minute) alone, and candesartan plus CGP42112 . In both SHR and WKY, 4-hour infusions of saline and CGP42112 alone did not alter MAP. In WKY, both doses of candesartan alone caused small decreases in MAP, which were similar when combined with CGP42112 . In SHR, candesartan (0.1 mg/kg) caused an immediate, marked decrease in MAP, which was unaffected when combined with CGP42112 . By contrast, in separate SHR, a 10-fold lower dose of candesartan (0.01 mg/kg) caused a slower-onset depressor response, which was enhanced when combined with CGP42112 . The involvement of AT 2 receptors was confirmed in another group of SHR, since this facilitation of the antihypertensive effect of candesartan by CGP42112 was abolished by the coinfusion of the AT 2 receptor antagonist PD123319 (50 μg/kg per minute) with the candesartan/CGP42112 combination. Collectively, these data suggest that in SHR, AT 2 receptor activation can facilitate the initial depressor response caused by an AT 1 receptor antagonist.

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