AT2 Receptor Stimulation Enhances Antihypertensive Effect of AT1 Receptor Antagonist in Hypertensive Rats

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 1999-11, Vol.34 (5), p.1112-1116
• Main Authors: Barber, Melissa N, Sampey, Donella B, Widdop, Robert E
• Format: Article
• Language: English
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Experimental diseases; Medical sciences
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.34.5.1112

In the present study, we investigated the role of the angiotensin type 2 (AT2) receptor in the regulation of blood pressure in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We tested the hypothesis that AT2 receptor activation may contribute to the antihypertensive effects of angiotensin type 1 (AT1) 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 combinationsthe AT1 receptor antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, the AT2 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 AT2 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 AT2 receptor antagonist PD123319 (50 μg/kg per minute) with the candesartan/CGP42112 combination. Collectively, these data suggest that in SHR, AT2 receptor activation can facilitate the initial depressor response caused by an AT1 receptor antagonist.