AT(2) receptor stimulation enhances antihypertensive effect of AT(1) receptor antagonist in hypertensive rats

In the present study, we investigated the role of the angiotensin type 2 (A T(2)) receptor in the regulation of blood pressure in spontaneously hyperte nsive rats (SHR) and Wistar-Kyoto rats (WKY). We tested the hypothesis that AT(2) receptor activation may contribute to the antihypertensive effects o f angiotensin type 1 (AT(1)) receptor antagonists. Mean arterial pressure ( MAP) and heart rate were measured over a 4-day protocol in various groups o f rats that received the following drug combinations: the AT(1) receptor an tagonist candesartan (0.01 or 0.1 mg/kg IV) alone, the AT(2) receptor agoni st CGP42112 (1 mu g/kg per minute) alone, and candesartan plus CGP42112. In both SHR and WKY, 4-hour infusions of saline and CGP42112 alone did not al ter 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 as lower-onset depressor response, which was enhanced when combined with CGP42112. The involvement of AT(2) re ceptors was confirmed in another group of SHR, since this facilitation of t he antihypertensive effect of candesartan by CGP42112 was abolished by the coinfusion of the AT(2) receptor antagonist PD123319 (50 mu g/kg per minute ) with the candesartan/CGP42112 combination. Collectively,these data sugges t that in SHR, AT(2) receptor activation can facilitate the initial depress or response caused by an AT(1) receptor antagonist.