Role of the angiotensin II AT(2)-subtype receptors in the blood pressure-lowering effect of losartan in salt-restricted rats

Objective The aim of this study was to evaluate the potential role of the a ngiotensin II (Ang II) AT(2) receptors (AT(2)) in the control of blood pres sure (BP) in the rat and the effects of AT(2) receptors on BP during AT(1) receptor (AT(1)) antagonism. Methods The study was performed in 52 Sprague-Dawley rats, which were preli minarily salt-restricted (SR) to enhance circulating and tissue renin-angio tensin system activity. To explore whether AT(2) plays a role in BP regulat ion, the BP effects of the selective AT(2) end AT(1) receptor antagonists P D123319 (PD) (50 mu g/kg/min) and losartan (Los) (10 mg/kg/day), were studi ed. Seven rats were used as a control group. To define whether AT(2) plays a role in the BP response observed during AT(1) antagonism, 17 Los treated rats were divided into two groups: seven were treated with both antagonists (Los + PD) and 10 rats received Los + vehicle. The effects of both drugs w ere also studied in bilaterally nephrectomized rats (NX). All treatments we re maintained for 1 week. Results Los reduced BP significantly in both intact (P < 0.001) and NX (P < 0.05) rats, while PD increased BP in intact and NX rats (both P< 0.001). I n the Los + PD group BP levels were significantly higher (P < 0.001 vs Los and Los + vehicle, P = ns vs pretreatment), while vehicle infusion did not modify the BP response to Los. Conclusion The results show that in salt-restricted rats AT(2) blockade off sets the BP-lowering effect of losartan and suggest that AT(2) receptors co ntribute to the hypotensive effects of losartan. Thus, AT(1) receptor antag onists such as losartan, which are becoming widely used in the clinical tre atment of hypertension, may reduce BP not only by blockade of AT(1) recepto rs, but also through the stimulation of AT(2), receptors by the excess of a ngiotensin II. J Hypertens 1998, 16:2039-2043 (C) 1998 Lippincott Williams & Wilkins.