Role of the angiotensin II AT2-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 angiotensin II (Ang II) AT(2) receptors (AT(2)) in the control of blood pressure (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 preliminarily salt-restricted (SR) to enhance circulating and tissue renin-angiotensin system activity. To explore whether AT(2) plays a role in BP regulation, the BP effects of the selective AT(2) end AT(1) receptor antagonists PD123319 (PD) (50 mu g/kg/min) and losartan (Los) (10 mg/kg/day), were studied. 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 were also studied in bilaterally nephrectomized rats (NX). All treatments were 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). In 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 offsets the BP-lowering effect of losartan and suggest that AT(2) receptors contribute to the hypotensive effects of losartan. Thus, AT(1) receptor antagonists such as losartan, which are becoming widely used in the clinical treatment of hypertension, may reduce BP not only by blockade of AT(1) receptors, but also through the stimulation of AT(2), receptors by the excess of angiotensin II. J Hypertens 1998, 16:2039-2043 (C) 1998 Lippincott Williams & Wilkins.