VASODEPRESSOR ACTIONS OF ANGIOTENSIN-(1-7) UNMASKED DURING COMBINED TREATMENT WITH LISINOPRIL AND LOSARTAN

Blockade of angiotensin II (Ang II) function during 8 days of oral the rapy with lisinopril (20 mg/kg) and losartan (10 mg/kg) normalized the arterial pressure (112+/-3/70+/-3 mm Hg) and raised the plasma concen trations of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] of 2 1 male spontaneously hypertensive rats (SHR). Treated animals were the n given a 15-minute infusion of either mouse immunoglobulin G(1) or a specific monoclonal Ang-(1-7) antibody while their blood pressure and heart rate were recorded continuously in the awake state, The concentr ations of Ang II and Ang-(1-7) in arterial blood were determined by ra dioimmunoassay, Infusion of the Ang-(1-7) antibody caused significant elevations in mean arterial pressure that were sustained for the durat ion of the infusion and were accompanied by transient bradycardia. Alt hough the hemodynamic effects produced by infusion of the Ang-(1-7) an tibody had no effect on plasma levels of Ang II, they caused a twofold rise in the plasma concentrations of Ang-(1-7). A presser response of similar magnitude and characteristics was obtained in a separate grou p of SHR treated with the combination of lisinopril and losartan for 8 days during an infusion of [Sar(1)-Thr(8)]Ang II, The presser respons e induced by the administration of this competitive, non-subtype-selec tive Ang II receptor blocker was not modified by pretreatment of the r ats with an angiotensin type-2 (AT(2)) receptor blocker (PD123319). Pl asma concentrations of Ang II and Ang-(1-7) were not changed by the ad ministration of [Sar(1)-Thr(8)]Ang II either in the absence or in the: presence of PD123319 pretreatment, These results are the first to ind icate an important contribution of Ang-(1-7) in mediating the vasodila tor effects caused by combined inhibition of angiotensin-converting en zyme and AT(1) receptors. The comparable results obtained by administr ation of[Sar(1)-Thr(8)]Ang II suggest that the vasodepressor effects o f Ang-(1-7) during the combined treatment is modulated by a non-AT(1)/ AT(2) angiotensin subtype receptor.