LOSARTAN REDUCES PHENYLEPHRINE CONSTRICTOR RESPONSE IN AORTIC RINGS FROM SPONTANEOUSLY HYPERTENSIVE RATS - ROLE OF NITRIC-OXIDE AND ANGIOTENSIN-II TYPE-2 RECEPTORS

Nitric oxide seems to be involved in the mechanisms underlying the ant ihypertensive and renal responses of losartan in spontaneously hyperte nsive rats (SHR). We investigated the contribution of nitric oxide to the effect of this angiotensin II (Ang II) type 1 (AT(1)) receptor ant agonist on the constrictor response of phenylephrine in aortic rings f rom SHR. Furthermore, since it has been suggested that Ang II could bi nd to unblocked AT(2) receptors, during administration of an AT(1) rec eptor antagonist, we also studied the effect of the AT(2) receptor ant agonist PD 123319 on the contractile response to phenylephrine in aort ic rings from SHR. To this end, we studied dose-response curves of phe nylephrine (10(-9) to 10(-5) mol/L) in the presence and absence of los artan (10(-9), 10(-7), and 10(-5) mol/L) in SHR aortic rings. Preincub ation with losartan reduced the constrictor response to phenylephrine but not to KCl (10 to 120 mmoI/L) in a dose-dependent manner. On the o ther hand, the presence of captopril (10(-5) mol/L) in the incubation medium did not alter the response to phenylephrine, even at the dose o f 10(-3) mol/L. The reduced response to phenylephrine in the presence of losartan was abolished in both endothelium-denuded rings and rings treated with a nitric oxide synthesis inhibitor. A similar situation w as observed in PD 123319-pretreated rings, in which the effect of losa rtan on the contractile response to phenylephrine was reversed. Losart an was not able to stimulate the production of aortic cGMP compared wi th the control group. Likewise, losartan did not modify the relaxing r esponses to either acetylcholine or sodium nitroprusside in phenylephr ine-preconstricted aortic rings. Furthermore, losartan did not alter i sometric tension in aortic rings in either basal or phenyleph rine-pre constricted conditions. These data demonstrate that Ang II potentiates the vasoconstriction induced by phenylephrine through the stimulation of AT, receptors. Moreover, AT(2) receptors and nitric oxide appear t o be involved in this effect.