The effects of the administration of either the angiotensin converting enzyme (ACE) inhibitor, quinapril (10 mg/kg/day, orally), or the calcium antagonist, diltiazem (100 mg/kg/day, orally), on blood pressure (BP), renal function, and vascular reactivity in isolated perfused mesenteric beds were studied in rats treated for 8 weeks with the nitric oxide (NO ) synthesis inhibitor, iVG-nitro-Larginine methyl ester (LNAME, 40 mglkglday). The oral administration of LNAME significantly increased systolic BP values, which reached the levels of 186 t 7 mm Hg at week 8. Both quinapril and diltiazem reduced this, although the ACE inhibitor was more effective than the calcium antagonist. The chronic inhibition of NO resulted in an increase in water excretion whether or not the increase in systolic BP was prevented by the coadministration of either quinapril or diltiazem. At the end of the experiment, LNAMEtreated rats presented higher proteinuria than control rats (140 t 4 mg/24 hours v 21 t 1 mg/24 hours, P < .05). This elevated protein excretion was normalized by both antihypertensive drugs. None of the treatments was able to modify either natriuresis or plasma creatinine levels. Endothelium-dependent relaxations to acetylcholine (10 '12 to 10 mol/L) were comparable in all groups. However, the vasoconstriction induced by either the continuous infusion of phenylephrine (10 mol/L) or by a bolus of angiotensin II (1 nmol) was higher in the animals that received LNAME than in control ones. The antihypertensive therapy normalized the response to phenylephrine but not to angiotensin II. These data suggest that both quinapril and diltiazem are not only able to reduce BP elevation induced by the chronic administration of LNAME in rats, but also to prevent the renal damage and the hyperresponsiveness to phenylephrine induced by this NO synthesis inhibitor. Am J Hypertens 1996; 9:1077-1083

Nitric oxide seems to be involved in the mechanisms underlying the antihypertensive and renal responses of losartan in spontaneously hypertensive rats (SHR). We investigated the contribution of nitric oxide to the effect of this angiotensin II (Ang II) type 1 (AT1) receptor antagonist on the constrictor response of phenylephrine in aortic rings from SHR. Furthermore, since it has been suggested that Ang II could bind to unblocked AT2 receptors, during administration of an AT1 receptor antagonist, we also studied the effect of the AT2 receptor antagonist PD 123319 on the contractile response to phenylephrine in aortic rings from SHR. To this end, we studied dose-response curves of phenylephrine (10(-9) to 10(-5) mol/L) in the presence and absence of losartan (10(-9), 10(-7), and 10(-5) mol/L) in SHR aortic rings. Preincubation with losartan reduced the constrictor response to phenylephrine but not to KCl (10 to 120 mmol/L) in a dose-dependent manner. On the other hand, the presence of captopril (10(-5) mol/L) in the incubation medium did not alter the response to phenylephrine, even at the dose of 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 was observed in PD 123319-pretreated rings, in which the effect of losartan on the contractile response to phenylephrine was reversed. Losartan was not able to stimulate the production of aortic cGMP compared with the control group. Likewise, losartan did not modify the relaxing responses to either acetylcholine or sodium nitroprusside in phenylephrine-preconstricted aortic rings. Furthermore, losartan did not alter isometric tension in aortic rings in either basal or phenylephrine-preconstricted conditions. These data demonstrate that Ang II potentiates the vasoconstriction induced by phenylephrine through the stimulation of AT1 receptors. Moreover, AT2 receptors and nitric oxide appear to be involved in this effect.

The consequences of aging for endothelium-dependent and endothelium-independent relaxations of rings from spontaneously hypertensive rats are ameliorated by losartan treatment, suggesting that angiotensin II plays a role via type 1 receptors. The effects of losartan on senescent spontaneously hypertensive rats were due not only to its blood-pressure-lowering action but also to the blockade of specific mechanisms derived from angiotensin II type 1 receptor antagonism, which might involve an increase in availability of NO.

Angiotensin II seems to participate in the vasoconstriction induced by both endothelin-1 and the thromboxane A2 analogue through the stimulation of AT1 receptors in SHR aortic rings, because losartan inhibited this effect. Moreover, nitric oxide appears to be involved in this action of losartan.

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