The objective of this study was to examine the effects of long-term antihypertensive therapy on blood pressure and vascular responses of resistance arteries during prolonged inhibition of nitric oxide synthesis. Four groups of 6-week-old Wistar-Kyoto rats were treated with either placebo as controls or Nitrogenomega-nitro-L-arginine methyl ester (L-NAME) alone or in combination with verapamil or with trandolapril. Drugs were given orally for 6 weeks or short-term in vitro to vessels obtained from untreated rats. Endothelium-dependent and -independent relaxations as well as contractions were studied in isolated perfused mesenteric and renal arteries with an arteriograph. Kidney nitric oxide synthase activity was also evaluated. Verapamil and trandolapril prevented the increase in systolic blood pressure and the blunted acetylcholine-induced relaxations that occurred with L-NAME treatment without improving the nitric oxide synthase activity. Both antihypertensive regimens also normalized sensitivity to sodium nitroprusside, which was enhanced by L-NAME. In contrast, short-term in vitro preincubation with verapamil or trandolaprilat in the presence of L-NAME did not improve the impaired relaxations to acetylcholine. Long-term but not short-term therapy with a calcium antagonist or angiotensin-converting enzyme inhibitor improved the blunted endothelium-dependent relaxations in nitric oxide-deficient hypertension. These findings strongly suggest that the role of other vasodilator systems, which normally do not regulate vascular tone, is enhanced with long-term but not short-term treatment with these drugs. These observations emphasize the potential importance of these treatments in the management of hypertension in which nitric oxide production is diminished. (Hypertension. 1996;27:25-31.)