We investigated the effects of the exposure of the rat vascular system to nitric oxide (NO), using infusion of either NO donor sodium nitroprusside (SNP) or S-nitroso-acetyl-DL-penicillamine (SNAP) on mean arterial pressure (MAP) responses to vasoconstrictors (phenylephrine, angiotensins I and II) and to vasodilators (bradykinin, acetylcholine, SNP, and iloprost). SNP (250 nmol/kg/ min) or SNAP (85 nmol/kg/min) infused for 30 min decreased MAP by 40 to 60 mm Hg. MAP returned to normal levels 5 to 10 min after the end of infusion. After infusion of SNP or SNAP the effects of phenylephrine, angiotensin I, and angiotensin II were reduced by 40 to 80%, whereas the responses to bradykinin or acetylcholine were enhanced by 50 to 80%. These changes in vascular responsiveness persisted for at least 24 h after the SNP infusion. Pretreatment with either tetraethylammonium (360 micromol/kg) or 4-aminopyridine (4-AP; 1 micromol/kg) did not alter the effects of phenylephrine or bradykinin in control animals, but prevented SNP-induced changes in responsiveness to phenylephrine or bradykinin. On the other hand, administration of tetraethylammonium, even 24 h after SNP infusion, reversed hyporesponsiveness to phenylephrine, whereas 4-AP was ineffective. Tetraethylammonium and 4-AP did not alter the increased responses to bradykinin. Glibenclamide was without effect in any situation. These results indicate that NO-induced changes on vascular responsiveness to vasoconstrictors and vasodilators are much more profound and long-lasting than described previously and that the effects of NO appear to be, at least in part, mediated by persistent activation of a tetraethylammonium-sensitive population of K+ channels.