To define the role of endogenous prostaglandin (PG) synthesis in the vasodilator response to minoxidil (MNX), whole body and regional hemodynamics were measured in conscious, MNX-pretreated dogs before and after the administration of the cyclooxygenase inhibitor indomethacin (INDO). Twenty minutes after an i.v. dose of 2.0 mg/kg, INDO did not affect the reductions in mean arterial pressure and total peripheral resistance achieved with 1.0 mg/kg of MNX i.v. INDO appeared to selectively reverse MNX's vasodilation in the skin and stomach, as vascular resistance in these two tissues increased to pre-MNX levels. Since INDO also exerts a selective vasoconstriction in the skin and stomach of conscious, nonpretreated dogs (Humphrey and Zins, 1983), the fact that skin and stomach resistances were near baseline with this drug combination implies that MNX continues to exert a net vasodilation in these vascular beds. In contrast to INDO's negligible hemodynamic interactions, MNX's vasodilation was nearly completely reversed by continuous i.v. infusions of the direct vasoconstrictor arginine vasopressin (ADH) administered at a mean dose of 35 mU/kg/min. MNX's reversal by ADH was not matched by maximally effective i.v. infusions of the alpha-adrenergic agonist norepinephrine at a mean dose of 0.4 micrograms/kg/min. These results indicate that the sustained peripheral vasodilation seen with MNX in the conscious dog is not dependent upon the synthesis of endogenous, PG-like dilator substances, as defined by concomitant INDO administration.