Differential effects of glibenclamide on responses to thromboxane A2 mimic, U46619, in the pulmonary and hindquarters vascular beds of the cat

Abstract

The inhibitory effects of the oral sulfonylurea, glibenclamide, on vasoconstrictor responses to the thromboxane A 2 mimic, U46619, were investigated in the pulmonary and hindquarters vascular beds of the cat under constant flow conditions. When lobar arterial tone was at resting conditions (14±2 mm Hg), intralobar injections of U46619, prostaglandin F 2 α , prostaglandin D 2, angiotensin II, norepinephrine, and BAY K 8644 caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following an intralobar infusion of glibenclamide (5 mg/kg), vasoconstrictor responses to U46619, prostaglandin F 2 α and prostaglandin D 2 were significantly reduced, whereas vasoconstrictor responses to norepinephrine and angiotensin II were not altered and responses to BAY K 8644 were significantly enhanced. When tone in the pulmonary vascular bed was raised to a high steady level (36±3 mm Hg), glibenclamide in a dose of 5 mg/kg i.a. markedly attenuated responses to injections of U46619 and reduced the vasodilator responses to the K +-ATP channel opener, levcromakalim, whereas responses to acetylcholine and S-nitroso- N-acetylpenicillamine (SNAP), a nitric oxide donor, were not changed. In the hindquarters vascular bed of the cat, administration of glibenclamide in a dose of 5 mg/kg i.a. had no significant effect on vasoconstrictor responses to U46619, norepinephrine or angiotensin II. Hindquarters vasodilator responses to levcromakalim, but not to nitric oxide, were decreased significantly following administration of glibenclamide. These data suggest that glibenclamide, in addition to inhibiting K +-ATP channels, has thromboxane A 2 receptor blocking activity in the pulmonary vascular bed of the cat. These data also suggest that vasoconstrictor responses to U46619 may be mediated by different thromboxane A 2 receptors with different binding affinities in the pulmonary and in the hindquarters vascular beds of the cat.