DIFFERENTIAL-EFFECTS OF GLIBENCLAMIDE ON RESPONSES TO THROMBOXANE A2 MIMIC, U46619, IN THE PULMONARY AND HINDQUARTERS VASCULAR BEDS OF THE CAT

The inhibitory effects of the oral sulfonylurea, glibenclamide, on vas oconstrictor responses to the thromboxane A(2) mimic, U46619, were inv estigated in the pulmonary and hindquarters vascular beds of the cat u nder constant flow conditions. When lobar arterial tone was at resting conditions (14 +/- 2 mm Hg), intralobar injections of U46619, prostag landin F-2 alpha prostaglandin D-2, angiotensin II, norepinephrine, an d BAY K 8644 caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following an intralobar infusio n of glibenclamide (5 mg/kg), vasoconstrictor responses to U46619, pro staglandin F-2 alpha and prostaglandin D-2 were significantly reduced, whereas vasoconstrictor responses to norepinephrine and angiotensin I l were not altered and responses to BAY K 8644 were significantly enha nced. When tone in the pulmonary vascular bed was raised to a high ste ady level (36 +/- 3 mm Hg), glibenclamide in a dose of 5 mg/kg i.a. ma rkedly attenuated responses to injections of U46619 and reduced the va sodilator responses to the K+-ATP channel opener, levcromakalim, where as responses to acetylcholine and S-nitroso-N-acetylpenicillamine (SNA P), a nitric oxide donor, were not changed. In the hindquarters vascul ar bed of the cat, administration of glibenclamide in a dose of 5 mg/k g i.a. had no significant effect on vasoconstrictor responses to U4661 9, norepinephrine or angiotensin II. Hindquarters vasodilator response s to levcromakalim, but not to nitric oxide, were decreased significan tly following administration of glibenclamide. These data suggest that glibenclamide, in addition to inhibiting K+-ATP channels, has thrombo xane A(2) receptor blocking activity in the pulmonary vascular bed of the cat. These data also suggest that vasoconstrictor responses to U46 619 may be mediated by different thromboxane A(2) receptors with diffe rent binding affinities in the pulmonary and in the hindquarters vascu lar beds of the cat. (C) 1997 Elsevier Science B.V.