Interspecies differences in thromboxane A2 receptors are distinguished by glibenclamide.
The ability of the thromboxane A2 receptor antagonist, GR32191 ([1R-[1alpha(Z),2beta3beta,5alpha]]-7-[5-[[(1,1'-biphe nyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid), and the sulphonylurea, glibenclamide, to antagonise contractions to the thromboxane A2 mimetic, U46619 ((15S)-hydroxy-11alpha,9alpha(epoxymethano)prosta-5Z, 13E-dienoic acid), were assessed in rat and guinea-pig isolated large (aorta) and small (mesentery and coronary) arteries. U46619 concentration-response curves were constructed in the absence and presence of GR32191 and glibenclamide and pKB values calculated. GR32191 caused significant rightward shifts in U46619 concentration-response curves and was a more potent antagonist in guinea-pig vessels (pKB approximately 9.4) than rat arteries (pKB approximately 7.9). Conversely, glibenclamide failed to inhibit contractions to U46619 in guinea-pig vessels but antagonised responses to U46619 in rat aorta (pKB = 6.1) and mesenteric artery (pKB = 6.3). In combination, GR32191 and glibenclamide caused a shift in the concentration-effect curve to U46619 in rat aorta that was additive. These results suggest that glibenclamide can discriminate between species differences in thromboxane A2 receptors and may exert its inhibitory effect upon U46619-mediated contractions at the level of the thromboxane A2 receptor.
Kemp
B K
BK
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
McPherson
G A
GA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001713:Biphenyl Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D017482:Receptors, Thromboxane / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity; D013895:Thoracic Arteries; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C060013:vapiprost; D005905:Glyburide