The thromboxane A2 and K(ATP) channel antagonist actions of a series of sulphonylurea derivatives in the pig coronary artery.
The ability of a series of sulphonylurea derivatives to antagonise the vasorelaxant actions of the ATP-dependent K+ channel (K(ATP)) opener, levcromakalim, and the vasoconstrictor responses of the thromboxane A2 mimetic, U46619, were assessed in the pig coronary artery. The sulphonylurea derivatives of glibenclamide caused a rightward shift in the concentration-vasorelaxant response curve obtained to levcromakalim in arterial segments pre-constricted with acetylcholine (0.5 microM). From these shifts pK(B) were calculated to estimate the potency of these compounds as levcromakalim antagonists. Similarly U46619 concentration-vasoconstrictor responses curves were constructed in the absence and in the presence of a sulphonylurea derivative and pK(B) values calculated. Regression analysis of pK(B) values showed that there was a significant correlation between the potency of these compounds in the two systems studied indicating similar structure-activity relationships apply in both cases. That sulphonylureas regulate K(ATP) channel opening is well known and they do so through a specific receptor associated with the channel. The results obtained in this study may indicate that a sulphonylurea receptor may also be associated with thromboxane A2 excitation-contraction coupling.
McPherson
G A
GA
Department of Pharmacology, Monash University, Clayton, Victoria, Australia. Grant.McPherson@med.monash.edu.au
Choi
R T
RT
Kong
D C
DC
Iskander
M N
MN
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors*; D003331:Coronary Vessels / Q000187:drug effects; D019806:Cromakalim; D005905:Glyburide / Q000031:analogs & derivatives / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011758:Pyrroles / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors*
D001578:Benzopyrans; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D011758:Pyrroles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019806:Cromakalim; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005905:Glyburide; C013289:tetraphenylphosphonium