Evidence that imidazol(id)ine- and sulphonylurea-based antagonists of cromakalim act at different sites in the rat thoracic aorta.
1. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mmol/L), and full concentration-relaxation curves constructed to cromakalim (0.01-30 mumol/L) in the absence and presence of increasing concentrations of glibenclamide, glipizide, tolbutamide (the sulphonylureas), alinidine (an imidazolidine), phentolamine (an imidazoline), and chlorpromazine (the phenothiazine derivative). Whereas the active sulphonylureas, glibenclamide and glipizide, displayed classical competitive antagonism, the remaining compounds (alinidine, phentolamine and chlorpromazine) caused shifts in the cromakalim concentration-effect curves associated with a reduction in the slope and maximum response. 2. A single concentration of each antagonist was selected and the shift in the concentration-effect curve determined. The possibility that sulphonylurea and imidazol(id)ine antagonists act at different sites was tested using the concentration-ratio method for combined antagonists described by Paton and Rang (1965). The combination of alinidine and phentolamine (collectively called imidazol(id)ines) at a number of different concentrations (10-30 mumol/L) resulted in a concentration-ratio to cromakalim which was additive, suggesting a common site of action. Similar results were obtained when examining the interaction between two sulphonylurea compounds (glibenclamide and glipizide). However, the interaction between sulphonylurea (glibenclamide) and imidazol(id)ine (alinidine) produced concentration-ratios which were multiplicative, suggesting a different or additional site of action for compounds from these two groups. Results indicated that chlorpromazine was able to block cromakalim via an action at the same site where alinidine and phentolamine act.(ABSTRACT TRUNCATED AT 250 WORDS)
Challinor
J L
JL
Baker Medical Research Institute, Prahran, Victoria, Australia.
McPherson
G A
GA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D001578:Benzopyrans / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019806:Cromakalim; D004347:Drug Interactions; D005913:Glipizide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010646:Phentolamine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D001578:Benzopyrans; D007093:Imidazoles; D015221:Potassium Channels; D011758:Pyrroles; D013453:Sulfonylurea Compounds; D014665:Vasodilator Agents; D019806:Cromakalim; D014044:Tolbutamide; C022192:alinidine; D003000:Clonidine; D005905:Glyburide; D002746:Chlorpromazine; D005913:Glipizide; D010646:Phentolamine