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EVIDENCE THAT IMIDAZOL(ID)INE‐ AND SULPHONYLUREA‐BASED ANTAGONISTS OF CROMAKALIM ACT AT DIFFERENT SITES IN THE RAT THORACIC AORTA
Author(s) -
Challinor Joanne L.,
McPherson Grant A.
Publication year - 1993
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.1993.tb01727.x
Subject(s) - cromakalim , glibenclamide , phentolamine , chemistry , pharmacology , aminophylline , medicine , endocrinology , propranolol , biochemistry , diabetes mellitus
SUMMARY 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 μmol/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 μmol/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. 3. The results from this study indicate that sulphonylurea—and imidazol(id)ine‐based K + channel antagonists interact at different sites to produce their observed antagonism of the vasorelaxation induced by cromakalim. These results indicate the possibility of multiple sites of action underlying the effects of compounds which antagonize the actions of K + channel opening drugs.