Influence of T-type Ca2+ (mibefradil) and Cl- (indanyloxyacetic acid 94) channel antagonists on alpha1-adrenoceptor mediated contractions in rat aorta.
The effects of the T-type and L-type Ca2+ channel antagonists, mibefradil and nifedipine, respectively, and those of a Cl- channel antagonist, indanyloxyacetic acid 94, on mechanical responses elicited by selective activation of alpha1-adrenoceptors using cirazoline were examined in rat isolated aortic rings. The presence of mibefradil (300 nM), indanyloxyacetic acid, 94 (30 microM) and nifedipine (300 nM) alone inhibited mechanical responses elicited by cirazoline. The concentration-response curves to cirazoline were displaced to the right with significant increases in the EC50 and significant depressions of the maximal responses in the presence of the individual agents mibefradil, indanyloxyacetic acid 94, or nifedipine. A combination of mibefradil and indanyloxyacetic acid 94 further inhibited the mechanical activity produced by cirazoline. The further reduction in the maximal response to cirazoline, in the presence of mibefradil and nifedipine, was insignificant when compared with the effects of nifedipine alone. In addition, maximal mechanical responses produced by cirazoline were not significantly affected by a combination of nifedipine and indanyloxyacetic acid 94 when compared with either nifedipine alone or mibefradil and indanyloxyacetic acid 94 combined. Our current findings indicate that mibefradil, indanyloxyacetic acid 94, and nifedipine can inhibit cirazoline-induced contractions to a varying degree. Moreover, based on our present data it would be reasonable to suggest that the contribution of T-type versus L-type Ca2+ channels to contractile responses obtained with cirazoline are approximately 21% and 35%, respectively, of the Emax. It would appear that L-type Ca2+ channels play a greater role in processes that are involved in excitation-contraction coupling subsequent to stimulation of alpha1-adrenoceptors. In addition, Cl- channels also appear to be involved in the process of contraction following alpha1-adrenoceptor activation.
Duggan
J A
JA
Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
Tabrizchi
R
R
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000502:physiology; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006016:Glycolates / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020748:Mibefradil / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D018118:Chloride Channels; D004232:Diuretics; D006016:Glycolates; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D020748:Mibefradil; C015765:MK 473; D009543:Nifedipine; C014282:cirazoline