Differential effects of the calcium antagonist mibefradil in epicardial and intramyocardial coronary arteries.
The efficacy of vasodilation depends on the drug and the contractile agonist involved. Furthermore, vasodilation also may be detrimental (i.e., coronary steal), possibly depending on the anatomic site and/or action of the vasodilator. We investigated the effects of Ca2+ antagonism in porcine epicardial and intramyocardial coronary arteries suspended in organ chambers filled with physiological salt solution (95% O2/5% CO2, 37 degrees C); isometric tension was measured. In epicardial vessels contracted with KCl, the thromboxane analogue U 46619, or endothelin-1 (ET-1), relaxations to the Ca2+ antagonist mibefradil were most effective after precontraction with KCl, followed by U 46619 and ET-1. In intramyocardial vessels, the contraction to KCl, U 46619, and particularly ET-1, was much more effectively inhibited by mibefradil than in epicardial arteries. In vessels preincubated with mibefradil, the drug was moderately effective in preventing the initiation of contractions. Preincubation with the inhibitor of nitric oxide production (NO), L omega-nitro arginine methyl ester (L-NAME) or endothelium removal, did not increase relaxations to mibefradil. However, epicardial but not intramyocardial vessels incubated with mibefradil exhibited enhanced relaxations to bradykinin (BK) and sodium nitroprusside (SNP) as compared with control. Thus, Ca2+ antagonism is particularly effective in intramyocardial coronary arteries. In addition to its inhibitory effects on contractility, calcium antagonism facilitates the effects of endothelium-derived NO in epicardial coronaries at the level of vascular smooth muscle (VSM).
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D020748:Mibefradil; D009569:Nitric Oxide / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D013552:Swine; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D016232:Endothelins; D013764:Tetrahydronaphthalenes; D014665:Vasodilator Agents; D009599:Nitroprusside; D020748:Mibefradil; D009569:Nitric Oxide; D011189:Potassium Chloride; D000109:Acetylcholine; D002118:Calcium