Effects of mibefradil on large and small coronary arteries in conscious dogs: role of vascular endothelium.
The systemic and coronary hemodynamic effects of mibefradil, a "nondihydropyridine" calcium antagonist acting on both L- and T-type calcium channels, were investigated in chronically instrumented conscious dogs before and after local endothelium removal of the circumflex coronary artery by angioplasty. After intravenous infusion, mibefradil (0.2 mg kg-1 min-1) decreased mean arterial blood pressure (MAP; -15 +/- 1%), increased heart rate (HR; 58 +/- 9%), and coronary blood flow (CBF; 103 +/- 14%) (all p < 0.05). Before endothelium removal, mibefradil increased the diameter of the left circumflex epicardial coronary artery (LCX) by 7.8 +/- 1.2% from 3,006 +/- 219 microns, but this dilatory effect was significantly reduced by 69% (p < 0.001) and 45% (p < 0.01), 3 and 21 days after endothelium removal, respectively. Mibefradil also reduced by 46% (p < 0.01) the potent coronary constrictor effect of ergonovine (300 micrograms intravenous bolus). These results demonstrate that mibefradil is a potent dilator of large and small coronary arteries in conscious dogs and that approximately 30% of its dilatory effect on large coronary artery is endothelium-independent. In addition, mibefradil prevents ergonovine-induced epicardial coronary constriction.
Karila-Cohen
D
D
Départment de Pharmacologie, Faculté de Médecine Paris-Sud, France.
Dubois-Randé
J L
JL
Giudicelli
J F
JF
Berdeaux
A
A
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects*; D004874:Ergonovine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D020748:Mibefradil; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D014665:Vasodilator Agents; D020748:Mibefradil; D004874:Ergonovine