Effects of cromakalim and pinacidil on large epicardial and small coronary arteries in conscious dogs.
The effects of i.v. bolus administration of cromakalim (1-10 micrograms/kg) and pinacidil (3-100 micrograms/kg) on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin (0.03-10 micrograms/kg). Nitroglycerin, up to 0.3 micrograms/kg, selectively increased circumflex artery diameter (CxAD) without simultaneously affecting any other cardiac or systemic hemodynamic parameter. In contrast, cromakalim and pinacidil at all doses and nitroglycerin at doses higher than 0.3 micrograms/kg simultaneously and dose-dependently increased CxAD, coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure. Cromakalim was approximately 8- to 9.5-fold more potent than pinacidil in increasing CxAD. Vasodilation of large and small coronary vessels and hypotension induced by cromakalim and pinacidil were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug-induced tachycardia was abolished. When circumflex artery blood flow was maintained constant, the increases in CxAD induced by cromakalim (10 micrograms/kg), pinacidil (30 micrograms/kg) and nitroglycerin (10 micrograms/kg) were reduced by 68 +/- 7, 54 +/- 9 and 1 +/- 1%, respectively. Thus, whereas nitroglycerin preferentially and flow-independently dilates large coronary arteries, cromakalim and pinacidil dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors-mediated rise in myocardial metabolic demand. Finally, two mechanisms at least, direct vasodilation and flow dependency, are involved in the cromakalim- and pinacidil-induced increase in CxAD.
Giudicelli
J F
JF
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicetre, France.
la Rochelle
C D
CD
Berdeaux
A
A
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D019806:Cromakalim; D004285:Dogs; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology; D020110:Pinacidil; D011758:Pyrroles / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D006146:Guanidines; D011758:Pyrroles; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; D019806:Cromakalim; D020110:Pinacidil; D005996:Nitroglycerin