Role of nitric oxide synthase, cytochrome P-450, and cyclooxygenase in the inotropic and lusitropic cardiac response to increased coronary perfusion.
Although studies have reported that increase in coronary perfusion (CP) results in positive inotropic effects, the underlying mechanisms of these actions and possible alterations in myocardial diastolic function are not well defined. Hypothesis was that nitric oxide (NO) and derivatives of cytochrome (CYT) P-450 or cyclooxygenase (COX) might contribute to interplay between coronary and myocardial compartments in these conditions. Using isovolumically contracting, isolated perfused hamster heart model, coronary flow (CF) was increased mechanically, stepwise in the physiologic range (+2 to +10 ml/min), before and after inhibition of NO synthase by NG-nitro-l-arginine methyl ester (l-NAME) (30 microM), CYT P-450 by SKF525A (1 microM), or COX by indomethacin (10 microM). CP pressure, left ventricular systolic pressure (VSP) and ventricular diastolic pressure (VDP), and heart rate (HR) were monitored continuously during the experiments. Mechanical increases in CF resulted in gradual change in CP pressure (+20% to +100%), left VSP (+5% to +40%) and VDP (+2% to +25%), whereas HR was not affected. In presence of l-NAME, the positive inotropic response and negative lusitropic effect of CF changes were similar. Exposure to SKF525A did not modify cardiac response to mechanical increases in CF. In presence of COX inhibitor indomethacin, left VSP rose to a level similar to that observed in control conditions, whereas VDP deteriorated further. These results suggest that mediators originating from NO synthase, CYT P-450, or COX do not contribute to positive inotropic response elicited by increased CP. However, COX derivatives seem to attenuate impairment of myocardial relaxation observed in these conditions. Such findings may have implications in development of therapeutics for patients with myocardial diastolic dysfunction.
Beaucage
Pierre
P
Département de pharmacologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada.
Massicotte
Julie
J
Jasmin
Gaëtan
G
Dumont
Louis
L
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008647:Mesocricetus; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases