Effect of the New Nitrate Ester ITF 296 on Coronary and Systemic Hemodynamics in the Conscious Dog

Abstract

The coronary and systemic hemodynamic effects of the novel nitrate ester ITF 296 were investigated in conscious, resting dogs and compared with nitroglycerin and nicorandil. ITF 296 at 1-25 micrograms/kg i.v. elicited selective, long-lasting, and dose-dependent increases in large epicardial coronary artery diameter (CD) without affecting coronary blood flow (CBF) or coronary vascular resistance (CVR). Blood pressure (BP) and heart rate (HR) were also unaltered. At 125 micrograms/kg, ITF 296 further increased CD but simultaneously reduced CVR and mean aortic pressure and increased CBF and HR. Nitroglycerin 1-25 micrograms/kg induced a shorter and less selective dilatation of large coronary conductance arteries, as it was accompanied by a decrease in CVR at all doses used. Nicorandil produced a selective increase in left circumflex CD only at the lowest dose used (10 micrograms/kg), whereas higher doses were effective on both CD and CVR. ITF 296 significantly reduced left ventricular end-diastolic pressure and increased stroke volume (SV) and cardiac output (CO) at doses that did not alter HR or BP, indicating an increase in cardiac efficiency. In contrast, the increases in CO produced by nitroglycerin and nicorandil were dependent on the augmentation of HR, because SV was unchanged at all doses used. Nitroglycerin dose-dependently decreased BP, whereas ITF 296 reduced BP only at the highest dose used. In conclusion, ITF 296 induces a selective, flow-independent dilatation of large coronary conductance arteries without affecting the tone of small coronary resistance vessels or systemic hemodynamics over a broad range of doses. An equally selective effect was elicited by nicorandil only at the lower dose used, whereas no selective effect of nitroglycerin on the diameter of coronary conductance arteries was seen at the doses utilized in this study.