Endothelial release of nitric oxide (NO) is an important control mechanism of vascular tone. Nitric oxide released from the endothelial lining of the coronary vasculature also influences myocardial performance. In isolated papillary muscles and in ejecting guinea-pig hearts, substance P, which releases NO from endothelial cells, shortened myocardial contraction through a relaxation hastening effect. Similar findings were observed with exogenous NO-donor substances such as sodium nitroprusside.

These observations were recently extended to the clinical setting because of demonstration in man of myocardial contractile effects of both exogenous and endogenous NO. In healthy control subjects, bicoronary infusion of the NO-donor sodium nitroprusside, reduced LV peak and end-systolic pressures through a relaxation-hastening effect and increased LV diastolic distensibility. Similar observations were made in transplant recipients and in patients with aortic stenosis. The occasional observation of a larger LV end-diastolic volume during intravenous NO-donor infusion supports the presence of direct myocardial relaxant effects of NO even during intravenous administration of NO-donors. Direct myocardial effects of NO could not be demonstrated in normal subjects or in heart failure patients during inhalation of NO probably because of rapid inactivation of NO by hemoglobin in the pulmonary circulation. In healthy control subjects and in transplant recipients, bicoronary infusion of substance P influenced LV performance in a similar way as bicoronary infusion of sodium nitroprusside by reducing LV peak and end-systolic pressures, by hastening the onset of LV relaxation and by increasing LV diastolic distensibility. These effects were attributed to a paracrine myocardial action of NO, released by substance P from the coronary endothelium and were potentiated in transplant recipients by simultaneous intracoronary infusion of L-arginine or by intravenous infusion of dobutamine. Because of recent demonstration of myocardial expression of inducible NO-synthase in certain cardiomyopathies, the cardiodepression observed in these conditions was linked to myocardial production of NO. The functional consequence of NO produced by inducible NO-synthase remains however unclear because, in contrast to NO derived from NO-donor or endothelial cells, expression of inducible NO-synthase impairs myocardial relaxation.

Myocardial relaxant effects of endothelially released NO are relevant to diastolic LV performance both acutely and chronically. Acute increases in LV workload augment coronary flow and increase endothelial release of NO, which through its paracrine myocardial action lowers LV filling pressures to promote subendocardial perfusion and hasten the onset of LV relaxation to prolong diastolic coronary perfusion time. Chronic enhancement of coronary endothelial release of NO as a result of chronic exercise or pacing could relate to the increased LV diastolic distensibility observed in athlete’s heart or in tachycardia-induced cardiomyopathy. Chronic reduction of coronary endothelial release of NO, as occurs with aging or after transplantation, could explain reduced diastolic LV distensibility in the elderly or in transplant recipients.