Emerging therapeutic targets in nitric oxide-dependent cardiac disease

Nitric oxide (NO) is a free radical gas that plays paracrine/autocrine and intracrine roles in maintaining physiological cardiovascular performance. In the coronary circulation, NO mediates endothelium-dependent vasodilator responses to shear stress and agonist-induced responses to neurohumoral stimulation. In the heart, NO modulates myocardial relaxation, β-adrenergic responses, mitochondrial respiration and substrate metabolism and excitation-contraction coupling. Endothelial dysfunction and the resulting decrease in the production, bioavailability and/or second messenger response-coupling has been implicated in coronary artery disease and complications associated with restenosis following coronary angioplasty, stent placement and coronary artery bypass grafting (CABG). However, there are a number of pathophysiological conditions (ischaemia-reperfusion, cardiac transplant rejection, myocarditis, sepsis) in which unregulated overproduction of NO and other reactive oxygen species (ROS) results in deleterious effects on cardiac function. Given the importance of NO in cardiac physiology/pathophysiology it may serve as a potential target for interventions aimed at deterring therapeutic failures of percutaneous or surgical treatments of cardiac disease as well as serving as a primary medical intervention. This review will examine the function of NO in mediating/modulating cardiac function, stressing the concept that, depending on the milieu, NO has the potential to exert either beneficial or deleterious effects on cardiac function. Moreover, this review will summarise studies in laboratory models and human studies in which NO activity, production, availability, or second messenger activation has been enhanced or inhibited in order to provide new insight for future targeting of this system for drug development. 2001