New perspectives on therapeutic application of nitrates as vasodilator agents for severe chronic heart failure.

Although nitrates produce marked decreases in ventricular filling pressures in patients with severe heart failure, their therapeutic value has long been believed to be limited because they were thought to exert minimal arterial dilating effects. Recently, however, new conceptual approaches to vasodilator drugs have been developed that have challenged this traditional view. These new perspectives indicate that nitrates exert dilator actions on both the arterial and venous circulations, and reduce both preload and afterload; such balanced circulatory responses are particularly evident when large doses of these drugs are used. Cardiac output increases markedly with nitrates in patients with a greatly increased systemic vascular resistance before treatment or with significant mitral regurgitation. The major reason for the limited increases in cardiac output noted in previous studies is the inclusion of patients with heart failure whose pretreatment values for cardiac output were within normal limits; in these persons nitrates markedly activate neurohumoral vasoconstrictor mechanisms that counteract the arterial dilating actions of these drugs. Long-term nitrate therapy attenuates exercise-induced increases in pulmonary venous pressures, which permit patients to undergo repeated submaximal exercise with fewer symptoms; this improves physical conditioning and exercise capacity, even in the absence of drug-related changes in cardiac output. The long-term hemodynamic and clinical benefits of nitrates in heart failure have been confirmed by two independent randomized double-blind placebo-controlled clinical trials.