Background The endothelium synthesizes and releases a relaxing factor with the physiochemical properties of nitric oxide (NO).However, the role of endothelium-derived NO in the basal regulation of systemic and pulmonary vascular resistance in humans is not known. Our primary objectives were to determine the effects of inhibiting NO synthesis on blood pressure and systemic vascular resistance and to establish the role of endothelium-derived NO in the regulation of normoxic pulmonary vascular tone.Methods and Results We studied the systemic and pulmonary hemodynamic effects of NG-monomethyl-l-arginine (L-NMMA, 0.03 to 1.0 mg x kg-1x min-1IV), an NO synthase inhibitor, in 11 healthy volunteers, aged 33+-2 years. An arterial cannula and a pulmonary artery catheter were placed in each subject to measure blood pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure. Cardiac output was determined by the Fick technique, and systemic and pulmonary vascular resistances were calculated. Serum NO levels (free and protein bound) were measured by chemiluminescence in 5 subjects. Six of the subjects also received phenylephrine (25 to 100 micrograms/min IV) to compare the cardiac hemodynamic effects of L-NMMA with those of a direct-acting vasoconstrictor. L-NMMA caused dose-dependent increases in both blood pressure and systemic vascular resistance. At the highest dose of L-NMMA, there was a 15.5+-1.3% increase in mean blood pressure and a 63.4+-8.2% increase in systemic vascular resistance (each P<.01). Pulmonary vascular resistance increased 39.8+-9.4% (P<.01), whereas mean pulmonary artery pressure did not change. Administration of L-NMMA also reduced cardiac output by 27.8+-2.9% and stroke volume by 15.4+-3.5% (each P<.01). Serum NO levels decreased 65+-10% from basal values (P<.05), confirming inhibition of endogenous NO production. Phenylephrine increased blood pressure to a level comparable to that observed with L-NMMA. The decline in stroke volume was greater with L-NMMA than with phenylephrine (P<.01).Conclusions This study demonstrates that basal release of endothelium-derived NO is directly involved in the determination of systemic vascular resistance and, therefore, blood pressure in healthy humans. In addition, NO regulates basal normoxic pulmonary vascular tone. The complex hemodynamic effects of NO are composite properties of its actions on systemic and pulmonary vascular resistance and cardiac function. (Circulation. 1994;89:2035-2040.)