Cardiovascular Effects of Systemic Nitric Oxide Synthase Inhibition with Asymmetrical Dimethylarginine in Humans

Abstract

Background-Increased blood concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) have been linked to excess cardiovascular morbidity and mortality and to progression of renal disease. We evaluated systemic cardiovascular effects of ADMA infusion in healthy subjects using invasive techniques, ie, right heart catheter and inulin/para-aminohippurate clearance. Methods and Results-Plasma ADMA concentrations encountered in patients with cardiovascular diseases, ie, between 2 and 10 μmol/L, caused a significant (P<0.05) decrease in concentrations of plasma cGMP, the main second messenger of NO. In addition, cardiac output was significantly lower (5.3±0.4 versus 5.8±0.6 L/min; P<0.05 versus baseline), and systemic vascular resistance was significantly higher (1403±123 versus 1221±100 dyn · s · cm-5.; P<0.05 versus baseline). The infusion of 0.25 mg ADMA · kg-1 · min-1 or 3 μg N G-nitro-L-arginine methyl ester · kg-1 · min-1, a potent synthetic NOS inhibitor with long action, resulted in a comparable decrease in effective renal plasma flow (from 670±40 to 596±29 mL · min-1; P·0.05) and an increase in renovascular resistance (from 79±5 to 90±7 mm Hg · mL -1 · min-1; P<0.05). Moreover, administration of ADMA caused significant sodium retention and blood pressure increase (both P<0.05). The observed effects of ADMA in the systemic circulation were sustained corresponding to a mean plasma half-life of 23.5±6.8 minutes, calculated from plasma ADMA decay curves in healthy subjects. Conclusions-Systemic ADMA infusion is responsible for a short-term, modest decrease in cardiac output with comparable decrease in effective renal plasma flow while increasing systemic vascular resistance and blood pressure in a dose-related manner.