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

J. T. Kielstein
2004 Circulation  
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
more » ... ular diseases, ie, between 2 and 10 mol/L, caused a significant (PϽ0.05) decrease in concentrations of plasma cGMP, the main second messenger of NO. In addition, cardiac output was significantly lower (5.3Ϯ0.4 versus 5.8Ϯ0.6 L/min; PϽ0.05 versus baseline), and systemic vascular resistance was significantly higher (1403Ϯ123 versus 1221Ϯ100 dyn · s ⅐ cm Ϫ5 ; PϽ0.05 versus baseline). The infusion of 0.25 mg ADMA · kg Ϫ1 · min Ϫ1 or 3 g N G -nitro-L-arginine methyl ester · kg Ϫ1 · min Ϫ1 , a potent synthetic NOS inhibitor with long action, resulted in a comparable decrease in effective renal plasma flow (from 670Ϯ40 to 596Ϯ29 mL ⅐ min Ϫ1 ; PϽ0.05) and an increase in renovascular resistance (from 79Ϯ5 to 90Ϯ7 mm Hg · mL Ϫ1 · min Ϫ1 ; PϽ0.05). Moreover, administration of ADMA caused significant sodium retention and blood pressure increase (both PϽ0.05). The observed effects of ADMA in the systemic circulation were sustained corresponding to a mean plasma half-life of 23.5Ϯ6.8 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. (Circulation. 2004;109:172-177.) Key Words: nitric oxide synthase Ⅲ vasculature Ⅲ asymmetrical dimethylarginine E ndothelium-derived nitric oxide (NO) plays a critical role
doi:10.1161/01.cir.0000105764.22626.b1 pmid:14662708 fatcat:elrxm3eptfaqrmyibn4ey5rgau