Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans.
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.


RESULTS
Plasma ADMA concentrations encountered in patients with cardiovascular diseases, ie, between 2 and 10 micromol/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 x s x cm(-5); P<0.05 versus baseline). The infusion of 0.25 mg ADMA x kg(-1) x min(-1) or 3 microg N(G)-nitro-L-arginine methyl ester x kg(-1) x 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 x min(-1); P<0.05) and an increase in renovascular resistance (from 79+/-5 to 90+/-7 mm Hg x mL(-1) x 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.
Kielstein
Jan T
JT
Department of Internal Medicine, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. kielstein@yahoo.com
Impraim
Burcu
B
Simmel
Solveig
S
Bode-Böger
Stefanie M
SM
Tsikas
Dimitrios
D
Frölich
Jürgen C
JC
Hoeper
Marius M
MM
Haller
Hermann
H
Fliser
Danilo
D
D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000098:blood supply; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects
D004791:Enzyme Inhibitors; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester