Central and peripheral effects of asymmetric dimethylarginine, an endogenous nitric oxide synthetase inhibitor.
We tested the hypothesis that the endogenous nitric oxide synthetase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), regulates cardiovascular function by central mechanisms. In in vivo studies, rats received intracerebroventricular (i.c.v.) injection of isotonic saline, ADMA (1 mg), l-arginine (3 mg), and N omega-nitro-l-arginine methylester (l-NAME, 1 mg). Baroreflex function was then assessed by intravenous (i.v.) injection of phenylephrine. Central application of exogenous NOS inhibitor, l-NAME, increased mean arterial blood pressure and decreased heart rate. However, application of the endogenous NOS inhibitor, ADMA, decreased mean arterial blood pressure and heart rate simultaneously (-39 +/- 6 mm Hg and -50 +/- 8 beats/min, respectively). Both l-NAME (i.c.v.) and ADMA (i.c.v.) significantly inhibited the baroreflex function, indicating a regulatory role of central nitric oxide in controlling baroreflex function. In contrast to the central effect, intravenous injection of ADMA caused dose-dependent increases in mean arterial blood pressure that could be blocked by l-NAME pretreatment. In vitro studies using aortic rings demonstrated that ADMA (10(-4)M) significantly increased the concentration of acetylcholine for the threshold response (EC15) and half-maximal response (EC50). This indicates that ADMA inhibits the constitutive isoform of NOS in the endothelium. ADMA may have functional importance in regulating cardiovascular function by mechanisms in addition to the inhibition of nitric oxide synthesis.
Jin
J S
JS
Department of Physiology, University of Michigan Medical School, Ann Arbor 48109-0622, USA.
D'Alecy
L G
LG
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017704:Baroreflex / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D019335:Nitroarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase