Asymmetric dimethylarginine endogenous inhibition of nitric oxide synthase causes differential vasculature effects
David George Cable, Andrea Carla Celotto, Paulo Roberto Barbosa Evora, Hartzell Vernon Schaff
Med Sci Monit 2009; 15(9): BR248-253
Available online: 2009-08-31
Asymmetric dimethylarginine (ADMA), produced during protein metabolism, is an endogenous inhibitor of nitric oxide synthase, but little is known about its direct vasoactive properties in different arterial beds.
Material and Method: Segments of canine coronary, renal, and femoral arteries were pretreated with increasing concentrations of ADMA, and endothelial function was evaluated in organ chambers.
Results: In precontracted canine coronary arteries, the highest concentrations of ADMA inhibited endothelium-dependent relaxation mediated by acetylcholine (n=7), but no concentration of ADMA inhibited receptor-independent relaxation mediated by calcium ionophore (n=7) (P<.001). The effect of ADMA on acetylcholine-mediated relaxation was shown to be competitive inhibition of the nitric oxide synthase pathway, because the addition of L-arginine (10(-3) M), but not D-arginine (10(-3) M), reversed the effect produced by 10-5 M ADMA. Further, ADMA did not alter endothelium-independent relaxation mediated by sodium nitroprusside (10(-9) to 10(-6) M; n=7). Femoral arteries (n=7) and renal arteries (n=7) were more sensitive to ADMA than were coronary arteries, and they demonstrated significant ADMA inhibition to receptor dependent relaxation induced by acetylcholine (P=.03 and P=.01, respectively) and to receptor-independent relaxation induced by calcium ionophore (P=.02 and P=.01, respectively).
Conclusions: Endothelium-dependent relaxation mediated by ADMA is more marked in femoral and renal arteries than in coronary arteries. The response in coronary arteries may be overall protective. Considering these different effects in various artery types, the role of ADMA as a confiable and specific cardiovascular risk factor is questioned.
Keywords: Nitric Oxide Synthase - metabolism, Muscle, Smooth, Vascular - physiology, Muscle Contraction - physiology, Enzyme Inhibitors - pharmacology, Endothelium, Vascular - metabolism, Dogs, Arteries - metabolism, Arginine - pharmacology, Animals, Tissue Culture Techniques