TETRAHYDROBIOPTERIN AND DYSFUNCTION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE IN CORONARY-ARTERIES

Background The L-arginine/nitric oxide pathway plays a key role in the regulation of arterial tone. Biosynthesis of nitric oxide requires ac tivation of nitric oxide synthase in the presence of tetrahydrobiopter in as a cofactor. Biochemical studies demonstrated that activation of purified nitric oxide synthase at suboptimal concentrations of tetrahy drobiopterin leads to production of hydrogen peroxide. The present exp eriments were designed to determine whether in coronary arteries inhib ition of tetrahydrobiopterin synthesis may favor nitric oxide synthase -catalyzed production of hydrogen peroxide. Methods and Results Primar y branches of canine left anterior descending artery were incubated fo r 6 hours in minimum essential medium in the presence or in the absenc e of the tetrahydrobiopterin synthesis inhibitor 2,4-diamino-6-hydroxy -pyrimidine (DAHP; 10(-2) mol/L). Arterial rings were suspended for is ometric tension recording. Production of cGMP was measured by radioimm unoassay. Experiments were performed in the presence of indomethacin ( 10(-5) mol/L). During contractions to the thromboxane A(2)/prostagland in H-2 receptor agonist U46619 (10(-7) mol/L), calcium ionophore A2318 7 (10(-9) to 10(-6) mol/L) caused endothelium-dependent relaxations. A nitric oxide synthase inhibitor, N-G-nitro-L-arginine methyl eater (3 x10(-4) mol/L), significantly inhibited these relaxations. In DAHP-tre ated arteries, relaxations to A23187 and its stimulating effect on cGM P production were significantly reduced in the presence of catalase (1 200 U/mL). By contrast, catalase did hot exert any effect in rings inc ubated in the absence of DAHP. Furthermore, the inhibitory effect of c atalase on A23187-induced relaxations was abolished when coronary arte ries were incubated in the presence of DAHP plus a liposoluble analogu e of tetrahydrobiopterin, 6-methyltetrahydropterin (10(-4) mol/L). Con clusions The present study suggests that hydrogen peroxide may be a me diator of endothelium-dependent relaxations in coronary arteries deple ted of tetrahydrobiopterin. This initially compensatory response, trig gered by a dysfunctional nitric oxide synthase, may represent an impor tant mechanism underlying oxidative vascular injury.