L-arginine, but not N alpha-benzoyl-L-arginine ethyl ester, is a precursor of endothelium-derived relaxing factor.
N alpha-benzoyl-L-arginine ethyl ester (BAEE) is a vasorelaxant which resembles an arginine-containing peptide; its action may be partially endothelium-dependent. Because L-arginine (ARG) has little potency as a vasorelaxant, it has been proposed that an arginine-containing peptide, rather than free ARG, is the immediate precursor of endothelium-derived relaxing factor/nitric oxide (EDRF/NO). In the present study we have characterized pharmacologically the vasorelaxant effect of BAEE and assessed the ability of BAEE to serve as a substrate for EDRF/NO synthesis. BAEE elicited a concentration-dependent vasorelaxation of guinea pig pulmonary artery (EC50 of 0.36 +/- 0.05 mM). This vasorelaxation was neither antagonized by -NG-methyl-L-arginine (100 microM), a competitive inhibitor of EDRF/NO synthesis from ARG, nor potentiated by superoxide dismutase (60 U/ml), a superoxide anion scavenger that prolongs EDRF lifetime. Additionally, compound LY 83583 (1 microM) and methylene blue (10 microM), inhibitors of soluble guanylyl cyclase, failed to block BAEE-induced vasorelaxation. Moreover, endothelium removal potentiated the vasorelaxant effect of BAEE 3-fold. Thus, BAEE-induced vasorelaxation is mediated by a direct action on vascular smooth muscle that is unrelated to EDRF/NO synthesis. Furthermore, ARG, but not BAEE, overcame the inhibition by NG-methyl-L-arginine of the acetylcholine-induced endothelium-dependent cyclic GMP accumulation in guinea pig aortic rings and of A23187-induced nitrite formation by cultured bovine aortic endothelial cells (nitrite is a convenient indicator of NO biosynthesis). Thus, BAEE cannot substitute for ARG as a substrate for EDRF/NO biosynthesis. Collectively, our findings support the notion that free ARG, rather than an arginine-containing peptide related to BAEE, is the immediate biosynthetic precursor of EDRF/NO.
Fasehun
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OA
Department of Pharmacology, Cornell University Medical College, New York, New York.
Gross
S S
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Rubin
L E
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Jaffe
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EA
Griffith
O W
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Levi
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R
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009566:Nitrates / Q000378:metabolism; D017942:Nitric Acid; D009569:Nitric Oxide / Q000096:biosynthesis*; D009638:Norepinephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D019323:omega-N-Methylarginine
D009566:Nitrates; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D017942:Nitric Acid; D001120:Arginine; C009727:benzoylarginine ethyl ester; D006152:Cyclic GMP; D000109:Acetylcholine; D009638:Norepinephrine