Endothelium-mediated effects of N-substituted arginines on the isolated perfused rat kidney.
Endothelium-derived relaxing factor (EDRF) has been suggested to be derived from the metabolism of arginine or an arginine-containing moiety. We have compared the vascular effects of arginine and some of its N-substituted derivatives on the perfusion pressure (Pp) of the isolated rat kidney preparation preconstricted with phenylephrine. Irrespective of the stereochemistry, high doses (10(-4) mol) of L- and D-arginine HCl produced a slight vasodilation. In contrast L- and D-arginine free base, at similar doses, further increased renal Pp. N-substituted L-arginine compounds, however, decreased Pp dose-dependently. Their order of potency (ED50) was as follows: N-alpha-benzoyl-L-arginine ethyl ester (BAEE, 3.8 x 10hm6 mol) greater than N-alpha-benzoyl-L-arginine methyl ester (2.5 x 10(-5) mol) greater than L-arginine ethyl ester (2.7 x 10(-5) mol) greater than L-arginine HCl (10(-4) mol). Methylene blue (10(-5) M), hemoglobin (10(-5) M) and NG-mono-methyl-L-arginine (5 mumol) antagonized the vasodilation elicited by infusion of BAEE. Similarly, injection of xanthine oxidase/xanthine (100 mU) reversed BAEE-induced renal vasodilation, but had no effect on dilation elicited by infusion of atrial natriuretic peptide. These data demonstrate that substituted arginine compounds are more potent renal vasodilators than L-arginine and their potency depends on the nature of the substitution. These compounds exert their effect, at least in part, via an endothelium-dependent mechanism. We conclude that exogenous L-arginine is a poor substrate for EDRF generation in the kidney, and that it may cause release of EDRF by another mechanism, possibly related to a change in the pH of the medium.
Farhat
M Y
MY
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, District of Columbia.
Ramwell
P W
PW
Thomas
G
G
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects*
D009569:Nitric Oxide; D001120:Arginine