Interaction of L-arginine analogs with L-arginine uptake in rat renal brush border membrane vesicles.
The dibasic amino acid, L-arginine, is a substrate for both nitric oxide synthase (NOS) and arginase and therefore, plays an important role in cell signaling and cell growth. We examined the effects of various NOS inhibitors on L-arginine transport into rat renal brush border membrane (BBM) vesicles. L-Arginine uptake was stimulated in the presence of an inwardly directed Na+ gradient and an imposed inside negative potential in BBM but not basolateral membrane vesicles. In BBM vesicles, the L-arginine analogs, N-iminoethyl-L-orinithine and Nw-monomethyl-L-arginine (L-NMMA) were potent inhibitors of L-arginine uptake (IC50 of 0.48 and 0.82 mM, respectively), while Nw-nitro-L-arginine was less active (IC50 = 10 mM) and Nw-nitro-L-arginine methyl ester (L-NAME) was inactive. The inhibition of L-arginine transport by L-NMMA was competitive in nature. L-NIO, L-NMMA as well as L-arginine and L-lysine but not Nw-nitro-L-arginine methyl ester, trans-stimulated L-arginine uptake when preloaded into BBM vesicles. The L-arginine analogs had no effect on the transport of the neutral amino acid, L-leucine, in the same preparations. The data suggest that in addition to inhibiting NOS, the L-arginine analogs, N-iminoethyl-L-orinithine, L-NMMA and to a lesser extent L-NA, also inhibit L-arginine transport across the BBM of proximal tubules.
Edwards
R M
RM
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Stack
E J
EJ
Trizna
W
W
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000493:pharmacokinetics* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester