Effects of NO donors and synthase agonists on endothelial cell uptake of L-Arg and superoxide production |
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Authors: | Ogonowski A A Kaesemeyer W H Jin L Ganapathy V Leibach F H Caldwell R W |
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Institution: | Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA. |
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Abstract: | It is commonly believed thatthe activity of NO synthase (NOS) solely controls NO production fromits substrates, L-Arg and O2. The Michaelis-Menten constant(Km) of NOS forL-Arg is in the micromolarrange; cellular levels of L-Argare much higher. However, evidence strongly suggests that cellularsupply of L-Arg may becomelimiting and lead to reduced NO and increased superoxide anion(O2·) formation, promotingcardiovascular dysfunction. Uptake ofL-Arg into cells occursprimarily (~85%) through the actions of aNa+-independent, carrier-mediatedtransporter (system y+). We haveexamined the effects of NOS agonists (substance P, bradykinin, and ACh)and NO donors(S-nitroso-N-acetyl-penicillamine and dipropylenetriamine NONOate) on transport ofL-Arg into bovine aorticendothelial cells (BAEC). Our results demonstrate that NOS agonistsincrease y+ transporter activity.A rapidly acting NO donor initially increases L-Arg uptake; however, afterlonger exposure, L-Arg uptake is suppressed. Exposure of BAEC withoutL-Arg to substance P and aCa2+ ionophore (A-23187) increasedO2· formation, which was blockedwith concurrent presence ofL-Arg or the NOS antagonistN-nitro-L-arginine methyl ester.We conclude that factors including NO itself controly+ transport function and theproduction of NO and O2·. |
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