Nitric oxide synthase inhibitors and cerebral vasospasm.
L-arginine is a source of nitric oxide (NO) that is cleaved from the terminal guanidino nitrogen atom by nitric oxide synthase (NOS). NO evokes, because of its free radical properties and affinity to heme, ferrous iron and cysteine, a wide spectrum of physiological and pathophysiological effects. For many years, different exogenous NOS inhibitors were used to elucidate the role of NOS and NO in health and disease. Later, endogenous NOS inhibitors, as asymmetric dimethylarginine (ADMA) were discovered. Endogenous inhibitors as ADMA are produced by post-translational methylation of L-arginine which is catalyzed by a family of protein N-methyltransferases (PRMT), using S-adenosylmethionine as a methyl group donor. ADMA is eliminated by dimethylarginine dimethylaminohydrolases (DDAH I or II). ADMA hydrolysis increases NOS activity and NO production. Furthermore, L-citrulline, a by-product of ADMA hydrolysis as well as of NO production by NOS, can in turn inhibit DDAH. Therefore, endogenous inhibition of NOS can be modified via different ways (1) changing the availability of L-arginine and/or of L-citrulline; (2) stimulating or inhibiting DDAH activity; (3) modifying methylation via regulating availability of adenosylmethionine; or (4) modifying PRMT activity. Research elucidating the role of NOS inhibitors in respect of delayed cerebral vasospasm after subarachnoid hemorrhage is summarized.
Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Carla.Jung@med.uni-heidelberg.de
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D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002956:Citrulline / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000201:enzymology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019323:omega-N-Methylarginine; D002956:Citrulline; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D012436:S-Adenosylmethionine; D001120:Arginine; D019001:Nitric Oxide Synthase