Role of spinal nitric oxide synthase-dependent processes in the initiation of the micturition hyperreflexia associated with cyclophosphamide-induced cystitis.
The aim of this study was to examine the participation of nitrergic neurotransmission in the initiation of micturition hyperreflexia associated to cyclophosphamide (CP)-induced cystitis in rats. Micturition threshold volume was significantly reduced 4 h after CP administration (100 mg/kg, i.p.); this reduction was attenuated by intra-arterially injected N(G)-nitro-l-arginine-methyl ester (l-NAME), a non selective nitric oxide synthase (NOS) inhibitor, but not by intravesical infusion of S-methyl-l-thiocitrulline (l-SMTC), another structurally different NOS inhibitor. Interestingly, l-NAME failed to affect micturition threshold volume in normal rats. The magnitude of isolated detrusor strips contractions elicited by either carbachol or nerve activation was significantly reduced in CP-treated rats but was unaffected by the addition of N(G)-nitro-l-arginine (l-NOARG), a nonselective NOS inhibitor. In contrast, intrathecal l-NAME and l-SMTC but not N(G)-nitro-d-arginine-methyl ester (d-NAME) administration augmented the micturition threshold volume in CP-treated rats in an l-arginine preventable manner. As with the systemic injection, intrathecal l-NAME also did not affect the micturition threshold volume in normal rats. Four hours after CP injection, the number of neuronal NOS immunoreactive or nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) positive neurons in spinal lumbosacral segments (L6-S2) was not altered whereas the number of c-Fos immunoreactive neurons increased significantly in the dorsal gray commissural nucleus (DGC), the parasympathetic sacral nucleus (PSN) and lamina X of these segments. Ca(2+)-dependent, but not Ca(2+)-independent NOS activity increased significantly in spinal L6-S2 segments but not in thoracic segments of CP-treated rats. These data indicate that the micturition hyperreflexia observed in the initial hours of CP-induced cystitis is associated with an increase in Ca(2+)-dependent NOS activity in spinal L6-S2 segments suggesting an increased production of nitric oxide (NO). The increased production of NO in these spinal segments appears to be necessary for the initiation of the micturition hyperreflexia.
Lagos
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P
Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-São Paulo, Brazil. plagos@fmed.edu.uy
Ballejo
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G
D000818:Animals; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D007278:Injections, Spinal; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017777:Parasympathetic Fibers, Postganglionic / Q000201:enzymology* / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012021:Reflex, Abnormal / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology / Q000201:enzymology* / Q000503:physiopathology; D001743:Urinary Bladder / Q000294:innervation* / Q000503:physiopathology*; D014554:Urination / Q000187:drug effects / Q000502:physiology; D014555:Urination Disorders / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology
D004791:Enzyme Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D009569:Nitric Oxide; D003520:Cyclophosphamide; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase; D019331:NG-Nitroarginine Methyl Ester