RESUMO
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.
Assuntos
Cistite/complicações , Óxido Nítrico Sintase/metabolismo , Fibras Parassimpáticas Pós-Ganglionares/enzimologia , Medula Espinal/enzimologia , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Transtornos Urinários/enzimologia , Animais , Ciclofosfamida , Cistite/induzido quimicamente , Cistite/fisiopatologia , Inibidores Enzimáticos/farmacologia , Feminino , Imuno-Histoquímica , Injeções Espinhais , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , NADPH Desidrogenase/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/antagonistas & inibidores , Fibras Parassimpáticas Pós-Ganglionares/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Reflexo Anormal/efeitos dos fármacos , Medula Espinal/citologia , Medula Espinal/fisiopatologia , Micção/efeitos dos fármacos , Micção/fisiologia , Transtornos Urinários/etiologia , Transtornos Urinários/fisiopatologiaRESUMO
The autoimmune sialadenitis developed by non-obese diabetic (NOD) mice is considered a suitable model to study the ethiopathogenic mechanisms leading to sicca symptoms in Sjögren's syndrome (SS). Evidence supporting a neural rather than immune origin of the secretory dysfunction has been provided. As both nitric oxide and vasoactive intestinal peptide (VIP) are common messengers to nervous and immune systems mediating secretory and inflammatory responses, we examined nitric oxide synthase (NOS) activity with special focus on VIP-mediated effects in salivary glands of NOD mice. We found a decreased NOS activity and expression in major salivary glands of NOD mice with respect to control mice. In addition, there was a deficient VIP-activated signaling associated with a reduced saliva and amylase secretion in response to VIP. Our results support the hypothesis of an impaired balance of neuroimmune interactions in salivary glands as early events to take place in the progressive loss of secretory function of NOD mice.