RESUMO
Hashimoto's Encephalopathy (HE) is a rare syndrome of steroid-responsive encephalopathy associated with elevated serum antithyroid antibody concentrations. The presentation of HE is highly variable making it difficult to recognize.
RESUMO
We investigate the role of M(2)-muscarinic receptors in maintaining neurogenic bladder contraction during hyperglycemia. Mice were injected with a single dose of streptozotocin (125 mg/kg), and neurogenic contraction of urinary bladder from wild type and M(2)-muscarinic receptor knockout (M(2) KO) mice was measured at 8 to 24 weeks after treatment. In wild-type bladder lacking urothelium, the summation of the cholinergic (64%) and purinergic (56%) components of the electrical-field-stimulated response exceeded 100%, indicating a reserve capacity. Although the cholinergic component was slightly less in the M(2) KO mouse, the total electrical-field-stimulated contraction was the same as wild type. The cholinergic and purinergic components of contraction in wild-type bladder were minimally affected by streptozotocin treatment. In M(2) KO bladder, streptozotocin treatment reduced both the cholinergic (after 8-9 and 20-24 weeks) and purinergic (after 20-24 weeks only) components. The loss of function was approximately 50 to 70%. Similar results were observed in bladder with intact urothelium. M(2) KO bladder was more sensitive to the relaxant effect of isoproterenol compared with wild type, and this difference significantly increased at the early and late time points after streptozotocin treatment. In the presence of urothelium, however, this difference in isoproterenol sensitivity was smaller with streptozotocin treatment, but this trend reversed over time. Our results show that M(2) receptors oppose urinary bladder distension in wild-type bladder and inhibit streptozotocin-induced neuropathy.
Assuntos
Antibióticos Antineoplásicos , Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M2/efeitos dos fármacos , Estreptozocina , Bexiga Urinaria Neurogênica/induzido quimicamente , Bexiga Urinaria Neurogênica/prevenção & controle , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Algoritmos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Estimulação Elétrica , Hiperglicemia/induzido quimicamente , Hiperglicemia/patologia , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Receptor Muscarínico M2/genéticaRESUMO
We investigated the contractile roles of M2 and M3 muscarinic receptors in urinary bladder from streptozotocin-treated mice. Wild-type and M2 muscarinic receptor knockout (M2 KO) mice were given a single injection of vehicle or streptozotocin (125 mg kg(-1)) 2-24 weeks prior to bladder assays. The effect of forskolin on contractions elicited to the muscarinic agonist, oxotremorine-M, was measured in isolated urinary bladder (intact or denuded of urothelium). Denuded urinary bladder from vehicle-treated wild-type and M2 KO mice exhibited similar contractile responses to oxotremorine-M, when contraction was normalized relative to that elicited by KCl (50 mM). Eight to 9 weeks after streptozotocin treatment, the EC(50) value of oxotremorine-M increased 3.1-fold in urinary bladder from the M2 KO mouse (N = 5) compared to wild type (N = 6; P < 0.001). Analogous changes were observed in intact bladder. In denuded urinary bladder from vehicle-treated mice, forskolin (5 microM) caused a much greater inhibition of contraction in M2 KO bladder compared to wild type. Following streptozotocin treatment, this forskolin effect increased 1.6-fold (P = 0.032). At the 20- to 24-week time point, the forskolin effect increased 1.7-fold for denuded as well as intact bladders (P = 0.036, 0.01, respectively). Although streptozotocin treatment inhibits M3 receptor-mediated contraction in denuded urinary bladder, muscarinic contractile function is maintained in wild-type bladder by enhanced M2 contractile function. M2 receptor activation opposes forskolin-induced relaxation of the urinary bladder, and this M(2) function is enhanced following streptozotocin treatment.