Eglezos A, Lecci A, Santicioli P, Giuliani S, Tramontana M, Del Bianco E, Maggi C A
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Arch Int Pharmacodyn Ther. 1992 Jan-Feb;315:96-109.
We have assessed the ability of compound 48/80, a mast cell degranulating agent, to activate the sensory and efferent function of capsaicin-sensitive primary afferents in the rat urinary bladder. Compound 48/80 produced a calcium-dependent release of calcitonin gene-related peptide-like immunoreactivity from the superfused rat urinary bladder. This effect was prevented by in vitro capsaicin desensitization, but was not affected by indomethacin, methysergide, ondansetron, chlorpheniramine or cimetidine, nor by systemic pretreatment with compound 48/80 at a dose regimen which prevented lethality produced by intravenous administration of it in anesthetized rats. Compound 48/80 also produced a contraction of the rat isolated bladder which was not reduced by methysergide, indomethacin or in vitro capsaicin desensitization. In vivo, topical application of compound 48/80 on the serosal surface of the rat urinary bladder activated a series of high amplitude rhythmic bladder contractions which were hexamethonium-sensitive (micturition reflex). This effect was prevented by systemic capsaicin desensitization while it was unchanged by chlorpheniramine, methysergide, indomethacin or ondansetron. Administered intravenously, compound 48/80 produced a plasma protein extravasation (Evans blue leakage technique) in the rat urinary bladder which was abolished by systemic capsaicin pretreatment or chlorpheniramine while it was unaffected by methysergide or indomethacin. The present findings provide direct neurochemical evidence that compound 48/80 activates the peripheral endings of capsaicin-sensitive primary afferent neurons, leading to a stimulation of their sensory and efferent functions in the rat urinary bladder. The possibility of a direct action of compound 48/80 in producing excitation of capsaicin-sensitive sensory nerves should be considered.
我们评估了肥大细胞脱颗粒剂化合物48/80激活大鼠膀胱中对辣椒素敏感的初级传入神经的感觉和传出功能的能力。化合物48/80可使灌注的大鼠膀胱释放降钙素基因相关肽样免疫反应物质，且这种释放依赖于钙。体外辣椒素脱敏可阻止此效应，但吲哚美辛、甲基麦角新碱、昂丹司琼、氯苯那敏或西咪替丁对其无影响，以能防止麻醉大鼠静脉注射该化合物致死的剂量方案进行全身预处理也不影响此效应。化合物48/80还可使大鼠离体膀胱收缩，甲基麦角新碱、吲哚美辛或体外辣椒素脱敏对此收缩无减弱作用。在体内，将化合物48/80局部应用于大鼠膀胱浆膜表面可激活一系列高幅度的节律性膀胱收缩，这些收缩对六甲铵敏感（排尿反射）。全身辣椒素脱敏可阻止此效应，而氯苯那敏、甲基麦角新碱、吲哚美辛或昂丹司琼对此无影响。静脉注射化合物48/80可使大鼠膀胱出现血浆蛋白外渗（伊文思蓝渗漏技术），全身辣椒素预处理或氯苯那敏可消除此现象，而甲基麦角新碱或吲哚美辛对此无影响。目前的研究结果提供了直接的神经化学证据，表明化合物48/80可激活对辣椒素敏感的初级传入神经元的外周末梢，从而刺激其在大鼠膀胱中的感觉和传出功能。应考虑化合物48/80直接作用于产生对辣椒素敏感的感觉神经兴奋的可能性。
