Alfieri A B, Malave A, Cubeddu L X
Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas.
Naunyn Schmiedebergs Arch Pharmacol. 2001 Mar;363(3):353-7. doi: 10.1007/s002100000371.
The role of inducible (iNOS) and neuronal nitric oxide (nNOS) synthases and of tachykinin NK1 receptors on the pathogenesis of cyclophosphamide (CYP)-induced cystitis was investigated, in rats. CYP-induced cystitis was characterized by large increases in bladder-protein plasma extravasation (PPE), increases in the urinary excretion of nitric oxide (NO) metabolites and histological evidences of urothelial damage, edema, extensive white blood cell infiltrates and vascular congestion of the bladder. The specific iNOS inhibitor, S-methylthiourea (MITU), produced marked inhibition (>90%) of CYP-induced increases in PPE associated with amelioration of tissue inflammatory changes. Treatment with 7-nitroindazole (7-NI; 20, 40 and 80 mg/kg), a selective nNOS inhibitor, did not significantly reduce CYP-induced increases in PPE and failed to produce histological improvement. In addition, treatment with MITU, but not with 7-NI, inhibited the increases in the urinary excretion of NO metabolites induced by CYP treatment. WIN 51,708 (17-beta-hydroxy-17-alpha-ethynyl-androstano[3,2-b]pyrimido[1,2-a]benzimidazole; WIN), a selective NK1-receptor antagonist, reduced the increases in EPP and ameliorated the inflammatory changes in the bladder induced by CYP. However, the maximal degree of protection achieved with WIN was significantly less than that produced by MITU. Combined treatment with the iNOS inhibitor and the NK1 antagonist produced no greater effect than that produced by the iNOS inhibitor alone. Our results suggest that NO plays a fundamental role in the production of the cystitis associated with CYP treatment. The iNOS, and not nNOS, seems responsible for the inflammatory changes. Part of the increases in NO may due to activation of NK1 receptors by neuropeptides such as substance P possibly released from primary afferent fibers.
在大鼠中，研究了诱导型（iNOS）和神经元型一氧化氮（nNOS）合酶以及速激肽NK1受体在环磷酰胺（CYP）诱导的膀胱炎发病机制中的作用。CYP诱导的膀胱炎的特征是膀胱蛋白血浆外渗（PPE）大幅增加、一氧化氮（NO）代谢产物尿排泄增加以及膀胱上皮损伤、水肿、广泛白细胞浸润和血管充血的组织学证据。特异性iNOS抑制剂S-甲基硫脲（MITU）对CYP诱导的PPE增加产生显著抑制（>90%），并伴有组织炎症变化的改善。用选择性nNOS抑制剂7-硝基吲唑（7-NI；20、40和80mg/kg）治疗，并未显著降低CYP诱导的PPE增加，也未能产生组织学改善。此外，用MITU而非7-NI治疗可抑制CYP治疗诱导的NO代谢产物尿排泄增加。选择性NK1受体拮抗剂WIN 51,708（17-β-羟基-17-α-乙炔基-雄甾烷[3,2-b]嘧啶并[1,2-a]苯并咪唑；WIN）可减少EPP增加，并改善CYP诱导的膀胱炎症变化。然而，WIN达到的最大保护程度明显低于MITU。iNOS抑制剂和NK1拮抗剂联合治疗产生的效果并不比单独使用iNOS抑制剂更大。我们的结果表明，NO在与CYP治疗相关的膀胱炎产生中起基本作用。iNOS而非nNOS似乎是炎症变化的原因。NO增加的部分原因可能是初级传入纤维可能释放的神经肽如P物质激活NK1受体。
