Sildenafil is a phosphodiesterase type 5 inhibitor used to treat male erectile dysfunction and pulmonary hypertension. A potential side effect of sildenafil is a noticeable decrease in seizure threshold. Oxytocin (OXT) secretion and the subsequent cAMP-responsive element-binding (CREB) phosphorylation are involved in proconvulsant effects of sildenafil in experimental models. The aim of the present study was to investigate the potential role of OXT receptors and their downstream calcineurin (CN)/inducible nitric oxide synthase (iNOS) pathways in proconvulsant effects of sildenafil. The pentylenetetrazole (PTZ)-induced seizure was used as a standard convulsion model in this study. Cortical CN activity, hippocampal nitrite levels, and proinflammatory cytokine content were measured. Our results indicated that following PTZ administration, sildenafil significantly increased CN activity at 40 mg/kg, respectively, in the control group. The combination of sildenafil and OXT receptor antagonist, atosiban (10 μg/kg, i.c.v) 30 min before sildenafil administration significantly reduced the CN activity. Also, the subeffective dose of CN inhibitor cyclosporine (5 mg/kg) 30 min before the administration of effective dose of sildenafil (40 mg/kg) reversed proconvulsant actions of sildenafil. This effect was iNOS-dependent because pretreatment of a low dose of aminoguanidine (20 mg/kg) 15 min before the administration of a low dose of cyclosporine (1 mg/kg) reversed the proconvulsant action of sildenafil (40 mg/kg). Finally, sildenafil induced the elevation of tumor necrosis factor alpha (TNF-α) and the nitrite level was blocked by the administration of cyclosporine in PTZ-treated mice. Collectively, our data provide insights into the role of OXT receptor/CN/iNOS pathway in the proconvulsant aspect of sildenafil.

中文翻译：

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催产素能系统介导西地那非的前惊厥作用：钙调神经磷酸酶的作用。

Sildenafil是5型磷酸二酯酶抑制剂，用于治疗男性勃起功能障碍和肺动脉高压。西地那非的潜在副作用是癫痫发作阈值明显降低。催产素（OXT）的分泌和随后的cAMP反应元件结合（CREB）磷酸化与西地那非在实验模型中的惊厥作用有关。本研究的目的是研究OXT受体及其下游钙调神经磷酸酶（CN）/诱导型一氧化氮合酶（iNOS）途径在西地那非前惊厥作用中的潜在作用。在这项研究中，以戊烯四唑（PTZ）诱发的癫痫发作为标准惊厥模型。测量了皮层CN活性，海马亚硝酸盐水平和促炎细胞因子含量。我们的结果表明，在执行PTZ之后，西地那非在对照组中分别以40 mg / kg显着增加CN活性。西地那非给药前30分钟，西地那非和OXT受体拮抗剂阿托西班（10μg/ kg，icv）的组合显着降低了CN活性。此外，在给予有效剂量西地那非（40 mg / kg）前30分钟，亚有效剂量的CN抑制剂环孢素（5 mg / kg）逆转了西地那非的惊厥作用。该作用是iNOS依赖性的，因为在给予低剂量的环孢菌素（1 mg / kg）之前15分钟对低剂量的氨基胍（20 mg / kg）进行预处理可以逆转昔多芬（40 mg / kg）的惊厥作用。最终，西地那非诱导了肿瘤坏死因子α（TNF-α）的升高，并且在PTZ治疗的小鼠中通过给予环孢霉素来阻断亚硝酸盐水平。