5-磷酸二酯酶抑制剂对庆大霉素所致豚鼠耳毒性影响的研究

The Experimental Study on the Effect of the Inhibitor of PDE5 on the Ototoxicity of Gentamicin in Guinea Pigs

目的探讨5-磷酸二酯酶(PDE5)抑制剂对庆大霉素所致豚鼠耳毒性的听功能及耳蜗形态学的影响。方法采用随机数字表法将36只豚鼠分为空白对照组、庆大霉素组和PDE5抑制剂组,每组各12只;其中空白对照组未给予特殊处理,庆大霉素组和PDE5抑制剂组给予连续腹腔注射庆大霉素120 mg·kg^(-1)·d^(-1)3周后,庆大霉素组继续给予腹腔注射生理盐水4 ml·kg^(-1)·d^(-1),PDE5抑制剂组给予腹腔注射他达那非(选择性5-磷酸二酯酶抑制剂)2 mg·kg^(-1)·d^(-1),均连续给药4周后,分别测试庆大霉素给药前1天、庆大霉素给药后3周、给药生理盐水和他达那非后1、2及4周三组豚鼠听性脑干反应(ABR)阈值及波Ⅰ潜伏期,扫描电镜观察生理盐水和他达那非给药4周后豚鼠耳蜗毛细胞的形态变化。结果在庆大霉素给药3周后,PDE5抑制剂组与庆大霉素组ABR阈值及波Ⅰ潜伏期较空白对照组明显升高及延长(均为P<0.01),PDE5抑制剂组与庆大霉素组之间差异无统计学意义(P>0.05)。在给予他达那非干预1、2、4周时,PDE5抑制剂组ABR阈移及波Ⅰ潜伏期均小于庆大霉素组,差异有统计学意义(均P<0.01)。用药4周后扫描电镜观察,庆大霉素组豚鼠耳蜗外毛细胞听毛紊乱、融合及缺失;而PDE5抑制剂组耳蜗病变较轻,听毛仅有轻微倒伏、融合现象。结论PDE5抑制剂能够减轻庆大霉素所致豚鼠耳蜗毛细胞损害,对庆大霉素引起的听力损伤有一定的治疗作用。

Objective To study the effects of the inhibitor of PDE5 on the hearing function and cochlea morphology of guinea pigs to the ototoxicity of gentamicin.Methods A total of 36 guinea pigs were randomly divided into control group,gentamicin control group and the inhibitor of PDE5 group,12 in each group.Three weeks after gentamicin 120 mg·kg^(-1)·d-1 injected into guinea pigs of the inhibitor of PDE5 group and gentamicin control group,tadalafil(2 mg·kg^(-1)·d-1)and NS(4 ml·kg^(-1)·d-1)were injected into guinea pigs of above two groups respectively.ABR thresholds and the PL of waveⅠwere measured respectively prior to the experiment,1,2 and 4 weeks post-drugs,the changes of cochlea hair cells were also observed by a scan electron microscope(SEM).Results The ABR threshold shifts and the PL of waveⅠin the inhibitor of PDE5 group were significantly fewer than that in the gentamicin control group after the administration.SEM showed that the outer hair cells in gentamicin control group displayed mess,fusion and imperfections.In the inhibitor of PDE5 group,the hair cells displayed slight pathological changes,there were no significant differences compared with normal group.Conclusion The inhibitor of PDE5 can significantly protect against the ototoxicity of gentamicin.