Xu S A, Shepherd R K, Chen Y, Clark G M
Department of Otolaryngology, University of Melbourne, Parkville, Victoria, Australia.
Hear Res. 1993 Nov;70(2):205-15. doi: 10.1016/0378-5955(93)90159-x.
Co-administration of kanamycin (KA) with the loop diuretic ethacrynic acid (EA) has previously been shown to produce a rapid and profound hearing loss in guinea pigs. In the present study we describe a modified technique for developing a profound hearing loss in cats. By monitoring the animal's hearing status during the intravenous infusion of EA the technique minimizes the effects of individual variability to the drug regime. Seven cats received a subcutaneous injection of KA (300 mg/kg) followed by intravenous infusion of EA (1 mg/min). Click-evoked auditory brainstem responses (ABRs) were recorded to monitor the animal's hearing during the infusion. When the ABR thresholds rose rapidly to levels in excess of 90 dB SPL the infusion of EA was stopped. This occurred at EA doses of 10-25 mg/kg, indicating considerable individual variability to the deafening procedure. However, there was a strong negative correlation (r = -0.93) between the EA dose and body weight which accounted for much of this variability. Subsequent ABR monitoring showed that this profound hearing loss was both bilateral and permanent. Significantly, blood urea and creatinine levels, monitored for periods of up to three days after the procedure, remained within the normal range. Furthermore, there was no clinical evidence of renal dysfunction as indicated by weight loss or oliguria. Cochlear histopathology, examined after a two months to three year survival period, showed an absence of all inner and outer hair cells in the majority of cochleas. The extent of loss of spiral ganglion cells was dependent on their distance from the round window and the period of survival following the deafening procedure. Clearly, the degeneration of spiral ganglion cells continued for several years following the initial insult. Finally, we observed no evidence of renal histopathology. In conclusion, the co-administration of KA and EA produces a profound hearing loss in cats without evidence of renal impairment. Monitoring the animal's hearing status during the procedure ensures that the dose of EA can be optimised for individual animals. Moreover, it may be possible to adapt this procedure to produce animal models with controlled high frequency hearing losses.
先前的研究表明，卡那霉素（KA）与袢利尿剂依他尼酸（EA）联合使用会使豚鼠迅速出现严重听力损失。在本研究中，我们描述了一种在猫身上造成严重听力损失的改良技术。通过在静脉输注EA期间监测动物的听力状态，该技术可将个体差异对药物治疗方案的影响降至最低。七只猫皮下注射KA（300mg/kg），随后静脉输注EA（1mg/min）。在输注过程中记录短声诱发的听觉脑干反应（ABR）以监测动物的听力。当ABR阈值迅速升至超过90dB SPL时，停止输注EA。这发生在EA剂量为10 - 25mg/kg时，表明致聋过程存在相当大的个体差异。然而，EA剂量与体重之间存在很强的负相关（r = -0.93），这解释了大部分这种差异。随后的ABR监测表明，这种严重听力损失是双侧且永久性的。值得注意的是，在该过程后长达三天的时间内监测的血尿素和肌酐水平仍在正常范围内。此外，没有体重减轻或少尿等肾功能不全的临床证据。在存活两月至三年后检查耳蜗组织病理学，发现大多数耳蜗中所有内毛细胞和外毛细胞均缺失。螺旋神经节细胞的损失程度取决于它们与圆窗的距离以及致聋过程后的存活时间。显然，在最初损伤后，螺旋神经节细胞的退化持续了数年。最后，我们没有观察到肾脏组织病理学的证据。总之，KA和EA联合使用会使猫出现严重听力损失，且无肾功能损害的证据。在该过程中监测动物的听力状态可确保为个体动物优化EA剂量。此外，有可能调整该程序以产生具有可控高频听力损失的动物模型。
