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Ototoxic side-effects of the I(Ks)-channel blocker HMR1556
Rainer Hartmann1, Uwe Gerlach, Rainer Klinke
1Physiologisches Institut II, Theodor-Stern-Kai 7, D-60590, Frankfurt/M, Germany.
Insights
The antiarrhythmic drug HMR1556, an inhibitor of I(Ks)-channels, caused hearing loss in cats. This ototoxic effect was dose-dependent, suggesting I(Ks)-channel inhibitors may harm hearing.
Area of Science:
- Pharmacology
- Ototoxicology
- Otorhinolaryngology
Background:
- I(Ks)-channels are present in cardiac tissue and the inner ear's stria vascularis and vestibular dark cells.
- HMR1556, an inhibitor of I(Ks)-channels, is a potential antiarrhythmic drug.
- The expression of I(Ks)-channels in the inner ear suggests potential ototoxic side effects of HMR1556.
Purpose of the Study:
- To investigate the potential ototoxic effects of HMR1556 on hearing.
- To evaluate the impact of HMR1556 on cochlear function in a feline model.
Main Methods:
- Cats were used to study the effects of HMR1556 on hearing.
- Cochlear action potential (CAP) thresholds and intensity functions were measured.
- Heart rate and ECG were monitored alongside auditory assessments.
Main Results:
- HMR1556 administration resulted in a significant elevation of hearing thresholds.
- A shift in CAP intensity functions was observed, indicating hearing impairment.
- A clear dose-effect relationship was established for the observed ototoxic effects.
- A tendency for recovery of hearing function was noted post-administration.
Conclusions:
- Inhibitors of I(Ks)-channels, such as HMR1556, may cause ototoxic effects.
- Ototoxicity is likely if these inhibitors can access the cochlear spaces.
- The findings highlight the importance of considering inner ear effects for I(Ks)-channel targeting drugs.
Abstract:
The inhibitor of I(Ks)-channels, HMR1556, a potentially antiarrhythmic drug, might possess ototoxic side-effects. The I(Ks)-channels are not only expressed in the heart but also in the stria vascularis of the inner ear and in the dark cells of the vestibular organ. Therefore possible effects of HMR1556 on hearing were studied in cats. Thresholds and intensity function of the cochlear action potential (CAP) were used as criteria. In addition to effects of the drug on heart rate and ECG, a substantial elevation of hearing thresholds and a shift in CAP intensity functions were observed. There was a clear dose-effect relationship. The hearing impairment observed showed a tendency for recovery. It is concluded that inhibitors of I(Ks)-channels may generally exert ototoxic effects provided they can reach the cochlear spaces.