The loop diuretics ethacrynic acid (EA) and furosemide (FU) were applied systemically to guinea pigs at dosages from 10–100 mg/kg. At high dosages the endolymphatic potential (EP) invariably turned negative. When the EP had reached maximum negative values due to EA, the ATP levels of the stria vascularis were moderately reduced, but P‐creatine levels were normal. In the case of FU both high energy phosphates remained at normal levels. When EA and FU intoxicated ears were subjected to ischemia, the rate of decline of ATP and P‐creatine was markedly less than the ischemic decline in nonintoxicated ears. These results suggest a strong interference with energy utilization, and in the case of EA a moderate impairment of energy generation. In severe intoxication by perilymphatically applied ouabain (10−3 M) strial ATP remained normal but P‐creatine was significantly increased. The reduction of the ischemic decline rate in ouabain intoxicated ears was even more marked than in the case of EA or FU, indicating a very strong interference with energy utilization, presumably due to complete inhibition of Na+K+‐ATPase. The I50 of the endolymphatic potential with regard to perilymphatically applied EA and FU was found to be 10−5 M and 2 x 10−4 M respectively. By K contrast, strial Na+K+‐ATPase was 50% inhibited with 5 x 10−3 M EA and not inhibited at all by FU. It is therefore unlikely that the effect of loop diuretics upon the endolymphatic potential is due to interference with strial Na+K+‐ATPase.
Severe bone destruction in a cholesteatoma is one of the characteristic clinical features. To clarify the mechanism of bone destruction in cholesteatoma, the matrix of cholesteatoma and the attached bone, obtained during middle ear surgery, was observed by light microscope. Rupture of the epithelial lining in a cholesteatoma and the escaping contents (keratin), which gave rise to intense characteristic granulations in subepithelial tissue, were found. Furthermore bone destruction was always found at the site of subepithelial tissue of cholesteatoma. From these facts, the escape of contents from the sac of cholesteatoma into the subepithelial layer is considered to be an important factor in the mechanism of bone destruction.
The effect of bumetanide upon the endocochlear potential (EP) was examined in 46 guinea pigs. The EP was reduced with dosages of 5 mg/kg or more. The maximum depression of the EP (reduction to -30 to -40 mV) was obtained at a dosage of 30 mg/kg. The recovery of the potential was incomplete at any dosage within three hours and the response pattern of the EP to bumetanide was similar to that to ethacrynic acid. The present experiments revealed that bumetanide, by weight, has a stronger ototoxic potency than the other "loop" diuretics--furosemide and ethacrynic acid. However, the diuretic effect of 1 mg bumetanide is equivalent to 40 to 60 mg furosemide or ethacrynic acid. Therefore, the relative ototoxic potency of bumetanide is much smaller suggesting that from a clinical standpoint bumetanide is much safer than the other "loop" diuretics.
The activity of adenylate cyclase and the steady state levels of cyclic AMP (cAMP) were determined in stria vascularis (SV) and organ of Corti (OC) of the guinea pig cochlea. The activities are 12 and 19 pmoles/mg dry weight/minute for OC and SV, respectively. The activity was increased two to four-fold by NaF. The base level of cAMP is 4.2 and 4.4 nmoles/g dry weight in OC and SV, respectively. In contrast to brain, neither ischemia nor barbiturates produced major changes of the steady state levels of cAMP. No in vitro effect of cAMP upon the state of activation of glycogen phosphorylase was noticeable in either tissue. cAMP did not exert a significant in vitro inhibition of strial Na+K+-ATPase. Perilymphatic perfusion of cAMP (10-3 M) and of theophylline (5 times 10-3 M) did not produce changes in the endolymphatic potential (EP), but dibutyryl cAMP (10-3 M) led to a significant increase of EP. The alpha adrenergic blocking agent, phentolamine, produced very complex changes of the cochlear potentials. A possible role of catecholamines and cAMP in the secretory phenomena of the SV and in the transduction and/or transmission processes of the auditory sense organ are discussed.
The influence of various toxic substances and of drugs with ototoxic side effects upon energy generation, energy utilization, and membrane processes of the cochlea were studied. None of the drugs tested interfered with energy generation to as great an extent as did anoxia or cyanide and 2,4‐dinitrophenol. Ouabain produced a pronounced interference with energy utilization of the stria vascularis. The “loop” diuretics ethacrynic acid and furosemide produced a reduction of energy utilization of a lesser degree than did ouabain. The “loop” diuretics do not seem to exert their toxic action upon strial Na+K+‐ATPase, but may act by interfering with strial adenylate cyclase. Aminoglycoside antibiotics and diuretic and nondiuretic mercurials seem to exert their primary noxious action upon cochlear function by interfering with membrane processes of the structures bounding the cochlear duct.
The effect of bumetanide upon the endolymphatic potential (EP) was examined using 46 healthy guinea pigs and following results were obtained. i) Within a few minutes after intravenous administration of this drug, the EP started to decline rapidly. After reaching the lowest level, the EP started to recover. This recovery could be devided into two phases, namely the initial rapid recovery and the later very slow one.The recovery up to the original level was not obtained in any case for 3 hours observation and the EP recovered to the level of only 30 to 40 mV in cases of a large dose administration (30 to 40 mg/kg).2) The minimal dose required to affect the EP was 5 mg/kg and the reduction of the EP became larger as the given dose increased. The maximum reduction (the reduction to about -40 mV) was obtained at the dose of 30 mg/kg or more .3) When the EP reached the lowest level, 20 animals put into ichemic condition by aorta section. The decline rate of the EP in the bumetanide intoxicated animals was much slower than that of the normal ones and approximately proportional to the lowest level reduced by bumetanide. When the lowest level was less than -20 mV, ischemia elevated the EP instead of reducing.These results were discussed combining our previous studies on furosemide and ethacrynic acid. In conclusion, the effect of bumetanide upon the cochlea is almost identical to ethacrynic acid and slightly different from furosemide, and taking the diuretic action into consideration, the present study indicates that bumetanide is less ototoxic than the other two.
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