Influence of High-Dose Verapamil on Beagle Lens Proteins (Chronic Toxicity Test)

Abstract

After oral long-term administration to beagle dogs at doses within toxic and lethal ranges, some animals showed impaired lens transparency. These changes could not be reproduced in rats, even with specifically designed investigations. In man a comparable influence on lens transparency could not be observed either. In the course of further experiments it was demonstrated that the beagle lens changes are a ‘species-specific process’ which may be attributed to the species-specificity of dog lens proteins. In this study verapamil's influence on the composition of water-soluble and water-insoluble dog lens proteins was tested. 4 beagle dogs were treated daily with a very high dose of 81 mg/kg b.w. verapamil •HCl for 19 months. 3 untreated animals were available as controls. During the mentioned test period microscopic observations with the slit lamp did not reveal any pathological lens findings. In the verapamil-treated animals, however, a lower lens fresh weight and a lower content of water-soluble proteins occurred at the end of the experiment, compared to the control animals of the same age. This indicates a slowing down of lens growth. The distribution of the water-soluble crystallin fractions of dog lenses was determined using thinlayer isoelectric focusing. Significant changes in the single crystallin fractions were demonstrated only in the equator of the lens and in the anterior layer of the cortex. The α-crystallin fraction was found to be increased, the β-crystallin fraction to be decreased. Changes within the β-crystallin spectrum show that the effect of very high-dosed verapamil •HCl on the beagle dog lens does not affect the β-crystallins on the whole, but specifically only some subfractions. As may be seen from slit lamp lens investigations, however, the protein changes observed do not influence lens transparency.