EFFECT OF HIGH-DOSE VERAPAMIL ADMINISTRATION ON THE CA2+ CHANNEL DENSITY IN RAT CARDIAC TISSUE

It is well known that beta-adrenergic receptors will down-regulate in the presence of high circulating levels of beta-adrenergic agonists ov er extended periods of time. However, less is known with respect to th e effect of Ca2+ channel antagonists on their receptors. The purpose o f this study was to determine if chronic administration of high dosage s of verapamil (in the toxic range) could alter the density of Ca2+ ch annels in the heart as determined by [H-3]PN 200-110 binding. A range of high verapamil concentrations was administered to rats via s.c. imp lantable slow-release pellets or s.c. injection. An increasing rate of mortality was observed as the dose of verapamil administered increase d. Quantitation of serum verapamil concentrations demonstrated that th e s.c. slow release implantable pellets were not releasing the drug ev enly and instead released toxic quantities of drug during the first 24 h after implantation. Serum verapamil levels determined from verapami l-injected animals demonstrated a dose-dependent increase in circulati ng levels. No significant alterations in Ca2+ channel characteristics (B-max and K-d) were noted in cardiac tissue obtained from either trea tment regime. Our results demonstrate that implantable pellets are not a reliable administration method for verapamil and cardiac Ca2+ chann els are unusually resistant to biochemical alterations even after admi nistration of verapamil dosages in the toxic range.