It is well known that beta-adrenergic receptors will down-regulate in the presence of high circulating levels of beta-adrenergic agonists over extended periods of time. However, less is known with respect to the effect of Ca2+ channel antagonist on their receptors. The purpose of this study was to determine if chronic administration of high dosages of verapamil (in the toxic range) could alter the density of Ca2+ channels in the heart as determined by [3H]PN 200-110 binding. A range of high verapamil concentrations was administered to rats via s.c. implantable slow-release pellets or s.c. injection. An increasing rate of mortality was observed as the dose of verapamil administered increased. Quantitation of serum verapamil concentrations demonstrated that the s.c. slow release implantable pellets were not releasing the drug evenly and instead released toxic quantities of drug during the first 24 h after implantation. Serum verapamil levels determined from verapamil-injected animals demonstrated a dose-dependent increase in circulating levels. No significant alterations in Ca2+ channel characteristics (Bmax and Kd) were noted in cardiac tissue obtained from either treatment regime. Our results demonstrate that implantable pellets are not a reliable administration method for verapamil and cardiac Ca2+ channels are unusually resistant to biochemical alterations even after administration of verapamil dosages in the toxic range.