It is well known that β-adrenergic receptors will down-regulate in the presence of high circulating levels of β-adrenergic agonists over extended periods of time. However, less is known with respect to the effect of Ca2+ channel antagonists 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.
Tension generation and Ca2+ flux in smooth muscle varies depending upon the diameter of a vessel and its location. The purpose of the present investigation was to determine if the biochemical characteristics of the Na(+)-Ca2+ exchanger and the Ca2+ channel differ in sarcolemmal membrane preparations isolated from a large conduit vessel (thoracic aorta) or from large and small coronary arteries. We also investigated the possibility of differences between sarcolemmal membranes isolated from coronary arteries dissected from the right and left ventricles. The purification of the sarcolemmal membranes was of a similar magnitude amongst the different groups. Contamination of the sarcolemmal membranes with other membranous organelles was negligible and similar amongst the groups. The Km and Vmax of Na(+)-dependent Ca2+ uptake in sarcolemmal vesicles was similar amongst the groups. Calcium channel characteristics were examined by measuring [3H] PN200-110 binding to sarcolemmal vesicles. The right coronary artery membranes from both large and small caliber vessels exhibited a higher Kd and the small right coronary artery sarcolemmal preparation had a lower maximal binding density for [3H] PN200-110. The results suggest that the right coronary artery, and in particular the small diameter right coronary artery, possesses altered Ca2+ channel characteristics in isolated sarcolemmal membranes.
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