Effect of High-Dose Verapamil Administration on the Ca²⁺ Channel Density in Rat Cardiac Tissue

Abstract

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 (B_max and K_d) 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.

Robust L‐type calcium current expression following heterozygous knockout of the Cav1.2 gene in adult mouse heart

“…We did not observe any effect of verapamil on Cav1.2 mRNA or protein expression in vivo . Our results are in agreement with multiple prior studies showing that there is no change in calcium channel protein expression following in vivo verapamil treatment, as assessed by dihydropyridine binding analysis (McCaughran & Juno, 1988; Lonsberry et al 1992, 1994; Chapados et al 1992).…”

Disposition and pharmacologic effects of R/S‐verapamil in patients with chronic atrial fibrillation: An investigation comparing single and multiple dosing

“…There are only few and controversial data from animal experiments about what effect long-term treatment with calcium channel blockers has on the biochemical characteristics and density of the myocardial calcium channels. [29][30][31][32][33] Our results would be best explained by an upregulation of calcium channels, as reported for long-term (ie, 25 days) nifedipine treatment in rabbits by Chiappe de Cingolani et al 33 As a clinical consequence of the decreased verapamil elimination during long-term oral treatment, a reduced or less frequent dosing has been suggested when steady-state conditions have been achieved in order to produce the desired serum concentrations and to minimize unwanted side effects. 15,17,18,21 Our combined kinetic and dynamic findings argue against a downward titration of the dose and provide the rationale that despite the accumulation of verapamil with multiple dosing maintenance of individual dosages from the beginning of the rate control therapy in patients with chronic atrial fibrillation may not only be clinically acceptable but even necessary.…”

Effect of multidrug resistance modulators on the activity of ivermectin and moxidectin against selected strains of Haemonchus contortus infective larvae

“…Clinical trials using the drug combination strategy in humans (verapamil and adriamycin) and verapamil alone in mice (Lonsberry et al 1994) have demonstrated that the MDR modulators can exhibit toxic side effects. The combination of the anthelmintics and the MDR modulators has been studied in jirds and in sheep .…”