PubMed · 3568334
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1987. Calcium-entry blockage: basic concepts and clinical implications.. https://pubmed.ncbi.nlm.nih.gov/3568334/
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The potential role that calcium antagonists play toward enhancing cardioprotection is discussed, while recognizing that they are much more heterogeneous than other classes of antihypertensive or antianginal agents. Similarities and differences between the mechanisms of action and clinical effects of individual drugs are discussed. Among these is the ability of some of them to reduce left ventricular hypertrophy rapidly while simultaneously and uniquely increasing right ventricular wall thickness. Although the clinical importance of this as a potential cardioprotective effect is undetermined, the renal protective effect of some calcium antagonists is discussed in detail.
The ability of dihydropyridine Ca2+ channel blockers (nicardipine, nimodipine and nisoldipine) to inhibit low density lipoprotein (LDL) oxidation and to prevent the cytotoxicity of oxidized LDL for lymphoid cells have been compared. The lipid peroxidation of LDL promoted either by UV radiation or by copper ions was inhibited (antioxidant effect) in a dose-dependent manner by nisoldipine (IC50 values were evaluated at around 10 microM), whereas nimodipine was less potent (IC50 around 50-100 microM) and nicardipine almost inactive. The cytotoxicity of LDL treated (by UV or by copper) in the presence of effective antioxidant concentrations of dihydropyridine Ca2+ channel blockers was less than that of unprotected oxidized LDL (i.e. LDL oxidized in the absence of any dihydropyridine Ca2+ channel blockers). The inhibition of the cytotoxic effect of LDL oxidized in the presence of dihydropyridine Ca2+ channel blockers correlated well with protection from oxidation by these compounds. Beside this indirect protective effect, dihydropyridine Ca2+ channel blockers exhibit a direct protective effect for cells against the toxicity of previously oxidized LDL. Although complete protection cannot be obtained because of the cytotoxicity of the dihydropyridine compounds per se, the IC50 values were 6 +/- 2 and 80 +/- 20 microM for nisoldipine and nimodipine, respectively. The potential relevance to the prevention of atherogenesis is discussed.
Calcium fluxes play a key role in controlling many physiologic processes and responses in the body. The past few years have witnessed major advances in understanding of L-type calcium channels and their blockade with calcium channel antagonists. The L-type calcium channels comprise 5 subunits termed alpha 1, alpha 2, beta, gamma, and delta. Elucidation of the mechanisms of action of the calcium channel antagonists has been advanced by cloning and genetic manipulation of these subunits. The alpha 1 subunit appears to be responsible for channel opening and voltage dependency, and it contains receptors for calcium channel antagonists; these geographically distinct receptors correspond to each of the 3 different chemical classes of antagonists, exemplified by diltiazem, nifedipine, and verapamil. Diltiazem appears to have an inhibitory effect on mitochondrial sodium-calcium exchange that is unique among calcium channel antagonists. Preliminary data suggest that a diltiazem-specific receptor also exists in the endothelium. It appears, therefore, that despite advances in the understanding of L-type calcium channels, much remains to be learned about other possible receptors for the calcium channel antagonists.