Calcium antagonists in experimental atherosclerosis. Use-dependence of isradipine: a potential explanation for enhanced action in atherosclerotic animals and tissue selectivity.
In the context of atherosclerosis, calcium antagonists should be evaluated from two points of view: their hemodynamic action on the atherosclerotic cardiovascular system, and their preventive action on atherosclerosis. Contraction of atherosclerotic vessels in response to vasoconstrictors, especially serotonin and acetylcholine, is enhanced mainly because of endothelial dysfunction. Due to their antivasoconstrictor effect, calcium antagonists partly compensate for this endothelial dysfunction. Agents which show a pronounced 'use-dependence', such as isradipine, are of particular interest as their action increases with the intensity of contraction. Therefore, their action is most prominent where it is most needed. Nevertheless, experiments in atherosclerotic animals indicate that the dose has to be chosen more cautiously than for young animals, as the dose-response curve for several effects is bell-shaped. Calcium antagonists also interfere with the process of atherosclerosis. In cholesterol-fed rabbits, lesion development is reduced, and regression after reverting to a normal diet is modestly enhanced. Calcium antagonists do not lower blood lipid levels. However, they attenuate proliferative lesions following endothelial damage due to a balloon catheter or electrical stimulation. The mechanism of these effects is still not clear. Blockade of the potential-sensitive L-type calcium channel is probably the important mechanism. Many types of cells (macrophages, other leukocytes and platelets, smooth muscle cells, connective tissue cells, endothelium, etc.) are involved in the genesis of atherosclerotic plaques, but it is not known which of these are the important targets of calcium antagonists. Calcium antagonists are most effective when administered at the onset of atherosclerosis, as they probably inhibit events occurring during the initiation of the atherosclerotic process.(ABSTRACT TRUNCATED AT 250 WORDS)
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Cardiovascular Unit of Preclinical Research, Sandoz Pharma, Basle, Switzerland.
Rüegg
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D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000517:prevention & control; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002319:Cardiovascular System / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017275:Isradipine; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects
D002121:Calcium Channel Blockers; D011725:Pyridines; D017275:Isradipine