Calcium Entry Blockade and Excitation Contraction Coupling in the Cardiovascular System (with an attempt of pharmacological classification)

Abstract

Calcium may be considered as the final intracellular messenger of excitation-contraction coupling. In this report the main mechanisms involved in the cellular regulation of calcium movements are reviewed. Most of the pharmacological agents actually available for therapy interfere with the processes responsible for increase in cytoplasmic activator calcium. Study of the relation between contraction and calcium movements shows that blockade of calcium entry may cause inhibition of contraction. This has allowed to illustrate some of the characteristics of calcium channels in smooth muscle. Potential-operated channels are activated by changes in membrane potential, that can be evoked by K-rich solutions. They are completely blocked by calcium antagonistic dihydropyridines and diphenylpiperazines. This blockade shows (time-)-use-dependence. They are opened by calcium agonistic dihydropyridines. Receptor-operated channels are activated by the interaction of an agonist with its receptors; they are incompletely blocked by calcium antagonistic dihydropyridines and diphenylpiperazines. Endothelium appears to modulate the response of the adjacent smooth muscle to vasoconstrictors. This may be accounted for by modulation of calcium metabolism, both at the level of membrane channels and of intracellular stores. As a consequence, endothelium modulates the action of calcium entry blockers. Study of isolated human tissues illustrates difference in drug sensitivity between cardiac and smooth muscle. Human isolated coronary arteries are sensitive to nifedipine concentrations found in the blood of patients receiving therapeutic regimen. These concentrations do not alter the contractility of the isolated human myocardium. Differences between drugs may be explained assuming that they may interact with one of the states (closed, open, inactivated) of the Ca channels. This also helps the understanding of tissue selectivity of some compounds. A pharmacological classification of calcium entry blockers may be proposed. This classification is a rationale to differentiate between the various clinical indications of drugs affecting calcium movements.