Calcium inhibitors : how do they act ?
J. Fournet (Grenoble)
Stimulation of the calcium ion is a cellular process involved in numerous biological phenomena [1,3,4]. This process is particularly essential to the contraction of smooth muscle. Numerous stimuli of the muscle cell (modification of membrane potential, neurotransmitters, hormones, mechanical deformation) produce a modification of ionic membrane permeability, notably for Na+ and Ca++. Thus Ca++, thanks to selective permeability, may passively enter the cell. After stimulation, the Ca++ concentration increases by a factor of around 100. Ca++ may also be liberated from intracellular sites, mitochondria and endoplasmic reticulum.
The selective penetration of Ca++ occurs by way of calcium channels, of which several types are known : 1) POC (potential-operated channels), which are channels capable of opening during depolarization. There are several types, the most important of which, especially in terms of pharmacologic control, are the type L (long-lasting) channels, 2) ROC (receptor-operated channels) which open by the mediation of membrane receptors, and 3) IROC (indirect operated channels) situated on the membrane of the sarcoplasmic reticulum. The voltage-dependent ionic channels [2] consist of a group of membrane proteins, excitable molecules capable of change in configuration in response to a given stimulus and allowing calcium penetration, itself responsible to depolarization. Within the cell, the ionized calcium behaves like a second messenger and unleashes a cascade of molecular reactions leading to the cell response.
The calciproteins are molecules capable of change in configuration during the increase in calcium concentration: in the smooth muscle the most important is calmodulin. The Ca++ - calmodulin complex interacts with light-chain myosin kinase (MKC1), the resulting enzyme function catalysing the phosphorylation of myosin. This action brings into play the entire process that initiates the formation of bridges between filaments of actin and myosin, the functional units which are the basis of contraction phenomena. This process involves the hydrolysis of ATP.
The inhibitors of the calcium channels act on voltage-dependent calcium channels. Verapamil, nifedipine and diltiazem serve to characterize the voltage-dependent channels of type L, and it is the interaction of these substances with this class of channels which underlies their therapeutic action. The inhibition of penetration of Ca++ ions is manifested by simultaneous phenomena: 1) interference with automatic cell activity and with the sudden depolarizations secondary to stimulation, and 2) modification of the calcium-dependent excitation-contraction coupling with decrease of the mechanical muscular response.
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