Pharmacological Actions of Calmidazolium, a Calmodulin Antagonist, in Cardiovascular System

Abstract

ABSTRACTThe effects of calmidazolium (CMZ) on various cellular functions in many cells, especially in heart, vascular smooth muscle (VSM), endothelial, and juxtaglomerular (JG) cells are summarized in this review. Many intracellular Ca2+ signals are mediated by the ubiquitous calcium binding protein, calmodulin (CaM), which functions as a Ca2+‐dependent regulator of a number of pathways including cyclic nucleotide metabolism, ion transport, protein phosphorylation/dephosphorylation cascades, cytoskeletal function, cell proliferation, and G protein‐mediated signaling. Therefore, many CaM‐dependent cellular functions can be modulated by calmodulin antagonists, including CMZ. The mechanism by which CaM antagonists inhibit CaM activity involves a direct binding of the drugs to CaM. Most CaM antagonists, including CMZ, contain a hydrophobic benzene‐ring structure. Therefore, lipid solubility may be one determinant of the ability of a drug to inhibit CaM, but other factors, such as its chemical structure or its ionic characteristics, are also involved. CMZ exerts its inhibitory effect on CaM‐regulated enzymes, not only via its binding to CaM, but probably also directly by interfering with the CaM‐target enzyme. However, CMZ has also some nonspecific effects, such as blockade of L‐type Ca2+, K+, Na+ channels, and sarcoplasmic reticulum (SR) Ca2+‐release channels. Therefore, it should be noted that CMZ, at high concentrations, may have other pharmacologic effects as well.SUMMARY AND CONCLUSIONSIn this review, we summarized the effect of CMZ on various cellular functions in many cells, especially those in the cardiovascular system (heart cells, VSM cells, endothelial cells, and JG cells). We tried to cover most of the effects of CMZ (acting by a variety of mechanisms) on the ion channels and ion pumps of cardiac muscle and vascular smooth muscle cells. CMZ affects many cellular functions via inhibition of CaM (Fig. 5). Since CaM is a ubiquitous calcium‐binding protein, which functions as a Ca2+‐dependent regulator of several pathways (such as MLCK, CaMK, and type I PDE), many CaM‐dependent cellular functions are modulated by the drug. For example, CMZ inhibits the activation of brain PDE by CaM with a 500 times higher potency than trifluoperazine. Therefore, CMZ seems to be the most powerful inhibitor of CaM‐regulated cellular functions. However, CMZ, has also some nonspecific effects, such as blockade of CaL channels, K+ channels, Na+ channels, and SR Ca2+‐release channels. With respect to CMZ blockade of CaL channels, CMZ reduces CaL current almost as much as CaL channel blockers (DHPs). However, when CMZ was introduced intracellularly via patch pipette, CMZ actually stimulated CaL current through inhibition of CaM‐dependent PDE (type I), which in turn stimulates cAMP/PKA system.In summary, the major goal of this review was to provide the reader with various specific and nonspecific actions of CMZ on cardiovascular system. We emphasized that at high concentrations CMZ exerts many different pharmacologic effects.