Consequences of uncontrolled calcium entry and its prevention with calcium antagonists

Abstract

Heart muscle fibres always undergo severe functional and structural alterations, finally resulting in necrotization, if free extracellular Ca²⁺ ions penetrate abundantly through the sarcolemma membrane into the myoplasm, so that the capacities of the Ca²⁺ binding or extrusion processes become overpowered. The crucial reaction consists of high-energy phosphate exhaustion which is brought about (a) by excessive activation of Ca²⁺-dependent intracellular ATPases, and (b) by Ca²⁺ induced impairment of the mitochondria. Intracellular Ca²⁺ overload proved to the common denominator in the pathogenesis of severe myocardial fibre injury and death produced under the following circumstances: Overdoses of β-adrenergic catecholamines, dihydrotachysterol or vitamin D₃ alimentary K⁺ or Mg²⁺ deficiency, hereditary cardiomyopathy of Syrian hamsters. Moreover, intracellular Ca²⁺ overload develops in the course of myocardial hypoxia or ischaemia thus causing additional precipitous damage of the mitochrondria. Following our first observations made in 1968, it has turned out that in all these cases, Ca²⁺ antagonists are capable of protecting myocardial cell integrity in that they prevent excessive transmembrane Ca²⁺ uptake. This is also true of the Ca²⁺ paradox: Ca²⁺ antagonists possibly inhibit the development of sarcolemmal leaks in the Ca²⁺ deprived myocardium. However, it is more likely that Ca²⁺ antagonists restrict the exaggerated influx of Ca²⁺ through these leaks, when the Ca²⁺ myocardial fibres return to a normal Ca²⁺ medium.