Consequences of uncontrolled calcium entry and its prevention with calcium antagonists.
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 beta-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 Ca+-deprived myocardial fibres return to a normal Ca2+-containing medium.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D009336:Necrosis / Q000517:prevention & control; D051381:Rats
D002121:Calcium Channel Blockers; D000255:Adenosine Triphosphate; D007545:Isoproterenol; D002118:Calcium