Pathophysiology of cardiomyocytes.
Isolated cardiomyocytes lend themselves very well to the quantification of pathological damage and to the determination of reversible versus irreversible changes. These single cells were used to study the cellular response to a variety of pathologic stimuli that impair structure and function. Degenerative alterations are accompanied by hyperactivation and irreversible rounding up of otherwise quiescent rod-shaped cells. Stereotypic degenerative changes and loss of sarcolemma-bound Ca2+ were seen during prolonged severe hypoxia, exposure to either depolarizing concentrations of potassium, veratrine, acylcarnitines, cationic amphiphiles, free-radical-generating systems, cardiac glycosides, or uncouplers of oxidative phosphorylation. Since the presence of extracellular Ca2+ is a prerequisite to obtain cell degeneration in most of these aggressive insults and since cellular Ca2+ overload parallels the damage, we studied the influence of representative compounds of the various subclasses of Ca2+ antagonists: verapamil, nifedipine, nicardipine, and diltiazem (Ca2+ blockers with high affinity for cardiac slow Ca2+ channels), cinnarizine, flunarizine, lidoflazine, and mioflazine (Ca2+ blockers with no affinity for cardiac slow Ca2+ channels). The non-slow-channel-blocking drugs were generally superior in protection against the imposed insults suggesting that prevention of Ca2+ overload is not correlated with slow channel blockade. For the latter group of drugs, other (hitherto not elucidated) mechanisms of membrane-drug interactions seem to be responsible for the preservation of Ca2+ homeostasis during the induction of pathological Ca2+ influx.
Borgers
M
M
Department of Life Sciences, Janssen Pharmaceutica, Beerse, Belgium.
Ver Donck
L
L
Vandeplassche
G
G
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006801:Humans; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure
D002121:Calcium Channel Blockers; D002118:Calcium