Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle.
Ca2+ overload is known to play a major role in cell dysfunctioning in ischaemia/reperfusion and in cardiac glycoside intoxication. Suppression of Ca2+ overload or its consequences may therefore improve cellular function in these pathological conditions. Recent evidence suggests that Ca2+ overload occurs secondary to Na+ overload. Both depressed efflux and increased influx mechanisms have been mentioned as factors contributing to Na+ load. Prevention of this initial Na+ overload, without interfering with the normal Na+ current during the action potential, may therefore represent a novel pharmacological approach in the management of Ca2+ overload. The new cardioprotective drug R 56865 potently protects the heart against Ca2+ overload: ischaemia induced and ouabain induced arrhythmias and cell death are prevented in the absence of negative inotropism (no L-type Ca2+ channel blockade). At least three interactions at the cellular level may be held responsible for protection in these conditions. First, excessive Na+ entry into myocardial cells due to non-inactivating Na+ channels in depolarised cells is inhibited at concentrations that do not affect action potential configuration or contractile force. This leads to prevention of Na+ overload and subsequent Ca2+ overload and cell death. Second, R 56865 inhibits the transient inward current in Ca(2+)-(over)loaded cells, thus effectively preventing after-depolarisations and triggered propagated contractions. It has been proposed that R 56865, independent of its action on Na+ loading, might reduce oscillatory Ca2+ release from the intracellular Ca2+ stores, without interfering with the normal release mechanisms. Third, the drug attenuates K+ efflux in Na+ and Ca2+ loaded cells. In this way, R 56865 may contribute to prevention of action potential shortening and inhomogeneous repolarisation.(ABSTRACT TRUNCATED AT 250 WORDS)
Ver Donck
L
L
Department of Physiology, Life Sciences, Janssen Research Foundation, Beerse, Belgium.
Borgers
M
M
Verdonck
F
F
D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000517:prevention & control; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D015220:Calcium Channels; D010880:Piperidines; D015221:Potassium Channels; D015222:Sodium Channels; D013844:Thiazoles; C054551:R 56865; D012964:Sodium; D002118:Calcium