Myocardial protection by R 56865: a new principle based on prevention of ion channel pathology.
Intracellular Ca2+ overload is considered to be the final pathway leading to cell death under pathological conditions. However, both the route of Ca2+ entry and the site of action of cardioprotective drugs remain obscure. This was investigated using isolated adult rat and rabbit cardiomyocytes exposed to the experimental pathological stimuli veratridine, singlet O2, lysophosphatidylcholine, and ouabain. Under these conditions, the majority of cells displayed irreversible hypercontraction as a consequence of intracellular Ca2+ overload. Nifedipine did not prevent Ca2+ overload, but tetrodotoxin (TTX) and reduction of the extracellular Na+ concentration protected against the above pathological stimuli. This strongly suggests that intracellular Ca2+ overload after exposure to these pathological stimuli may be mediated via fast Na+ channel dysfunction, causing excessive entry of Na+, followed by Ca2+ overload via Na(+)-Ca2+ exchange. The new cardioprotective drug R 56865 dose dependently prevented hypercontracture induced by each of these stimuli, suggesting that R 56865 may interfere with this modified Na+ channel that is in a way different from class I antiarrhythmic drugs. This is regarded as a new cardiac cytoprotective principle.
Ver Donck
L
L
Department of Life Sciences, Janssen Research Foundation, Beerse, Belgium.
Borgers
M
M
D000818:Animals; D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000517:prevention & control*; D006321:Heart / Q000187:drug effects; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D026082:Singlet Oxygen; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014701:Veratridine / Q000494:pharmacology
D052160:Benzothiazoles; D008244:Lysophosphatidylcholines; D010880:Piperidines; D015222:Sodium Channels; D013844:Thiazoles; D026082:Singlet Oxygen; D013779:Tetrodotoxin; D010042:Ouabain; D014701:Veratridine; C054551:R 56865; D012964:Sodium; D010100:Oxygen; D002118:Calcium