Protective effects of R 56 865 against ischemic damage in the isolated rabbit heart.
We examined the role of calcium in the pathogenesis of ischemic cardiac cell death in the isolated working rabbit heart subjected to normothermic global ischemia followed by reperfusion. Apart from measurements of cardiodynamic function and ultrastructural examination, we also used a cytochemical procedure to localize exchangeable calcium pools at the ultrastructural level. The effects of verapamil (1.5 x 10(-8) M, 3 x 10(-8) M) (high affinity for L-type calcium channels) were compared with those of R 56 865 (4 x 10(-7) M) (Ca2+ overload blocker with low affinity for the L-type calcium channels). A severe depression of cardiac function was observed after solvent or verapamil pretreatment and 25 min of ischemia followed by reperfusion. R 56 865 treatment resulted in a significantly improved postischemic recovery when compared to solvent and verapamil treatment groups. The ultrastructural and cytochemical results corroborated the hemodynamic findings. In solvent and verapamil-treated hearts, irreversible damage was observed mainly in mid- and endocardial areas. Ultrastructural changes were accompanied by shifts in calcium localization: i.e. loss of sarcolemmal calcium binding capacity, accumulation of calcium precipitate in the mitochondria. In the R 56 865 treatment group, damage was limited to some cells scattered in the midcardial areas. In conclusion, R 56 865, which has little affinity for the slow channels was highly effective in protecting against ischemic damage, indicating that, in this experimental set-up, the calcium responsible for cellular Ca2+ overload is not entering via L-type calcium channels.
Vandeplassche
G
G
Janssen Research Foundation, Beerse, Belgium.
Thoné
F
F
Borgers
M
M
D000818:Animals; D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003327:Coronary Disease / Q000517:prevention & control*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D052160:Benzothiazoles; D015220:Calcium Channels; D010880:Piperidines; D013844:Thiazoles; C054551:R 56865; D014700:Verapamil; D002118:Calcium