Protective effect of HOE642, a selective blocker of Na+-H+ exchange, against the development of rigor contracture in rat ventricular myocytes.
The objective of this study was to investigate the effect of Na+-H+ exchange (NHE) and HCO3--Na+ symport inhibition on the development of rigor contracture. Freshly isolated adult rat cardiomyocytes were subjected to 60 min metabolic inhibition (MI) and 5 min re-energization (Rx). The effects of perfusion of HCO3- or HCO3--free buffer with or without the NHE inhibitor HOE642 (7 microM) were investigated during MI and Rx. In HCO3--free conditions, HOE642 reduced the percentage of cells developing rigor during MI from 79 +/- 1% to 40 +/- 4% (P < 0.001) without modifying the time at which rigor appeared. This resulted in a 30% reduction of hypercontracture during Rx (P < 0.01). The presence of HCO3- abolished the protective effect of HOE642 against rigor. Cells that had developed rigor underwent hypercontracture during Rx independently of treatment allocation. Ratiofluorescence measurement demonstrated that the rise in cytosolic Ca2+ (fura-2) occurred only after the onset of rigor, and was not influenced by HOE642. NHE inhibition did not modify Na+ rise (SBFI) during MI, but exaggerated the initial fall of intracellular pH (BCEFC). In conclusion, HOE642 has a protective effect against rigor during energy deprivation, but only when HCO3--dependent transporters are inhibited. This effect is independent of changes in cytosolic Na+ or Ca2+ concentrations.
Ruiz-Meana
M
M
Servicio de Cardiología, Hospital General Universitari Vall d'Hebron, Paseo Vall d'Hebron 119-129, Barcelona 08035, Spain.
Garcia-Dorado
D
D
Juliá
M
M
Inserte
J
J
Siegmund
B
B
Ladilov
Y
Y
Piper
M
M
Tritto
F P
FP
González
M A
MA
Soler-Soler
J
J
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012298:Rigor Mortis / Q000201:enzymology / Q000517:prevention & control*; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*
D001639:Bicarbonates; D004791:Enzyme Inhibitors; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D012964:Sodium; D007770:L-Lactate Dehydrogenase; D002118:Calcium