Inhibitors of swelling-activated chloride channels increase infarct size and apoptosis in rabbit myocardium.
Apoptosis is a significant contributor to myocardial cell death during ischemia-reperfusion and swelling-activated chloride channels (I(Cl,swell)) contribute to apoptosis. However, the relationship between I(Cl,swell) ischemia-reperfusion and apoptosis remains unknown. To further investigate this, New Zealand rabbits underwent a 20-min coronary artery occlusion (CAO) followed by 72 h of coronary artery reperfusion (CAR). Two I(Cl,swell) blockers, 5-nitro-2-[3-phenylpropylamino]benzoic acid (NPPB) and indanyloxyacetic acid 94 (IAA-94) (both 1 mg/kg), were administered prior to CAO and throughout the 72 h CAR. Infarct size (IS) was increased with NPPB and IAA-94 compared with control (vehicle) rabbits (51 +/- 2% and 48 +/- 3% and vs. 35 +/- 2%, respectively, P < 0.05). Similar results were found when NPPB was administered only during the reperfusion period. The percentage of TUNEL-positive nuclei in the border zone of the infarct was increased with NPPB compared with control (37 +/- 2% vs. 25 +/- 31%, P < 0.05) as well as the number of cytoplasmic histone-associated DNA fragments (0.45 +/- 0.06 vs. 0.33 +/- 0.04 absorbance units, P < 0.05). These findings support the concept that I(Cl,swell) channels play an important role in the determination of myocardial infarct size and apoptosis during ischemia-reperfusion.
Souktani
Rachid
R
Laboratoire de Pharmacologie, INSERM E 00.01 et IFR 93, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Ghaleh
Bijan
B
Tissier
Renaud
R
d'Anglemont de Tassigny
Alexandra
A
Aouam
Karim
K
Bedossa
Pierre
P
Charlemagne
Danièle
D
Samuel
Janelyse
J
Henry
Patrick
P
Berdeaux
Alain
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006016:Glycolates / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D009579:Nitrobenzoates / Q000494:pharmacology; D011817:Rabbits
D018118:Chloride Channels; D006016:Glycolates; D009579:Nitrobenzoates; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; C015765:MK 473