Cariporide, a highly selective Na+/H+ exchange inhibitor, suppresses the reperfusion-induced lethal arrhythmias and "overshoot" phenomenon of creatine phosphate in situ rat heart

The effects of a highly selective Na+/H+ exchange inhibitor cariporide on t he reperfused in situ heart were assessed. Male Sprague-Dawley (SD) rats we ighing 200-300 g were anesthetized with pentobarbital sodium (60 mg/kg, i.p .) and divided into four groups; sham-operated (n = 6), vehicle (n = 15), 0 .1 mg/kg (n = 15), and 1.0 mg/kg (n = 15) groups. The left coronary artery was ligated for 5 min and then released with ECG and blood pressure monitor ing. Cariporide was intravenously given as a bolus 2 min before the reperfu sion. The heart was rapidly excised and frozen 3 min after the onset of ven tricular fibrillation, otherwise 10 min after the reperfusion. The adenosin e triphosphate (ATP), creatine phosphate (CP), and glycogen contents were m easured in the reperfused ischemic myocardium by using an enzymatic fluorom etric assay technique. The incidence of the lethal ventricular fibrillation was 53% in the vehicle, 27% in the low-dose and 7% in the high-dose group. The concentrations (mean I SEM) of ATP, CP (nmol/mg protein), and glycogen (nmol as glucose/mg protein) were 74 +/- 4, 255 +/- 19, and 164 +/- 21 in the sham, 23 +/- 4, 763 +/- 70, and 61 +/- 7 in the vehicle, 27 +/- 4, 180 +/- 16, and 104 +/- 14 in the low-dose, and 32 +/- 4, 178 +/- 24, and 108 /- 8 in the high-dose groups, respectively, indicating that cariporide sign ificantly blunted CP overshoot as well as glycogenolysis during reperfusion . Thus cariporide can be expected to depress arrhythmogenesis and protect t he metabolic status of the heart.