Effects of Cariporide (HOE642) on Myocardial Infarct Size and Ventricular Arrhythmias in a Rat Ischemia/Reperfusion Model: Comparison with Other Drugs

Abstract

The effects of pretreatment with cariporide on myocardial infarction and ventricular arrhythmias in a rat model of ischemia/reperfusion were compared with those of nicorandil, propranolol, and nifedipine. Each drug was administered intravenously before coronary occlusion. Cariporide at 0.1, 0.3, and 1 mg/kg significantly reduced the infarct size (infarct mass/risk mass) from 28 ± 4% (vehicle control value) to 9 ± 3, 9 ± 3, and 5 ± 2%, respectively. Propranolol at 2.5 mg/kg also significantly reduced the infarct size to 11 ± 1%. Neither nicorandil nor nifedipine was effective when given at 0.1 mg/kg. Cariporide dose dependently decreased the number of ischemia-induced ventricular premature beats (VPB), incidence and duration of ventricular tachycardia, and the number of reperfusion-induced VPB. Nicorandil was effective against only VPB after reperfusion, and propranolol reduced only postischemic arrhythmias, but nifedipine had no effect on either type of arrhythmia. In summary, cariporide reduced the infarct size and dose dependently suppressed arrhythmias induced by ischemia/reperfusion in rats. In contrast, in the present rat model, the doses of the other three drugs used in this study did not show comparable effects.

Cardioprotective Effects of [5-(2-Methyl-5-Fluorophenyl)furan-2-ylcarbonyl]guanidine (KR-32568) in an Anesthetized Rat Model of Ischemia and Reperfusion Heart Injury

“…The arrhythmogenicity in our experimental model appeared to be more severe compared to the similar rat model with a protocol of 20 min ischemia/2 h reperfusion [10] , in part due to the longer period of ischemia and reperfusion, despite which most of the VPBs, VT and VF were observed to occur throughout the period of ischemia and up to the fi rst 10 min of reperfusion in our model as reported by others [10,23] . KR-32568 dose-dependently and signifi cantly reduced the occurrence of all three types of ventricular arrhythmia during ischemia/reperfusion as refl ected in total number of VPBs, total events and duration of VT and VF, these effects being in line with those for cariporide, a well-characterized prototype NHE-1 selective inhibitor in the similar rat model of ischemia/reperfusion heart injury [10,30] , probably due to its peculiar mode of action as described in the following section. The differential antiarrhythmic effects on VPBs, VT and VF appear to depend on the types of drugs, the multiplicity of their action and the variable mechanisms of arrhythmogenesis [31].…”

“…0.05). These cardioprotective effects of KR-32568 were comparable to those of a prototype selective NHE-1 inhibitor cariporide demonstrated in various animal models of ischemia/reperfusion heart injury [10,20,[30][31][32] .…”

“…IC 50 values for cariporide and eniporide: 0.075 and 0.044, respectively, in rat platelets, and 0.023 and 0.04, respectively, in human platelets). The area at risk and the infarct size were 48.9 and 66.6% for the control group in rats subjected to a 30-min occlusion of coronary artery followed by 2.5-hour reperfusion, whereas those values were 50 and 28%, respectively, in a similar rat model adopting a protocol of 20 min ischemia/2 h reperfusion, thus indicating the induction of a more severe cardiac injury by our experimental protocol and technique [10] . KR-32568 administered by i.v.…”

“…With respect to pharmacological modulation of ischemia/reperfusion heart injury, selective sodium/hydrogen exchanger isoform-1 (NHE-1) inhibitors such as cariporide, eniporide and zoniporide are reported to hold considerable promise for the immediate future as novel therapeutic modality to protect against ischemia/reperfusion heart injury [1,[9][10][11][12][13] based on the following mechanism [14,15] . During cardiac ischemia, cytosolic acidosis-stimulated NHE-1 causes Na + infl ux in exchange for H + effl ux, resulting in Na + overload within the cardiac cell with concurrent inhibition of Na + /K + ATPase during ischemia.…”

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

“…We found that reduction of vasospasm from nifedipine treatment partially reversed cardioprotection. Nifedipine administration, itself, is not thought to be effective at reducing infarct size, although it may improve left ventricular function following ischemia [25][26][27]. Therefore, it is possible that nifedipine may be inhibiting cardioprotection via a cardiomyocyte specific mechanism that requires calcium.…”