Abstract. The cardioprotective effects of the novel sodium / hydrogen exchanger-1 (NHE-1) inhibitor KR-32560 {[5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine} were studied in an anesthetized rat model of 30-min ischemia / 2.5-h reperfusion heart injury. KR-32560 (0.01 -1 µM) dose-dependently inhibited NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. KR-32560 at 0.1 and 1.0 mg / kg (i.v. bolus, given 10 min before ischemia) reduced infarct size from 65.9% (control) to 49.7% and 32.7%, respectively, while reducing the extension of myocardial injury (mm 3 / g of left heart weight) from 405.1 (control) to 302.9 and 185.4, respectively (all P<0.05 vs control). KR-32560 dose-dependently reduced the total number of ventricular premature beats (VPBs) during ischemia from 510.2 (control) to 353.8 and 134.2 beats (all P<0.05, n = 6), while reducing ventricular tachycardia (VT) incidence from 49.3 (control) to 26.8 and 4.3 and VT duration from 249.2 s (control) to 150.5 and 26.7 s (all P<0.05, n = 6). KR-32560 dose-dependently reduced ventricular fibrillation (VF) incidence from 19.0 (control) to 9.2 and 1.2 and VF duration from 88.0 s to 34.5 and 2.8 s (all P<0.05, n = 6). KR-32560 also exerted similar effects on reperfusion arrhythmias, except for VPBs. These results indicate that KR-32560 may exert significant cardioprotective effects in ischemia/ reperfusion heart injury.

The effects of a novel sodium/hydrogen exchanger-1 (NHE-1) inhibitor, KR-32568, were studied in an anesthetized rat model of 30 min ischemia/2.5 h reperfusion heart injury. KR-32568 dose-dependently inhibited NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. In our anesthetized rat model, KR-32568 reduced infarct size from 67 (control) to 43 and 24% at 0.1 and 1.0 mg/kg (i.v. bolus, given 10 min before ischemia), respectively. KR-32568 at the same doses also significantly reduced the total number of ventricular premature beats during ischemia/reperfusion from 530 (control) to 266 and 115 beats, ventricular tachycardia (VT) incidence from 51 (control) to 21 and 8, VT duration from 238 s (control) to 63 and 33 s, ventricular fibrillation (VF) incidence from 17 (control) to 8 and 0, and VF duration from 85 s to 18 and 1 s. These results indicate that KR-32568 may exert potent cardioprotective effects in rats via inhibition of sodium/hydrogen exchanger-1.