Effects of [5-(2-Methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine (KR-32560), a Novel Sodium/Hydrogen Exchanger-1 Inhibitor, on Myocardial Infarct Size and Ventricular Arrhythmias in a Rat Model of Ischemia/Reperfusion Heart Injury

Abstract

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.

Pravastatin Inhibits Arrhythmias Induced by Coronary Artery Ischemia in Anesthetized Rats

“…During 30 min of ischemia, most VF occurred between 4 and 8 min. This arrhythmogenicity is similar to that reported by others using a similar rat model of ischemia / reperfusion with 30 min of ischemia (29). It is easily to understand that the ischemia-injured myocardium undergoes a period vulnerable to arrhythmogenic factors.…”

KR-31761, a Novel K+ATP-Channel Opener, Exerts Cardioprotective Effects by Opening Both Mitochondrial K+ATP and Sarcolemmal K+ATP Channels in Rat Models of Ischemia/Reperfusion-Induced Heart Injury

“…), and the surgical procedure was performed as previously described (16,32). The trachea was intubated and connected to a rodent ventilator (SAR 830 / P ventilator; CWE, Inc., Ardmore, PA, USA) for artificial ventilation with room air (stroke volume, 10 ml / kg; 60 strokes / min) to keep blood gases (pCO 2 and pO 2 ) within normal ranges.…”

Cardioprotective effects of the novel Na+/H+ exchanger-1 inhibitor KR-32560 in a perfused rat heart model of global ischemia and reperfusion: Involvement of the Akt-GSK-3β cell survival pathway and antioxidant enzyme

“…1) is significantly more potent in inhibiting intracellular pH recovery in PS120/NHE-1 (h NHE-1 transfected) cells compared to cariporide (Lee et al, 2005c). We also reported that KR-32560 significantly reduces myocardial infarction as well as the incidence of various types of ventricular arrhythmias in an anesthetized rat model of I/R heart injury (Park et al, 2005). It also exerts an inhibitory effect on the aggregation of washed rabbit platelets induced by collagen and arachidonic acid .…”

“…It also exerts an inhibitory effect on the aggregation of washed rabbit platelets induced by collagen and arachidonic acid . KR-32560 appears to mediate its beneficial effects through NHE-1 inhibition, as evidenced by its reduction of Na + propionate-induced, NHE-1-mediated rabbit platelet swelling (Park et al, 2005). In the present study, we evaluated the cardioprotective effects of KR-32560 in globally ischemic isolated rat hearts with special emphasis on elucidating the involvement of prosurvival proteins (Akt, GSK-3β and eNOS) and antioxidant enzymes.…”