Inhibitory Effects of Pre-ischemic and Post-ischemic Treatment With FR 168888, a Na+/H+ Exchange Inhibitor, on Reperfusion-Induced Ventricular Arrhythmias in Anesthetized Rat

Article

Author: Zhu, Bing-Mei ; Kamiya, Kazunori ; Miyamoto, Shigeki ; Komori, Sadayoshi ; Hashimoto, Keitaro

Effects of pre-ischemic and post-ischemic treatment with FR 168888 (5-hydroxymethyl-3-(pyrrol-1-yl) benzoylguanidine methanesulfonate), a Na+/H+ exchange inhibitor, on reperfusion-induced ventricular arrhythmias were examined in an ischemia/reperfusion model of anesthetized rat. FR 168888 (0.3 mg/kg) significantly reduced the incidence of ventricular fibrillation (VF) and mortality induced by reperfusion following 5-min coronary occlusion, when it was intravenously administered 5 min before coronary artery occlusion. Post-ischemic treatment with FR 168888 (0.3-10 mg/kg), i.e. given 3 min after the start of occlusion, reduced the incidence of VF and mortality. In order to examine the optimal time of administration, FR 168888 (3 mg/kg) was administered 1 or 3 min after the start of occlusion or immediately before reperfusion. There was no significant difference in the reduction of VF and mortality among the three post-ischemic treatment groups. FR 168888 (3 and 10 mg/kg) significantly increased the blood pressure during ischemia without affecting the heart rate. These results indicate that FR 168888 has antiarrhythmic effects on reperfusion-induced arrhythmias even administered after coronary occlusion.

01 Jan 1999·Japanese Journal of Pharmacology

Protective Effect of FR168888, a New Na+/H+ Exchange Inhibitor, on Ischemia and Reperfusion-Induced Arrhythmia and Myocardial Infarction in Rats: In Comparison With Other Cardioprotective Compounds

Article

Author: Yamamoto, Nobuhiro ; Sugimoto, Toshiko ; Seki, Jiro ; Maeda, Kazuhiro ; Ohkubo, Kazumi ; Goto, Toshio ; Ohara, Fumihiro ; Ozaki, Tohru

We have studied the effects of FR168888 (5-hydroxymethyl-3-(pyrrol-1-yl)benzoylguanidine methanesulfonate), a new Na+/H+ exchange inhibitor, on ischemia and reperfusion-induced arrhythmia and myocardial infarction in anesthetized rats and compared them with those of other cardioprotective compounds. FR168888 had a potent inhibitory effect on Na+/H+ exchange of rat lymphocytes acidified with Na+-propionate with a Ki value of 6.4 nM. Pretreatment with FR168888 (0.032-0.32 mg/kg, i.v.) reduced or completely abolished the ventricular fibrillation (VF) induced by reperfusion after 5 min of regional ischemia, while lidocaine, a class I antiarrhythmic agent, showed less effect against VF as compared with FR168888. The size of myocardial infarction induced by 60-min ischemia and 60-min reperfusion was attenuated by FR168888 dose-dependently (1.0-10 mg/kg, i.v.), and ventricular tachycardia and VF were significantly reduced during the ischemic period. In contrast, propranolol and diltiazem did not show such protective effects on myocardial infarct size. In addition, FR168888 did not change hemodynamic parameters in rats. These results indicate that FR168888 has a strong inhibitory effect on Na+/H+ exchange and that treatment with FR168888 can protect the heart from arrhythmia and myocardial cell death in ischemic and reperfused situations.

01 Apr 1997·The Annals of Thoracic SurgeryQ2 · MEDICINE

The Contribution of Na/H Exchange to Ischemia-Reperfusion Injury After Hypothermic Cardioplegic Arrest

Q2 · MEDICINE

Article

Author: Hajime Ichikawa ; Kazuhiro Maeda ; Hikaru Matsuda ; Yoshiki Sawa ; Koji Kagisaki ; Norihide Fukushima ; Ryota Shirakura ; Takashi Yamauchi

BACKGROUNDNa+/H+ exchange has been reported to be one of the key mechanisms in myocardial ischemia-reperfusion injury. However, the effect of temperature on Na+/H+ exchange is not fully understood.METHODSSodium-propionate-induced cell swelling, an indicator of the function of the Na+/H+ exchanger, was measured in rat thymic lymphocytes. A Langendorff perfused rat heart model was also employed to investigate the effect of the pharmacologic inhibition of Na+/H+ exchange on the recovery of cardiac function after hypothermic ischemia. This was done using FR168888, an inhibitor of Na+/H+ exchange.RESULTSIn the in vitro study, rat lymphocytes were observed to swell at 17 degrees, 22 degrees, and 27 degrees C, indicating that the Na+/H+ exchanger remains functional even under hypothermic conditions. FR168888 was found to significantly inhibit Na+/H+ exchange-induced cell swelling, even at 17 degrees C. In the in vivo study, pretreatment with FR168888 was found to prevent the deterioration of ventricular function, even after 5 hours of hypothermic cardioplegic arrest. This was associated with a decrease in the reperfusion-induced elevation in resting tension.CONCLUSIONSThese results suggest that Na+/H+ exchange in the heart still occurs, even under hypothermic conditions, and contributes to reperfusion injury, even after hypothermic cardioplegic arrest.

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Indication	Highest Phase	Country/Location	Organization	Date
Myocardial Infarction	Discovery	JP	Fujisawa Pharmaceutical Co., Ltd.	-

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