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.
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.
Ohara
F
F
Department of Cardiovascular Diseases, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Sugimoto
T
T
Yamamoto
N
N
Ohkubo
K
K
Ozaki
T
T
Maeda
K
K
Seki
J
J
Goto
T
T
D000758:Anesthesia; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D019905:Benzyl Alcohol / Q000494:pharmacology; D001592:Benzyl Alcohols; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006146:Guanidines / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D017202:Myocardial Ischemia / Q000188:drug therapy*; D011422:Propionates / Q000737:chemistry; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000517:prevention & control*
D001592:Benzyl Alcohols; D006146:Guanidines; D011422:Propionates; D008012:Lidocaine; D011433:Propranolol; D004110:Diltiazem; C029658:propionic acid; D019905:Benzyl Alcohol; C400288:FR 168888