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Effects of KR‐33028, a novel Na + /H + exchanger‐1 inhibitor, on ischemia and reperfusion‐induced myocardial infarction in rats and dogs
Author(s) -
Oh KwangSeok,
Seo Ho Won,
Yi Kyu Yang,
Lee Sunkyung,
Yoo Sungeun,
Lee Byung Ho
Publication year - 2007
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2007.00491.x
Subject(s) - bolus (digestion) , coronary occlusion , lactate dehydrogenase , ischemia , anesthesia , occlusion , myocardial infarction , chemistry , fissipedia , medicine , creatine kinase , cardiology , biochemistry , enzyme
The present study was performed to evaluate the cardioprotective effects of KR‐33028, a novel Na + /H + exchanger subtype 1 (NHE‐1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45‐min coronary occlusion and a 90‐min reperfusion, KR‐33028 at 5 min before occlusion (i.v. bolus) dose‐dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively ( P < 0.05). In anesthetized beagle dogs that underwent a 1.0‐h occlusion followed by a 3.0‐h reperfusion, KR‐33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle‐treated group to 16.4% ( P < 0.05), and reduced the reperfusion‐induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin‐I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. In separate experiments to assess the effects of timing of treatment, KR‐33028 (1 mg/kg, i.v. bolus) given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle‐treated group. In all studies, KR‐33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR‐33028 (30 μ m ), which was added to the heart preservation solution (histidin–tryptophan–ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and d P /d t max after reperfusion. Taken together, these results indicate that KR‐33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.