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Cardioprotective effects of KR-30450, a novel K+(ATP) opener, and its major metabolite KR-30818 on isolated rat hearts.

Authors
Jung, YS; Moon, CH; Cho, TS; Yoo, SE; Shin, HS
Citation
Japanese journal of pharmacology, 76(1):65-73, 1998
Journal Title
Japanese journal of pharmacology
ISSN
0021-51981347-3506
Abstract
The cardiac effects of KR-30450 ((-)-(2R)-2-([1,3]-dioxolan-2-yl)-2-methyl-4-(2-oxopyrrolidin++ +-1-yl)-6-nitro-2H-1-benzopyran), a newly synthesized potassium channel activator, and its major metabolite KR-30818 ((-)-(2R)-2-hydroxymethyl-2-methyl-4-(2-oxopyrrolidin-1-yl)-6-nitr o-2H-1-benzopyran) were compared with those of lemakalim, a prototype of this class, in isolated globally ischemic rat hearts. KR-30450 and KR-30818 significantly improved reperfusion cardiac function (LVDP, left ventricular developed pressure; double product, LVDP x heart rate/1000), their potency being 5.2-fold and 0.7-fold greater than lemakalim (ED50 for recovering predrug double product: 0.10, 0.80 and 0.54 microM, respectively). KR-30450 and KR-30818 significantly attenuated reperfusion contracture and lactate dehydrogenase release with potency greater than and equal to lemakalim, respectively. They significantly increased time to contracture (TTC) during ischemia in a dose-dependent manner with a greater potency than lemakalim (EC25 for increasing TTC: 1.2, 2.1 and 3.2 microM, respectively). The protective effects of three compounds on the measured parameters were reversed by glyburide, a selective K+(ATP) blocker. In non-ischemic hearts, KR-30450 and lemakalim exerted weak negative inotropism at high concentrations and KR-30818 had no effects, whereas the three compounds significantly increased coronary flow at doses studied. Glyburide completely reversed preischemic cardiodepressant effects of these compounds but not their effects on coronary flow. In conclusion, KR-30450, a recently developed K+(ATP) opener, exerted more potent cardioprotective effects than lemakalim, and its major metabolite KR-30818 may play a significant role in its action in vivo.
MeSH terms
AnimalsAntihypertensive Agents/pharmacologyBenzopyrans/antagonists & inhibitors/metabolism/*pharmacologyCromakalim/pharmacologyDose-Response Relationship, DrugGlyburide/pharmacologyHeart/*drug effectsHeart Rate/drug effectsHypoglycemic Agents/pharmacologyL-Lactate Dehydrogenase/metabolismMaleMyocardial Contraction/*drug effectsMyocardial Ischemia/drug therapyMyocardial Reperfusion Injury/drug therapyPotassium Channel BlockersPotassium Channels/*agonistsPyrimidines/antagonists & inhibitors/*pharmacologyPyrrolidinones/metabolism/*pharmacologyRatsRats, Sprague-DawleyRegional Blood Flow/drug effectsVasodilator Agents/pharmacology
PMID
9517406
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
정, 이숙문, 창현
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