Differential action of KR‐31378, a novel potassium channel activator, on cardioprotective and hemodynamic effects

Abstract

The cardioprotective and hemodynamic effects of KR-31378, a highly cardioselective ATPsensitive potassium channel activator with minimal hypotensive effect, were evaluated in rats and dogs, and compared with those of BMS-191095 and lemakalim. KR-31378 did not show any significant effect on methoxamine-induced aortic constriction up to doses of 300 µM, whereas BMS 191095 produced a moderately potent relaxant effect (IC 50 : 9.0 µM). In conscious rats, KR-31378 slightly increased blood pressure only at high dose (100 mg/kg, iv), unlike BMS-191095 that dose-dependently decreased blood pressure (ED 20 : 2.03 mg/kg). In anesthetized beagle dogs, KR-31378 was approximately 100-fold less potent than BMS-191095 for most hemodynamic parameters (iv ED 20 for blood pressure lowering: 33.7 and 0.37 mg/ kg, respectively). In anesthetized rats subjected to 45-min coronary occlusion and 90-min reperfusion, KR-31378 (iv) dose-dependently reduced the infarct zone from 58.6% to 42.1%, 36.6%, and 34.3% for 0.1, 0.3, and 1.0 mg/kg, respectively (P < 0.05), the effects being comparable to those of BMS 191095. In anesthetized beagle dogs that underwent 2-h occlusion followed by 4.5-h reperfusion, KR-31378 (2 mg/kg, iv infusion) markedly reduced the infarct zone from 48.7% in controls to 19.1% at a dose of 2 mg/kg (P < 0.05). The reduction in infarct zone afforded by KR-31378 in rats was inhibited by pretreatment with selective ATP-sensitive potassium channel blockers, sodium 5-hydroxydecanoate and glibenclamide. These results indicate that KR-31378 is a potent cardioprotective agent with potentially minimal hypotensive effects. Thus, it could be potentially useful in the prevention and treatment of acute myocardial infarction. Drug Dev.

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

“…Despite its status as the first cardioselective K + ATP -channel opener to dissociate vasorelaxant activity from cardioprotective activity (14,15,18,19), BMS-180448 was shown to still exert significant vasorelaxant activity in rat aorta contracted with various types of vasoconstrictors (phobol 12,13-dibutyrate, PGF 2α , U46619, KCl, and phenylephrine) via multiple mechanisms (36). Another cardioselective mitoK + ATP -channel opener BMS 191095 was reported to still retain significant vasorelaxant effect on methoxamine-contracted rat aortic preparations with an IC 50 value of 8.96 μM, despite its claimed high cardioselectivity over vasculature (7,16). Thus, the findings from the present study indicate that KR-31761 has greatly improved selectivity for a cardioprotective effect over a vasorelaxant effect when compared with other K + ATP -channel openers of the first generation including cromakalim and more recent cardioselective mitoK + ATPchannel openers such as BMS-180448 and BMS-191095.…”

“…Thus, the findings from the present study indicate that KR-31761 has greatly improved selectivity for a cardioprotective effect over a vasorelaxant effect when compared with other K + ATP -channel openers of the first generation including cromakalim and more recent cardioselective mitoK + ATPchannel openers such as BMS-180448 and BMS-191095. The cardioselectivity over vasorelaxant activity has been one of the important pharmacological properties required for cardioprotective K + ATP -channel openers (37), leading to the discovery of KR-31378, a highly cardioselective K + ATP -channel opener almost devoid of vasorelaxant activity (16). In agreement with its weak vasorelaxant effect on isolated rat aorta, KR-31761 induced a slight increase in both preischemic and reperfusion coronary flow only at the highest concentration, but without any significant difference compared with the vehicle group, indicating that the cardioprotective effect of KR-31761 can be directly attributed to its effect on myocardium rather than to a coronary dilatation.…”

“…), 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.…”

Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury

“…), placed on a homeothermic blanket control unit at 37 o C and then thoracotomized at the fifth intercostal space under artificial respiration (60 strokes/min, 10 ml/kg). Coronary artery occlusion was produced as previously described (Lee et al, 2001(Lee et al, , 2004. After 30 min or 45 min of occlusion, the coronary artery was reperfused by removal of the polyethylene tube.…”

KR-31378 Protects Cardiac H9c2 Cells from Chemical Hypoxia-Induced Cell Death via Inhibition of JNK/p38 MAPK Activation

“…1), was synthesized by the Korea Research Institute of Chemical Technology (Daejeon, Korea) as a chemical preconditioning agent [8]. KR-31378 is an antioxidant K ATP channel opener that has been shown to protect rat cortex neurons against iron-induced oxidative injury, and it significantly reduces infarct size in a model of rat transient cerebral ischemia [9][10][11]. KR-31378 is a potent reactive oxygen species (ROS) scavenging agent and demonstrates an antiapoptotic effect in smooth muscle cells [12].…”