KR-31378, a novel benzopyran analog, attenuates hypoxia-induced cell death via mitochondrial KATP channel and protein kinase C-ɛ in heart-derived H9c2 cells

Diazoxide acts more as a PKC‐ɛ activator, and indirectly activates the mitochondrial KATP channel conferring cardioprotection against hypoxic injury

“…As in the case of our previous study with KR-31378, a novel K ATP opener (Moon et al, 2004), the cardioprotective effect of diazoxide was observed only in the 'pre/during' group and not in the 'pre' or the 'during' group (Figure 3a and d). These results are inconsistent with other studies showing that cardioprotective efficacy was still demonstrable when diazoxide treatment was commenced during reperfusion (Hausenloy et al, 2004) or only before exposure to H 2 O 2 (Akao et al, 2003).…”

“…Other pharmacological actions of diazoxide have been known to include inhibition of succinate dehydrogenase (SDH) (Schafer et al, 1969); the present study, however, did not consider the contribution of SDH inhibition to diazoxide-induced cardioprotection, because the concentration of diazoxide used in our study was much lower (100 mM) than that needed to achieve SDH inhibition (B400 mM) (Schafer et al, 1969;Grimmsmann and Rustenbeck, 1998). As in the case of our previous study with KR-31378, a novel K ATP opener (Moon et al, 2004), the cardioprotective effect of diazoxide was observed only in the 'pre/during' group and not in the 'pre' or the 'during' group (Figure 3a and d). These results are inconsistent with other studies showing that cardioprotective efficacy was still demonstrable when diazoxide treatment was commenced during reperfusion (Hausenloy et al, 2004) or only before exposure to H 2 O 2 (Akao et al, 2003).…”

“…Soluble/particulate fractionation Subcellular soluble/particulate fractionation of cells was performed by a method previously described (Kim et al, 2003;Moon et al, 2004). Briefly, the cells were lysed using lysis buffer (20 mM Tris-HCl (pH 7.4), 2 mM ethylenediamine-N,N,N 0 ,N 0 -tetraacetic acid (EDTA), 5 mM ethylene glycol-bis-(2-aminoethyl ether)-N,N,N 0 ,N 0 -tetraacetic acid (EGTA), 5 mM dithiothreitol, 6 mM b-mercaptoethanol, 1 mM phenylmethylsulphonyl fluoride, 20 mM leupeptin, 50 mg/ml aprotinin).…”

Patents related to therapeutic activation of KATPand K2Ppotassium channels for neuroprotection: ischemic/hypoxic/anoxic injury and general anesthetics

“…However, by means of K ATP openers like diazoxide (known to stimulate insulin secretion) it is channel activation that is thought to confer cardio-and neuroprotection [18,20]. The neuroprotective effects of K ATP openers in conditions of cellular insults and injury such as ischemic/hypoxic/anoxic conditions, like iptakalim [21], arise from suppression of seizure propagation, suggesting a role for K ATP channels in acquired brain tolerance or 'preconditioning' as a neuroprotection mechanism [22][23][24][25][26][27][28][29][30], including inhalation anesthetic (i.e., sevoflurane, halothane and xenon preconditioning) [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], and as brain glucose metabolic sensors in hyperglycemia and hypoglycemia (i.e., brain regions of important K ATP expression include neurons in the hippocampus, hypothalamus, dorsal vagal nerve, substantia nigra, neocortex, and in glial cells). As K ATP channels contribute to regulation of food intake and body weight [50][51][52][53], they are also implicated in the development of obesity and diabetes.…”

KR-31378, a Potassium-Channel Opener, Induces the Protection of Retinal Ganglion Cells in Rat Retinal Ischemic Models

“…KR-31378, (2S,3S,4R)-N''-cyano-N(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine, is a newly developed benzopyran analog synthesized by the Korea Research Institute of Chemical Technology (Daejeon, Korea) (22). It was reported to be a potent K ATP -channel opener and it exhibited an antioxidant effect and antiapoptotic activities against ischemic brain injuries in rats in vitro (23 -25).…”