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The cardioprotective effects of KR-31761, a newly synthesized K+ATP opener, were evaluated in rat models of ischemia/reperfusion (I/R) heart injury. In isolated rat hearts subjected to 30-min global ischemia/30-min reperfusion, KR-31761 perfused prior to ischemia significantly increased both the left ventricular developed pressure (% of predrug LVDP: 17.8, 45.1, 54.2, and 62.6 for the control, 1 μM, 3 μM, and 10 μM, respectively) and double product (DP: heart rate × LVDP; % of predrug DP: 17.5, 44.9, 56.2, and 64.5 for the control, 1 μM, 3 μM, and 10 μM, respectively) at 30-min reperfusion while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31761 (10 μM) significantly increased the time to contracture during the ischemic period, whereas it concentration-dependently decreased the lactate dehydrogenase release during reperfusion. All these parameters were significantly reversed by 5-hydroxydecanoate (5-HD, 100 μM) and glyburide (1 μM), selective and nonselective blockers of the mitochondrial K+ATP (mitoK+ATP) channel and K+ATP channel, respectively. In anesthetized rats subjected to 30-min occlusion of left anterior descending coronary artery/2.5-h reperfusion, KR-31761 administered 15 min before the onset of ischemia significantly decreased the infarct size (72.2%, 55.1%, and 47.1% for the control, 0.3 mg/kg, i.v., and 1.0 mg/kg, i.v., respectively); and these effects were completely and almost completely abolished by 5-HD (10 mg/kg, i.v.) and HMR-1098, a selective blocker of sarcolemmal K+ATP (sarcK+ATP) channel (6 mg/kg, i.v.) administered 5 min prior to KR-31761 (72.3% and 67.9%, respectively). KR-31761 only slightly relaxed methoxamine-precontracted rat aorta (IC50: >30.0 μM). These results suggest that KR-31761 exerts potent cardioprotective effects through the opening of both mitoK+ATP and sarcK+ATP channels in rat hearts with a minimal vasorelaxant effect. Keywords:: KR-31761, cardioprotection, KATP, ischemia/reperfusion, rat heart

This study was designed to characterize vasorelaxant effects of BMS-180448 ((3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)), a prototype cardioselective ATP-sensitive potassium channel opener, in rat aorta. BMS-180448 relaxed phenylephrine-precontracted endothelium-intact aortic rings (IC(50): 0.97 +/- 0.29 micro M), the effect being significantly attenuated by removal of functional endothelium (IC(50): 1.95 +/- 0.23 micro M) and pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue. BMS-180448 completely relaxed endothelium-denuded aorta contracted with phorbol 12,13-dibutyrate, PGF(2)(alpha), and U46619 with a significantly greater potency (IC(50): 0.069 +/- 0.002, 0.055 +/- 0.002, and 0.068 +/- 0.008 micro M, respectively, P

We investigated whether oral administration of curcumin suppressed type II collagen–induced arthritis (CIA) in mice and its effect and mechanism on matrix metalloproteinase (MMP)-1 and MMP-3 production in CIA mice, RA fibroblast-like synoviocytes (FLS), and chondrocytes. CIA in mice was suppressed by oral administration of curcumin in a dose-dependent manner. Macroscopic observations were confirmed by histological examinations. Histological changes including infiltration of immune cells, synovial hyperplasia, cartilage destruction, and bone erosion in the hind paw sections were extensively suppressed by curcumin. The histological scores were consistent with clinical arthritis indexes. Production of MMP-1 and MMP-3 were inhibited by curcumin in CIA hind paw sections and tumor necrosis factor (TNF)-α–stimulated FLS and chondrocytes in a dose-dependent manner. As for the mechanism, curcumin inhibited activating phosphorylation of protein kinase Cδ (PKCδ) in CIA, FLS, and chondrocytes. Curcumin also suppressed the JNK and c-Jun activation in those cells. This study suggests that the suppression of MMP-1 and MMP-3 production by curcumin in CIA is mediated through the inhibition of PKCδ and the JNK/c-Jun signaling pathway. Keywords:: curcumin, matrix metalloproteinase (MMP)-1, MMP-3, protein kinase Cδ (PKCδ), collagen-induced arthritis

The cardioprotective effects of the novel sodium/hydrogen exchanger-1 (NHE-1) inhibitor KR-32560 {[5-(2-methoxy-5-fluorophenyl)furan-2-ylcarbonyl]guanidine} were studied in an anesthetized rat model of 30-min ischemia / 2.5-h reperfusion heart injury. KR-32560 (0.01 – 1 µM) dose-dependently inhibited NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. KR-32560 at 0.1 and 1.0 mg/kg (i.v. bolus, given 10 min before ischemia) reduced infarct size from 65.9% (control) to 49.7% and 32.7%, respectively, while reducing the extension of myocardial injury (mm3/g of left heart weight) from 405.1 (control) to 302.9 and 185.4, respectively (all P