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B-type natriuretic peptide (BNP) has been reported to be released from the myocardium during ischemia. We hypothesized that BNP mediates cardioprotection during ischemia-reperfusion and examined whether exogenous BNP limits myocardial infarction and the potential role of ATP-sensitive potassium (K(ATP)) channel opening. Langendorff-perfused rat hearts underwent 35 min of left coronary artery occlusion and 120 min of reperfusion. The control infarct-to-risk ratio was 44.8 +/- 4.4% (means +/- SE). BNP perfused 10 min before ischemia limited infarct size in a concentration-dependent manner, with maximal protection observed at 10(-8) M (infarct-to-risk ratio: 20.1 +/- 5.2%, P < 0.01 vs. control), associated with a 2.5-fold elevation of myocardial cGMP above the control value. To examine the role of K(ATP) channel opening, glibenclamide (10(-6) M), 5-hydroxydecanoate (5-HD; 10(-4) M), or HMR-1098 (10(-5) M) was coperfused with BNP (10(-8) M). Protection afforded by BNP was abolished by glibenclamide or 5-HD but not by HMR-1098, suggesting the involvement of putative mitochondrial but not sarcolemmal K(ATP) channel opening. We conclude that natriuretic peptide/cGMP/K(ATP) channel signaling may constitute an important injury-limiting mechanism in myocardium.

Ischaemia-reperfusion injury causes cell death by both necrosis and apoptosis. Caspase activation is a major event in apoptosis. We therefore examined the e ect of caspase inhibitors during reperfusion upon myocardial infarction. Rat isolated hearts were subjected to 35 min coronary occlusion and 120 min reperfusion. Treatment groups were perfused with caspase inhibitors during early reperfusion. We assessed a non-selective caspase inhibitor (Z-VAD×fmk, 0.1 mM), a caspase-8 inhibitor (Z-IETD×fmk, 0.07 mM), a caspase-9 inhibitor (Z-LEHD×fmk, 0.07 mM) and a caspase-3 inhibitor (Ac-DEVD×cmk, 0.07 mM). All caspase inhibitors limited infarct size (infarct-risk ratio per cent: control 38.5+2.6; Z-VAD×fmk 24.6+3.4; Z-LEHD×fmk 19.3+2.4; Z-IETD×fmk 23.0+5.4; AcDEVD×cmk 27.8+3.3; P50.05 when compared with control value, 1-way ANOVA). We conclude that caspase inhibition during early reperfusion protects myocardium against lethal reperfusion injury.

Background-The sulfonylurea glibenclamide (Glib) abolishes the cardioprotective effect of ischemic preconditioning (IP), presumably by inhibiting mitochondrial K ATP channel opening in myocytes. Glimepiride (Glim) is a new sulfonylurea reported to affect nonpancreatic K ATP channels less than does Glib. We examined the effects of Glim on IP and on the protection afforded by diazoxide (Diaz), an opener of mitochondrial K ATP channels. Methods and Results-Rat hearts were Langendorff-perfused, subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion, and assigned to 1 of the following treatment groups: (1) control; (2) IP of 2ϫ 5 minutes each of global ischemia before lethal ischemia; or pretreatment with (3) 30 mol/L Diaz, (4) 10 mol/L Glim, (5) 10 mol/L Glib, (6) IPϩGlim, (7)

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Objective-To determine whether exercise is capable of protecting the myocardium from experimental infarction and to explore the involvement of protein kinase C, a key signalling protein, in the development of any protection observed. Methods-Rats were exercised on a treadmill for 30 minutes at 23-27 m/min. Sham treated animals were placed on the stationary treadmill but not exercised. Twenty four hours later, hearts were LangendorV perfused and subjected to 35 minute left main coronary artery occlusion followed by 120 minute reperfusion. Infarct size was determined by tetrazolium staining and expressed as a percentage of the risk zone (I/R%). To examine the potential signalling pathway, animals were treated with either the selective protein kinase C inhibitor chelerythrine, 5 mg/kg intraperitoneally, or with vehicle 10 minutes before the exercise or sham treadmill period. Results-In the non-exercised group, mean (SEM) I/R was 48.4 (3.0)%. In the exercised group, infarct size was reduced to 17.3 (3.0)% (p < 0.01). Infarct size limitation induced by exercise was abolished by chelerythrine (I/R 45.0 (6.0)%). Chelerythrine pretreatment alone did not have any eVect on infarct size (I/R 51.1 (3.9)%). DiVerences in infarct size were independent of risk zone size and myocardial contractile function during ischaemia-reperfusion. Conclusions-Experimental moderate exercise induces protection against myocardial infarction 24 hours later. Protein kinase C activation during exercise appears to be an important signal mediator of this protective response. (Heart 2001;85:331-336)

Rabbit hearts were preconditioned with four 5 min coronary artery occlusions 24 h before 30 min coronary occlusion with 120 min reperfusion. Preconditioning significantly reduced the percentage of myocardium infarcting within the risk zone from 49.1±4.3% to 31.8±3.5% (P<0.05). When the protein kinase C (PKC) inhibitor, chelerythrine, was administered just before preconditioning, the delayed protection against infarction 24 h later was abolished. We conclude that the delayed cytoprotective response associated with ischaemic preconditioning of myocardium is likely to involve the early activation of one or more PKC subtypes.