m&b-28-767 and Myocardial-Infarction

We have previously identified prostaglandin EP(3)receptors in left ventricular myocardium. To assess the potential contribution of this receptor subtype to the anti-ischemic properties of E-type prostaglandins (i.e. PGE(1)), two groups of anesthetized open-chest minipigs were subjected to LAD occlusion (1 h) and reperfusion (3 h). In one group, the selective EP(3)receptor agonist M&B 28.767 (2 pmol/kgxmin) was infused into the LAD from 20 min before ischemia until the end of reperfusion. The other group received vehicle. M&B 28.767 did not alter the systemic hemodynamics, but significantly reduced infarct size (tetrazolium staining) and creatine kinase release by 53% and 48%, respectively. Ischemia-induced ventricular arrhythmias were mostly reduced. Further experiments analysed the effects of EP(3)receptor stimulation on normoxic myocardium. PGE(1), an unselective agonist to all EP receptor subtypes, as well as M&B 28.767 (2 pmol/kgxmin of each into the LAD) reduced the action potential duration (epicardial monophasic electrodes) and almost prevented the inotropic response to intravenous isoprenaline. This dual response is consistent with the EP(3)receptor coupling to an inhibitory G protein. This was confirmed in separate experiments with stable Chinese hamster ovary cell transfectants expressing the porcine EP(3)receptor, where M&B 28.767 inhibited the forskolin-induced increase in cAMP in a concentration-dependent manner. It is concluded that the protection of reperfused ischemic myocardium by E-type prostaglandins is mediated by EP(3)receptors, which seems to involve a combined activation of repolarizing membrane currents and an inhibition of deleterious effects caused by ischemia-induced catecholamine release.

Topics: Action Potentials; Adenylyl Cyclases; Adrenergic beta-Agonists; Alprostadil; Animals; Arrhythmias, Cardiac; Cardiotonic Agents; CHO Cells; Colforsin; Coronary Vessels; Creatine Kinase; Cricetinae; Cricetulus; Cyclic AMP; Female; GTP-Binding Protein alpha Subunits, Gi-Go; Heart Ventricles; Hemodynamics; Infusions, Intra-Arterial; Isoenzymes; Isoproterenol; Male; Muscle Proteins; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Second Messenger Systems; Staining and Labeling; Swine; Swine, Miniature; Transfection

1. This study investigates the effects of two agonists of the prostanoid EP3-receptor (M&B 28767 and GR 63799X) on the infarct size caused by regional myocardial ischaemia and reperfusion in the anaesthetized rat. 2. One hundred and sixty-seven, male Wistar rats were anaesthetized (thiopentone, 120 mg kg(-1) i.p.), ventilated (8-10 ml kg(-1), 70 strokes min(-1), inspiratory oxygen concentration: 30%; PEEP: 1-2 mmHg) and subjected to occlusion of the left anterior descending coronary artery (LAD, for 7.5, 15, 25, 35, 45 or 60 min) followed by reperfusion (2 h). Infarct size was determined by staining of viable myocardium with a tetrazolium stain (NBT), histological evaluation by light and electron microscopy and determination of the plasma levels of cardiac troponin T. 3. M&B 28767 (0.5 microg kg(-1) min(-1), i.v., n=7) or GR 63799X (3 microg kg(-1) min(-1), i.v., n=7) caused significant reductions in infarct size from 60+/-3% (25 min ischaemia and 2 h reperfusion; saline-control, n=8) to 39+/-6 and 38+/-4% of the area at risk, without causing a significant fall in blood pressure. Pretreatment of rats with 5-hydroxydecanoate (5-HD), an inhibitor of ATP-sensitive potassium channels, attenuated the cardioprotective effects of both EP3-receptor agonists. The reduction in infarct size afforded by M&B 28767 was also abolished by glibenclamide and the protein kinase C (PKC) inhibitors staurosporine and chelerythrine. 4. Thus, M&B 28767 and GR 63799X reduce myocardial infarct size in the rat by a mechanism(s) which involves the activation of PKC and the opening of ATP-sensitive potassium channels.

Topics: Alprostadil; Anesthesia; Animals; Hemodynamics; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Potassium Channels; Prostaglandins E, Synthetic; Protein Kinase C; Rats; Rats, Wistar; Receptors, Prostaglandin E; Troponin T