defibrotide and Arrhythmias--Cardiac

Nitric oxide (NO) and cyclooxygenase-derived prostaglandins, such as prostacyclin (PGI2), are involved in vascular homeostasis. To better understand the reciprocal role of both NO and PGI2 on myocardial infarction in the rat, we have investigated the cardioprotective effect of nitro-naproxen, isosorbide dinitrate (ISDN), L-arginine, defibrotide and naproxen. In this study, male Wistar rats were treated orally once a day for 5 consecutive days with the compounds under investigation and then, under anesthesia, the animals were subjected to acute myocardial ischemia (30 min) and reperfusion (120 min). Systemic blood pressure, left ventricular pressure and related parameters of cardiac mechanics were recorded. Ventricular arrhythmias and infarct size of the left ventricular wall were also evaluated. Furthermore, cardiac myeloperoxidase (MPO) and plasma creatine phosphokinase (CPK) activities were determined. Defibrotide, nitro-naproxen, ISDN and L-arginine all provided a cardioprotection characterized by significant prevention of arrhythmias with high survival rate of the rats. Infarct size restriction was paralleled by reduction of both cardiac MPO and plasma CK. Cardioprotection of nitro-naproxen, ISDN and L-arginine involve nitrites/nitrates and PGI2-increased in the circulation associated to a reduction of thromboxane B2 (TXB2) in the blood. Defibrotide displays a cardioprotection by increasing PGI2 release and by reducing TXB2 in the blood. Naproxen was devoid a lower protecting activity on myocardial infarction, and PGI2 inhibition may have played a critical role in this context. The results suggested that the increase of both NO and PGI2 brings about a cascade of integrated cellular and molecular events which are of paramount importance in prevention of myocardial ischemic insult.

Topics: Animals; Arginine; Arrhythmias, Cardiac; Cardiotonic Agents; Creatine Kinase; Epoprostenol; Isosorbide Dinitrate; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Naproxen; Nitric Oxide; Peroxidase; Polydeoxyribonucleotides; Random Allocation; Rats; Rats, Wistar; Thromboxane B2

1. Two polydeoxyribonucleotides, produced by the controlled hydrolysis of DNA of mammalian lung (defibrotide and its lower molecular weight fraction, P.O. 085 DV), were studied for their ability to modify the release of nitrite and the coronary flow in perfusates collected from isolated, normally perfused hearts of guinea-pigs and from hearts subjected to regional ischaemia and reperfusion. 2. In guinea-pig normally perfused hearts, both defibrotide (DFT) and its fraction, P.O. 085 DV, increase the amount of nitrite appearing in perfusates in a concentration-dependent fashion. At the highest concentration studied (10(-6) M), P.O. 085 DV was more effective than DFT. A concomitant increase in the coronary flow was observed. 3. The increase in nitrite in perfusates and the increase in coronary flow induced by both DFT and P.O. 085 DV were significantly reduced by NG-monomethyl-L-arginine (L-NMMA, 10(-4) M), an inhibitor of nitric oxide synthase (NOS). 4. The endothelium-dependent vasodilator, acetylcholine (ACh), enhances the formation of nitrite and the coronary flow. Both the increase in coronary flow and in the formation of nitrite were significantly reduced by L-NMMA (10(-4) M). 5. In guinea-pig hearts subjected to ischaemia and reperfusion, the effect of both compounds in increasing the amount of nitrite in perfusates was more evident and more pronounced with P.O. 085 DV. 6. Reperfusion-induced arrhythmias were significantly reduced by both compounds to the extent of complete protection afforded by compound P.O. 085 DV. 7. The cardioprotective and antiarrhythmic effects of DFT and P.O. 085 DV are discussed.

Topics: Acetylcholine; Animals; Arginine; Arrhythmias, Cardiac; Chemical Fractionation; Coronary Circulation; Disease Models, Animal; DNA; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fibrinolytic Agents; Guinea Pigs; Male; Molecular Weight; Myocardial Reperfusion Injury; Nitric Oxide; Nitric Oxide Synthase; Nitrites; omega-N-Methylarginine; Polydeoxyribonucleotides