Polydeoxyribonucleotides and nitric oxide release from guinea-pig hearts during ischaemia and reperfusion.
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.
Masini
E
E
Department of Preclinical and Clinical Pharmacology, M. Aiazzi-Mancini, Florence University, Italy.
Lupini
M
M
Mugnai
L
L
Raspanti
S
S
Mannaioni
P F
PF
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D005591:Chemical Fractionation; D003326:Coronary Circulation / Q000187:drug effects*; D004247:DNA / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D008297:Male; D008970:Molecular Weight; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019323:omega-N-Methylarginine
D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D009573:Nitrites; D011089:Polydeoxyribonucleotides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C036901:defibrotide; D004247:DNA; D001120:Arginine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine