Stimulation of prostacyclin synthesis by defibrotide: improved contractile recovery from myocardial "stunning".
Prostacyclin (PGI2) improves regional contractility of postischemically dysfunctional ("stunned") myocardium. We determined whether defibrotide, a fraction of mammalian DNA known to stimulate endogenous formation of PGI2, also improves contractile recovery of stunned myocardium. Anesthetized, open-chest minipigs were subjected to coronary occlusion of 5 min (left anterior descending branch, LAD) followed by 120 min of reperfusion. The animals were treated with defibrotide (32 mg x kg-1 x h-1, intravenously, i.v.) or vehicle throughout the experimental period. Defibrotide improved regional contractility in the ischemic reperfused area from 30 (vehicle) to 78% of the preischemic control without altering the contractility of nonischemic myocardium. Transcardiac PGI2 formation, determined from the difference between coronary venous and arterial plasma concentrations, was elevated from 437 (preischemic control) to 869 pmol x l-1 in defibrotide-treated animals, but was unchanged in the vehicle-treated and a sham-operated group. Thromboxane A2 (TXA2) release was not modified. Defibrotide reduced ischemia-induced formation of platelet aggregates but did not affect the activity of polymorphonuclear neutrophil granulocytes. The data demonstrate an improvement of contractile recovery from stunning by defibrotide that may be related to an inhibition of ischemia-induced platelet activation and (or) membrane protection owing to enhanced transcardiac formation of PGI2.
Hohlfeld
T
T
Institut für Pharmakologie, Heinrich-Heine Universität Düsseldorf, G.F.R.
Strobach
H
H
Schrör
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D003331:Coronary Vessels / Q000502:physiology; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009504:Neutrophils / Q000502:physiology; D010976:Platelet Count / Q000187:drug effects; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013552:Swine; D013556:Swine, Miniature; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol