Production and biologic interactions of prostacyclin and platelet-activating factor in acute myocardial ischemia in the perfused rabbit heart.
This study showed that the 1-O-hexadecyl form of platelet-activating factor (PAF) is released along with 6-keto-prostacyclin1 alpha (6-keto-PGF1 alpha) in the perfusates of ischemic-isolated rabbit heart. During the early phase of the reperfusion, the release of PAF and 6-keto-PGF1 alpha was particularly increased (PAF, from 5.4 +/- 1.2 to 19.7 +/- 2.0 ng/min; 6-keto-PGF1 alpha, from 2.3 +/- 0.1 to 27.4 +/- 1.8 ng/min) and this event was coupled with the characteristic mechanical alterations of myocardial performance and perfusion pressure (PP). These changes were effectively antagonized by pretreatment of the hearts with both prostacyclin (PGI2, 20 ng/ml) and the PGI2-releaser defibrotide (400 micrograms/ml). The protecting activity observed with PGI2 was paralleled by a reduction in the rate of PAF release during reperfusion (from 19.7 +/- 2.0 to 6.8 +/- 0.2 ng/min). In defibrotide-treated preparations, inhibition of PAF formation was associated with a pronounced stimulation of 6-keto-PGF1 alpha generation, which was particularly marked on reperfusion (from 27.4 +/- 1.8 to 197.5 +/- 8.2 ng/min). Indomethacin (1 microgram/ml) ablated the antiischemic effect of defibrotide but did not potentiate the rate of formation of PAF despite inhibition of 6-keto-PGF1 alpha biosynthesis. From these results, we conclude that in a model of severe myocardial ischemia, in which the major determinants of cardiac performance are under control, generation of PAF and PGI2 appears to play an important biologic role in determination of the severity of myocardial ischemic damage.
Department of Pharmacology, Chemotherapy, Medical Toxicology, San Raffaele, Italy.
F
F
Berti
F
F
Magni
G
G
Rossoni
L
L
De Angelis
G
G
Galli
D000818:Animals; D011464:Epoprostenol / Q000096:biosynthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D011089:Polydeoxyribonucleotides / Q000494:pharmacology; D011817:Rabbits
D010972:Platelet Activating Factor; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D011464:Epoprostenol; D007213:Indomethacin