VASOCONSTRICTION TO POLYMORPHONUCLEAR LEUKOCYTES IN THE ISOLATED, PERFUSED RABBIT HEART - INHIBITION BY PROSTACYCLIN MIMETICS

Perfusion of the isolated rabbit heart with 5 x 10(6) human polymorpho nuclear leukocytes (PMNL), under recirculating conditions (50 mi) and challenge with A-23187 (0.5 mu M) increased coronary perfusion pressur e (CPP) sixfold; accompanied by increased levels of sulfidopeptide leu kotrienes (CYS-LT), which had previously shown to correlate linearly w ith the increase in CPP. Pretreatment (20 min) of isolated rabbit hear ts with the prostacyclin (PGI(2)) analogue iloprost (3 nM) resulted in significant protection against the increase in CPP and in almost comp lete inhibition of 5-lipoxygenase (5-LO) product synthesis. Similarly, pretreatment of isolated rabbit heart with defibrotide (200 mu g/ml), a polydeoxyribonucleotide derivative known to inhibit PMNL activation and enhance PGI(2) production by heart endothelial cells, produced si gnificant protection against the increase in CPP and almost complete i nhibition of 5-LO product synthesis. Neither iloprost nor defibrotide affected the A-23187-induced arachidonic acid (AA) metabolism in isola ted PMNL alone. Inhibition of rabbit cyclooxygenase by intravenous (i. v.) administration of lysine-acetylsalicylate (60 mg/kg) 2 h before th e animals were killed significantly reduced the protection provided by defibrotide, with a parallel fivefold increase in sulfidopeptide LT l evels, returning to values in the range observed in control hearts. Co ntrol of endogenous modulators of leukocyte-vascular wall interactions such as PGI(2) results in significant changes in sulfidopeptide LT pr oduction in an organ model of transcellular metabolism of LT A(4), sug gesting a novel mechanism of action for cardioprotective drugs in myoc ardial ischemia.