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 polymorphonuclear leukocytes (PMNL), under recirculating conditions (50 ml) and challenge with A-23187 (0.5 mu M) increased coronary perfusion pressure (CPP) sixfold, accompanied by increased levels of sulfidopeptide leukotrienes (CY-SLT), which had previously shown to correlate linearly with the increase in CPP. Pretreatment (20 min) of isolated rabbit hearts with the prostacyclin (PGI(2)) analogue iloprost (3 nM) resulted in significant protection against the increase in CPP and in almost complete 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 significant protection against the increase in CPP and almost complete inhibition of 5-LO product synthesis. Neither iloprost nor defibrotide affected the A-23187-induced arachidonic acid (AA) metabolism in isolated PMNL alone. Inhibition of rabbit cyclooxygenase by intravenous (i.v.) administration of lysine-acetylsalicylate (60 mg/kg) 2 h before the animals were killed significantly reduced the protection provided by defibrotide, with a parallel fivefold increase in sulfidopeptide LT levels, returning to values in the range observed in control hearts. Control of endogenous modulators of leukocyte-vascular wall interactions such as PGI(2) results in significant changes in sulfidopeptide LT production in an organ model of transcellular metabolism of LT A(4), suggesting a novel mechanism of action for cardioprotective drugs in myocardial ischemia.
Rossoni
G
G
Center for Cardiopulmonary Pharmacology, Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy.
Sala
A
A
Buccellati
C
C
Maclouf
J
J
Folco
G C
GC
Berti
F
F
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D010477:Perfusion; D011089:Polydeoxyribonucleotides / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects
D011089:Polydeoxyribonucleotides; C036901:defibrotide; D016285:Iloprost