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Vasoconstriction to polymorphonuclear leukocytes in the isolated, perfused rabbit heart: inhibition by prostacyclin
G Rossoni1, A Sala, C Buccellati
1Center for Cardiopulmonary Pharmacology, Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy.
Abstract:
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.
Insights
Prostacyclin analogue iloprost and defibrotide protect rabbit hearts from leukocyte-induced injury by inhibiting leukotriene synthesis. This suggests novel cardioprotective drug mechanisms involving endogenous modulators in myocardial ischemia.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Inflammation Research
Background:
- Human polymorphonuclear leukocytes (PMNL) can cause myocardial injury.
- Leukotriene production is linked to increased coronary perfusion pressure (CPP) in isolated rabbit hearts.
Purpose of the Study:
- To investigate the protective effects of iloprost and defibrotide against PMNL-induced myocardial injury.
- To explore the role of prostacyclin (PGI(2)) and leukotrienes in this model.
- To elucidate potential novel mechanisms of cardioprotective drugs.
Main Methods:
- Isolated rabbit hearts were perfused with PMNL and challenged with A-23187.
- Hearts were pretreated with iloprost or defibrotide.
- Arachidonic acid (AA) metabolism in PMNL was assessed.
- Cyclooxygenase was inhibited with lysine-acetylsalicylate.
Main Results:
- PMNL perfusion increased CPP and sulfidopeptide leukotriene (CY-SLT) levels.
- Iloprost and defibrotide pretreatment significantly reduced CPP increase and CY-SLT synthesis.
- Neither drug affected A-23187-induced AA metabolism in isolated PMNL.
- Inhibition of cyclooxygenase abolished defibrotide's protective effect and increased CY-SLT levels.
Conclusions:
- Iloprost and defibrotide offer cardioprotection by inhibiting leukotriene synthesis.
- Defibrotide's protective effect is partly mediated by prostacyclin production.
- Modulation of endogenous factors like PGI(2) offers a novel cardioprotective strategy in myocardial ischemia.