title: Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit.
abstract: Morphological and functional modifications occurring in Langendorff rabbit heart preparations perfused with purified human leukocytes (PMNL), as an organ model of sulfidopeptide-leukotrienes (sLT) transcellular biosynthesis, were studied. Coronary perfusion pressure (CPP), monitored as an index of coronary vasospasm, increased by 295% after challenge with the Ca(2+)-ionophore A-23187 (0.5 micromol/L) for 30', accompanied by a significant formation of sLT. Increase in CPP was prevented by PMNL pretreatment with the 5-lipoxygenase inhibitor MK-886 (1 micromol/L) or by heart pretreatment with LTD4-receptor antagonist SKF 104353, indicating a pivotal role of PMNL-derived 5-lipoxygenase (5-LO) products in the observed functional modifications. Similar effects were obtained using granulocyte macrophage-colony stimulating factor-primed PMNL challenged with the tripeptide n-formyl-methionyl-leucyl-phenylalanine. Scanning electron microscopy (SEM) of coronary arteries showed craters on the vessel luminal surface, PMNL adhering to endothelial cells (EC), increased number of microvilli on EC, presence of nonviable, desquamating, fusiform EC. SEM and transmission electron microscopy of myocardial microvessels, showed presence of perivascular and intermuscle edema, presence of activated PMNL and decreased number of patent microvessels. These morphological alterations were significantly blunted by MK-886 or SKF 104353. These data provide evidence of close interaction between PMNL and myocardial EC, resulting in enhanced sLT formation via transcellular biosynthesis, originating from transfer of PMNL-derived LTA4 to EC. These potent proinflammatory autacoids are responsible for coronary vasospasm and the morphological alternations observed.
authors.affiliation: Center for Cardiopulmonary Pharmacology, University of Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sala
authors.forename: G M
authors.initials: GM
authors.lastname: Aliev
authors.forename: G
authors.initials: G
authors.lastname: Rossoni
authors.forename: F
authors.initials: F
authors.lastname: Berti
authors.forename: C
authors.initials: C
authors.lastname: Buccellati
authors.forename: G
authors.initials: G
authors.lastname: Burnstock
authors.forename: G
authors.initials: G
authors.lastname: Folco
authors.forename: J
authors.initials: J
authors.lastname: Maclouf
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D003329:Coronary Vasospasm / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins; D008833:Microcirculation; D008855:Microscopy, Electron, Scanning; D009206:Myocardium / Q000648:ultrastructure; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010477:Perfusion; D011817:Rabbits; D018077:Receptors, Leukotriene; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D002722:Chlorobenzenes
chemical_list: D000001:Calcimycin; D003998:Dicarboxylic Acids; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007211:Indoles; D007476:Ionophores; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D018077:Receptors, Leukotriene; C060893:MK-886; D002722:Chlorobenzenes; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C052393:pobilukast