title: Chronic oral defibrotide counteracts hypercholesterolemia noxious effects on cardiovascular function in the rabbit.
abstract: The aim of the present work was to assess if the cardioprotective drug defibrotide could counteract the hypercholesterolemia noxious effects on cardiovascular function. Aortas and hearts from normal- or cholesterol-fed rabbits, treated or not with chronic oral defibrotide (100 mg/kg/day) for 45 days, were used in in vitro tests throughout the experiment. Hypercholesterolemia worsened: aorta stickiness toward polymorphonuclear leukocytes, aorta relaxation to acetylcholine, heart left ventricular end-diastolic pressure and coronary perfusion pressure, heart left ventricular diastolic pressure, acetylcholine and endothelin-1 activity on coronary perfusion pressure, and heart generation of 6-Keto-prostaglandin F1alpha. Oral defibrotide counteracted and/or obliterated the above hypercholesterolemia noxious effects. Particularly, oral defibrotide counteracted the parameters associated with early endothelial cell disfunction: that is, increased adherence of leukocytes to endothelium and endothelial vasorelaxation induced by acetylcholine, which acts through the release of endothelium-derived relaxing factor. These activities of defibrotide are probably exerted through the increased generation of prostacyclin. The fact that acetylcholine induced vasorelaxation is partially protected by oral defibrotide points to a partial rescue of endothelial ability to generate endothelium-derived relaxing factor, as acethylcoline acts through the release of endothelium-derived relaxing factor, by defibrotide itself. Defibrotide's endothelial protection could, in turn, explains why defibrotide protected cardiovascular function. This is not surprising as, in a few cases, endothelial dysfunction, observed in hypercholesterolemia, was found to be prevented or reversed, pharmacologically, by PN-2001-10, a calcium channel blocker, dipyridamole, and lovastatin.
authors.affiliation: Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Rossoni
authors.forename: F
authors.initials: F
authors.lastname: Berti
authors.forename: F
authors.initials: F
authors.lastname: Trento
authors.forename: F
authors.initials: F
authors.lastname: Cattaneo
authors.forename: R
authors.initials: R
authors.lastname: Porta
authors.forename: R
authors.initials: R
authors.lastname: Pescador
authors.forename: L
authors.initials: L
authors.lastname: Ferro
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002791:Cholesterol, Dietary; D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D015121:6-Ketoprostaglandin F1 alpha