Chronic oral defibrotide counteracts hypercholesterolemia noxious effects on cardiovascular function in the rabbit.
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.
Rossoni
G
G
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy.
Berti
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Trento
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Cattaneo
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Porta
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Pescador
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Ferro
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L
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
D002791:Cholesterol, Dietary; D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D015121:6-Ketoprostaglandin F1 alpha