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Defibrotide normalizes cardiovascular function hampered by established atherosclerosis in the rabbit
1Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy. giuseppe.rossoni@unimi.it
Insights
Defibrotide demonstrates significant cardiovascular benefits even after atherosclerosis is established. This drug improves aortic relaxation, prostaglandin generation, and heart function in diseased rabbits, suggesting a cardioprotective role.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Atherosclerosis Research
Background:
- Previous research indicated defibrotide's efficacy in preventing atherosclerosis.
- Established atherosclerosis significantly impairs cardiovascular function, including vascular reactivity and cardiac hemodynamics.
Purpose of the Study:
- To investigate the therapeutic potential of defibrotide in established atherosclerosis.
- To evaluate defibrotide's effects on specific cardiovascular parameters compromised by atherosclerosis.
Main Methods:
- Defibrotide infusion was administered to rabbits with established atherosclerosis.
- Key cardiovascular functions were assessed, including aorta relaxation, prostaglandin generation (PGE2, 6-keto-PGF1α), and cardiac pressures (LVEDP, CPP, LVDP).
- The vasopressor activity of acetylcholine and endothelin-1 was also evaluated.
Main Results:
- Defibrotide significantly improved rabbit aorta relaxation in response to acetylcholine.
- Increased generation of prostaglandin E2 and 6-keto-prostaglandin F1α was observed in both aortas and hearts.
- Cardiac function markers, including left ventricular end-diastolic pressure, coronary perfusion pressure, and left ventricular developed pressure, showed significant amelioration.
Conclusions:
- Defibrotide exerts beneficial cardiovascular effects even when atherosclerosis is established.
- The cardioprotective activity of defibrotide may be linked to increased prostacyclin and prostaglandin E2 levels.
- Defibrotide holds potential as a therapeutic agent for managing established cardiovascular disease.
Abstract:
In a previous paper we gave evidence that chronic oral defibrotide antagonizes the noxious effect of developing atherosclerosis in the cardiovascular system. In the present paper we give evidence that defibrotide is still capable of exerting beneficial effects on cardiovascular function once atherosclerosis is established. In fact, there was statistically significant amelioration by defibrotide infusion in the following, all of which were hampered by established atherosclerosis: in rabbit aorta relaxation to acetylcholine, prostaglandin E2, and 6-keto-prostaglandin F1alpha generation from rabbit aortas, rabbit heart left ventricular end-diastolic pressure, coronary perfusion pressure, and left ventricular developed pressure, vasopressor activity of acetylcholine and endothelin-1 on coronary perfusion pressure, and 6-keto-prostaglandin F1alpha generation from the rabbit heart. Since prostacyclin takes part in NO generation, is cellular protective, and inhibits 5-lipoxygenase product synthesis, its increase, caused by defibrotide, could explain defibrotide cardioprotective activity. Prostacyclin activity could be backed by prostaglandin E2, another cardioprotective prostaglandin.