defibrotide and Body-Weight

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.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Aorta; Arteriosclerosis; Blood Pressure; Body Weight; Cardiovascular Physiological Phenomena; Cholesterol, Dietary; Dinoprostone; Endothelin-1; Fibrinolytic Agents; Heart; In Vitro Techniques; Lipids; Male; Muscle Contraction; Muscle, Smooth, Vascular; Organ Size; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Rabbits; Reperfusion; Ventricular Function, Left

The present study demonstrates the antiatherosclerotic property of Defibrotide (DFT) in an experimental model in which the pathology is secondary to calcium deposition in the vessel wall and various organs. Rats were treated by gavage for 21 consecutive days with Vitamin D3 and/or, twice a day, with DFT or Nifedipine (N). The calcium contents of aorta, heart and kidney were determined by atomic absorption spectrometry. Specimens of these tissues were examined histologically. DFT or N administered alone did not modify the calcium contents of aorta, heart or kidney. On the contrary, Vitamin D3 caused a huge increase in the calcium concentration in the aorta and in the kidney, whereas the heart content was only double that of control animals. In rats treated with Vitamin D3, contemporaneous administration of DFT or N sharply and highly significantly reduced the aorta calcium concentration and there were less striking, although still significant, reductions in the other two tissues. Histological examination paralleled these data; the effect of DFT or N in reducing the mineralization of aorta and heart was very evident, and more pronounced for DFT. These results confirm that DFT, even though not belonging to the class of the calcium antagonists, has comparable antiatherosclerotic properties, possibly due to its endothelial protective efficacy, as evidenced by the lesser amount of calcium in the aortic tissue.

Topics: Animals; Arteriosclerosis; Body Weight; Calcium; Calcium Channel Blockers; Male; Nifedipine; Polydeoxyribonucleotides; Rats