dv-7028 and Disease-Models--Animal

From 0.5 to 3 days after subcutaneous injection of monocrotaline (MCT) 60 mg/kg, prominent accumulation of platelets in the pulmonary capillaries accompanied with significant elevation of the plasma serotonin level was observed. To clarify the role of serotonin, the in vivo and in vitro effects of the selective 5-HT2 receptor antagonist, DV-7028, on MCT-induced pulmonary hypertension were studied. Oral administration of DV-7028 (10 mg/kg, twice daily) significantly suppressed the MCT-induced elevation of pulmonary arterial pressure, right ventricular hypertrophy and medial thickening of the muscular-type pulmonary arteries which occurred 23 days after MCT administration. The plasma level achieved by oral administration of 10 mg/kg DV-7028 was more than 10(-7) M. The hyperreactivity to serotonin in isolated pulmonary artery segments from MCT-treated rats was significantly reduced by DV-7028 (10(-7) M). The present study suggests that serotonin, released from platelets and accumulated in pulmonary capillaries, contributes to the initiation and/or progression of pulmonary hypertension in MCT-treated rats.

Topics: Animals; Blood Platelets; Disease Models, Animal; Hypertension, Pulmonary; In Vitro Techniques; Lung; Male; Monocrotaline; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Triazines; Vasoconstriction

The aim was to study the combined effect of DV-7028, a selective 5-hydroxytryptamine2 receptor antagonist, and aspirin or heparin on cyclic flow reductions in the canine coronary artery.. Anaesthetised open chest beagle dogs under artificial respiration were used. Cyclic flow reductions were induced by partial occlusion of the left anterior descending coronary artery at the site of endothelial injury. After induction of cyclic flow reductions, test drugs were given to the animals intravenously.. DV-7028 (0.1 mg.kg-1) reduced the frequency of cyclic flow reductions by 77% and improved the nadir of coronary blood flow velocity that indicated the severity of cyclic flow reductions. Also, aspirin (1 or 3 mg.kg-1) or heparin (200 U.kg-1) attenuated the cyclic flow reductions. In experiments with drug combinations, DV-7028 was given to animals that had already received aspirin (1 mg.kg-1) or heparin (200 U.kg-1). DV-7028 (0.1 mg.kg-1) completely abolished the cyclic flow reductions remaining after aspirin treatment in three of four animals. Heparin inhibited the cyclic flow reductions in one of five animals and the addition of DV-7028 abolished the remaining cyclic flow reductions in the other four animals. After combined injection of DV-7028 with aspirin or heparin, the coronary blood flow with cyclical reductions returned to the baseline.. The 5-HT2 receptor antagonist DV-7028 can inhibit the cyclic flow reductions that are resistant to aspirin or heparin. The combined regimen of DV-7028 and aspirin or heparin in treatment of acute coronary stenosis is more effective than that of aspirin or heparin alone.

Topics: Animals; Aspirin; Blood Pressure; Coronary Circulation; Coronary Disease; Disease Models, Animal; Dogs; Drug Synergism; Heart Rate; Heparin; Piperidines; Serotonin Antagonists; Triazines; Ventricular Function, Left

The aim was to determine the role of 5-HT derived from activated platelets in the formation of intracoronary thrombi in dogs.. Canine coronary thrombi were produced by inserting a small catheter filled with collagen powder into the endothelial-injured partially occluded left anterior descending coronary artery. The effects of intravenous DV-7028, a selective 5-HT2 receptor antagonist (bolus of 0.1 mg.kg-1, followed by 0.3 mg.kg-1.h-1 by infusion), and intravenous aspirin (1 mg.kg-1, followed by 3 mg.kg-1.h-1) in this experimental thrombus model were examined.. 43 dogs of either sex were used. In experiment A, DV-7028 (n = 12) or saline (n = 11) was given. In experiment B, aspirin (n = 10) or saline (n = 10) was given.. DV-7028 significantly reduced the formation of coronary thrombi by 51% and attenuated the decrease in coronary blood flow without affecting systemic blood pressure and heart rate. There was a significant relationship between the thrombus weight and the decrease in coronary blood flow (p less than 0.005). Aspirin failed to prevent the formation of coronary thrombi.. The results suggest that 5-HT is involved in the platelet thrombosis and that inhibitory effect of DV-7028, a 5-HT2 receptor antagonist, on coronary thrombus formation was superior to that of aspirin.

Topics: Animals; Aspirin; Coronary Thrombosis; Disease Models, Animal; Dogs; Drug Administration Schedule; Piperidines; Serotonin Antagonists; Triazines