ono-3708 and Shock--Septic

The effects of ONO 3708, a new thromboxane A2 (TXA2) receptor antagonist, on platelet aggregation in human plasma, the survival rate of rats subjected to lethal endotoxin shock, and the pathophysiological consequences of endotoxin shock in anesthetized dogs were investigated. ONO 3708 inhibited dose dependently human platelet aggregation induced by 2.5 microM of STA2, analogue of TXA2. Treatment with ONO 3708, 1 mg/100 g i.v., significantly improved the survival rate of rats in endotoxin shock from 38 to 72% at 24 hr and from 27 to 61% at 48 hr. ONO 3708 significantly attenuated endotoxin-induced thrombocytopenia, but not leukopenia. In anesthetized dogs, endotoxin-induced pulmonary hypertension was completely prevented, and increased airway pressure was significantly attenuated by ONO 3708. These results suggest that ONO 3708, the antagonist of TXA2 receptor, has beneficial effects during endotoxin shock, at least in part by inhibiting platelet aggregation.

Topics: Animals; Dose-Response Relationship, Drug; Endotoxins; Escherichia coli; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Thromboxane A2

The effects of ONO 3708, a new thromboxane A2 receptor antagonist, on cardiovascular and airway responses, at an early phase during endotoxin shock were investigated in anesthetized dogs. The i.v. infusion (1mg.kg-1) of E.coli endotoxin caused an increase in mean pulmonary artery pressure (MPAP) from 9.9 +/- 1.0 to 19.1 +/- 2.3 mmHg at 5 min, and at 15 min after infusion, elevated MPAP returned toward the control level. Pretreatment with ONO 3708 abolished these effects of endotoxin on pulmonary artery pressure at an early phase. The change in airway pressure reached a maximum of 14.4 +/- 1.7 cmH2O from 10.0 +/- 1.9 at 5 min, followed by a gradual decline toward a baseline value at 30 min in the control group. ONO 3708 significantly attenuated increase in airway pressure induced by E. coli endotoxin. But pretreatment with ONO 3708 could not prevent decrease in systemic arterial pressure and cardiac output induced by endotoxin. These results suggest that role of thromboxane A2 on the cardiovascular response during endotoxin shock is played only on pulmonary vascular changes, and ONO 3708 has a beneficial effect at least during the early phase of endotoxin shock.

Topics: Animals; Dogs; Hemodynamics; Shock, Septic; Thromboxane A2; Time Factors