DTTX30, a combined thromboxane receptor antagonist and thromboxane synthetase inhibitor, prevents coronary thrombosis in anesthetized dogs.

Abstract

Combined thromboxane A2 receptor blockade and thromboxane synthetase inhibition facilitates local prostacyclin production at the site of platelet activation thereby providing a potent antithrombotic effect. The efficacy of DTTX30, a combined thromboxane A2 receptor blocker-thromboxane synthetase inhibitor, in inhibiting recurrent coronary thrombosis was evaluated in vivo using a canine model of unstable angina pectoris. Pentobarbital-anesthetized dogs (total of 25) were used in which acute damage of the proximal left circumflex coronary artery, together with mechanical stenosis, produced an occlusive thrombosis. When the platelet plug was removed by rubbing the vessel, the occlusion returned reproducibly for at least 2 hours in control studies. To evaluate the antithrombotic efficacy of DTTX30, a reproducible pattern of occlusive coronary thrombi was first established over a period of one hour. Thereafter, DTTX30 (0.12 mg/kg i.v. bolus plus 0.29 mg/kg/hr), acetylsalicylic acid (ASA, 5 mg/kg, i.v. bolus), vapiprost (1.0 mg/kg i.v. bolus plus 1.0 mg/kg/ hr), or vehicle was administered and observations continued for one additional hour. At the end of the one hour observation period, epinephrine (0.3 microgram/kg/min i.v.) was infused (with continued DTTX30, vapiprost or vehicle infusion) and observations were continued for an additional 30 min. DTTX30 eliminated the recurrent arterial thrombus formation in all dogs without significant systemic or left ventricular hemodynamic effects. Infusion of epinephrine to further provoke thrombus formation produced a significant enhancement of left ventricular pressure development (LV dP/dt) and arterial diastolic and systolic pressures but failed to initiate thrombus formation. DTTX30 inhibited fully collagen-induced platelet aggregation ex vivo and produced an approximate 3-fold prolongation of the sublingual bleeding time. ASA eliminated thrombus formation in 4 of 5 dogs, but the additional prothrombotic stimulus of epinephrine infusion produced recurrent thrombus formation in all dogs. Collagen-induced platelet aggregation ex vivo was inhibited by acetylsalicylic acid, but sublingual bleeding time was unaffected. Vapiprost inhibited arterial thrombus formation in all dogs, but thrombus formation returned with the addition of epinephrine. There was a tendency for prolonged bleeding times with vapiprost administration and collagen-induced platelet aggregation ex vivo was effectively inhibited. These studied indicate that the combined inhibition of the thromboxane A2 receptor together with inhibition of thromboxane synthetase provides superior antithrombotic activity in vivo than does thromboxane A2 receptor blockade alone (vapiprost) or inhibition of cyclooxygenase (ASA). Thrombus formation even with the additional stimulation of epinephrine was inhibited by DTTX30 but neither vapiprost nor ASA was effective in this setting.