vapiprost and Coronary-Thrombosis

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.

Topics: Animals; Aspirin; Biphenyl Compounds; Chlorobenzenes; Coronary Thrombosis; Cyclooxygenase Inhibitors; Dogs; Enzyme Inhibitors; Female; Heptanoic Acids; Male; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thromboxane; Thromboxane-A Synthase

Vapiprost (GR32191, a TxA2 antagonist), r-hirudin, aspirin, ticlopidine and aspirin plus ticlopidine were examined for their ability to prevent electrically-induced thrombosis in an artificially stenosed coronary artery in the anaesthetised dog. Drugs or vehicle were administered prior to a 2 h period of electrical damage which was followed by a further 2 h observation period. In all vehicle-treated animals, blood flow markedly declined with onset of the damaging current; 80% completely occluded. All treatments reduced the incidence of complete occlusion to a similar extent. Vapiprost and r-hirudin also largely prevented the decline in blood flow both during and following the damage period whilst aspirin and ticlopidine, either alone or in combination were much less effective. With r-hirudin treatment, marked cyclic changes in flow occurred throughout the experiment; these were abolished by administration of vapiprost. In this dog model, TxA2 and thrombin appear to work in concert to produce coronary thrombosis, ADP being of minor importance. The superior effect of vapiprost over aspirin suggests a beneficial role for endogenous prostacyclin.

Topics: Anesthesia; Animals; Aspirin; Biphenyl Compounds; Blood Coagulation Tests; Coronary Circulation; Coronary Thrombosis; Dogs; Drug Synergism; Drug Therapy, Combination; Electric Stimulation; Female; Fibrinolytic Agents; Heptanoic Acids; Hirudin Therapy; Hirudins; Male; Platelet Aggregation; Recombinant Proteins; Thrombin; Thromboxane A2; Ticlopidine

Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However, experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists, in addition to TXA2. As a consequence, greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However, a recent clinical trial, combining tissue plasminogen activator (t-PA) with the prostacyclin analog, iloprost, did not detect such a benefit. To address the mechanism of this response, we compared the effect of iloprost, a stable analog of prostacyclin, with GR32191, a TXA2/prostaglandin endoperoxide receptor antagonist, on the response to i.v. t-PA in a closed chest, canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6, P less than .05), consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast, iloprost increased the time to reperfusion by 50% (n = 5, P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments, steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8, P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect, as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.

Topics: Alprostadil; Animals; Biphenyl Compounds; Coronary Thrombosis; Dogs; Drug Interactions; Heptanoic Acids; Iloprost; Male; Platelet Aggregation; Reperfusion; Thrombolytic Therapy; Thromboxane A2; Tissue Plasminogen Activator