iloprost and Coronary-Thrombosis

The coronary artery often reoccludes soon after the flow has been restored with recombinant tissue-type plasminogen activator (TPA) in dogs with electrically-induced thrombosis. The coronary artery reocclusion relates to intense in situ platelet activation and thrombin generation in the reperfused coronary artery. To determine the effect of a potent platelet inhibitor, the prostacyclin analog iloprost, in the prevention of coronary artery reocclusion, an occlusive thrombus was created in the left anterior descending coronary artery in 23 dogs. Coronary artery reflow occurred in 17 dogs after TPA (1 mg/kg over 20 minutes intravenously) administration. After the reflow was established, 10 dogs were given saline and 7 dogs were given iloprost (4 micrograms/kg over 40 minutes). In the saline-treated group, the coronary artery reoccluded in 8 of 10 dogs over 90 minutes (reocclusion rate 80%). In the iloprost-treated group, the coronary artery reoccluded in five of seven dogs (reocclusion rate 71%; p = NS vs TPA alone). The magnitude of peak coronary blood flow and duration of flow were similar in dogs given saline or iloprost after TPA-induced thrombolysis. Scanning electron microscopy showed residual thrombus and the appearance of coronary arterial narrowing distal to the thrombus in all dogs examined. Thus residual thrombus formation and coronary artery narrowing continue to occur after TPA-induced thrombolysis in dogs whether the animals are treated with saline or iloprost. Administration of iloprost after reflow does not modulate the frequency of coronary artery reocclusion.

Topics: Animals; Coronary Circulation; Coronary Thrombosis; Coronary Vessels; Dogs; Female; Iloprost; Male; Microscopy, Electron, Scanning; Recurrence; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator

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

Thrombolytic effects of tissue-type plasminogen activator (t-PA) are limited by in vivo platelet activation and dynamic coronary vasoconstriction. To examine if the concurrent administration of a fibrin(ogen)-degradation product, pentapeptide 6A (Ala-Arg-Pro-Ala-Lys) with t-PA would improve the thrombolytic effects of t-PA, dogs with electrically induced coronary thrombus were given t-PA alone or with peptide 6A. In dogs given t-PA alone (0.75 mg/kg over 20 min), coronary blood flow was restored in 69% of animals (9 of 13 dogs), with a mean time to reflow of 21 +/- 10 min and duration of reflow of 35 +/- 18 min. Reocclusion occurred in 77% of dogs (7 of 9 dogs). With concurrent administration of peptide 6A (200 mumol), coronary venous 6-keto-PGF1 alpha concentrations increased from 221 +/- 71 to 422 +/- 161 pg/ml (p less than 0.05), but not with t-PA given alone. Coronary blood flow was restored in 7 of 11 dogs (reperfusion rate 64%), with mean time to reflow of 17 +/- 7 min and duration of reflow of 35 +/- 15 min. The coronary reocclusion rate was 86%. All these indices of thrombolysis were similar to those in dogs given t-PA alone. In ex vivo experiments, we also demonstrated release of endothelium-derived relaxing factor from canine coronary artery rings in response to peptide 6A. To further examine the role of prostacyclin (PGI2) in thrombolytic response to t-PA, eight other dogs were given t-PA with a PGI2 analog iloprost (100 ng/kg/min for 40 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Circulation; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Epoprostenol; Hemodynamics; Iloprost; Male; Nitric Oxide; Tissue Plasminogen Activator

Platelets play an important role in the formation of a coronary thrombus and reocclusion after thrombolysis. Therefore, we examined the thrombolytic potential of concomitant intravenous administration of potent platelet inhibitor iloprost, a prostacyclin analogue, with tissue-type plasminogen activator (t-PA; n = 8) and t-PA alone (n = 9) in dogs with an electrically induced occlusive coronary artery thrombus. t-PA (0.75 mg/kg) was given over 20 minutes, and iloprost (4 micrograms/kg) was given over 40 minutes. Reperfusion rate was 63% (five of eight dogs) in the t-PA plus iloprost group and 67% (six of nine dogs) in the t-PA alone group (p = NS). The time to thrombolysis (or reperfusion) in the t-PA plus iloprost group was almost twice as great as in the t-PA alone group (33.0 +/- 13.3 vs. 18.5 +/- 6.7 minutes, mean +/- SD, p less than 0.02), and the duration of reperfusion was much shorter (3.4 +/- 1.8 vs. 39.3 +/- 17.4 minutes, p less than 0.005). Peak coronary artery blood flow after reperfusion in the t-PA plus iloprost group was also less (20 +/- 17 ml/min) than in the t-PA alone group (58 +/- 21 ml/min, p less than 0.005). Reocclusion occurred in all dogs given t-PA with iloprost despite potent synergistic platelet inhibitory effects of t-PA and iloprost, whereas four of six dogs given t-PA alone reoccluded. Neither regimen exerted a significant beneficial effect on regional myocardial shortening during coronary reperfusion. Plasma levels of t-PA were lower when iloprost was given with t-PA (1,022 +/- 360 vs. 1,459 +/- 270 ng/ml in t-PA alone group, p less than 0.05). The detrimental effects of iloprost identified in this study may relate to the reduction in plasma t-PA concentrations by its degradation in the liver caused by the prostacyclin analogue iloprost.

Topics: Animals; Coronary Disease; Coronary Thrombosis; Dogs; Drug Interactions; Drug Therapy, Combination; Epoprostenol; Iloprost; Male; Myocardial Reperfusion; Platelet Aggregation Inhibitors; Recurrence; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator