Circulation, Vol 86, 1993-1999, Copyright © 1992 by American Heart Association
SK Yao, JC Ober, JJ Ferguson, HV Anderson, J Maraganore, LM Buja and JT Willerson
BACKGROUND. The efficacy of thrombolytic therapy in treating patients with
acute myocardial infarction is limited by failure to achieve reperfusion in
some patients, by the prolonged time required to achieve reperfusion, and
by reocclusion of some coronary arteries. We designed this study to examine
the effect of combined inhibition of thrombin and thromboxane synthesis and
blockade of thromboxane A2 receptors in addition to tissue-type plasminogen
activator (t-PA) on thrombolysis and reocclusion in an experimental canine
model with coronary thrombosis. METHODS AND RESULTS. Blood flow velocity in
the left anterior descending coronary artery (LAD) of 32 anesthetized
mongrel dogs was monitored by a pulsed Doppler flow probe. Coronary
thrombosis was induced by applying electrical stimulation to the LAD at the
site where an external constrictor was used to narrow the artery. Three
hours after the formation of occlusive thrombus, animals were randomly
assigned to receive one of the following: 1) t-PA (80 micrograms/kg + 8
micrograms.kg-1.min-1 i.v.) and saline; 2) t-PA and hirulog, a hirudin-
based synthetic peptide and specific thrombin inhibitor (2 mg/kg + 2
mg.kg-1.hr-1 i.v.); 3) t-PA and ridogrel, a combined thromboxane A2
synthetase inhibitor and receptor antagonist (5 mg/kg + 2.5 mg.kg-1.hr- 1
i.v.); or 4) t-PA, hirulog, and ridogrel. Reperfusion developed in 14% (one
of seven) of dogs treated with t-PA alone at an average of 86 +/- 4 minutes
after treatment, in 78% (seven of nine) of dogs treated with t-PA plus
hirulog at 53 +/- 11 minutes, in 13% (one of eight) of dogs treated with
t-PA plus ridogrel at 85 +/- 5 minutes, and in 88% (seven of eight) of dogs
treated with t-PA, hirulog, and ridogrel at 37 +/- 10 minutes (comparison
of the frequency of and the time to reperfusion, both p < 0.01). Among
the dogs with reestablished coronary blood flow, reocclusion developed in
the one treated with t-PA alone at 36 minutes after reperfusion, in seven
of the seven treated with t-PA plus hirulog at 66 +/- 15 minutes, and in
two of the seven treated with t-PA, hirulog, and ridogrel at 151 +/- 21
minutes (comparison of the frequency of and time to reocclusion, both p
< 0.05). Reocclusion was not detected in the one dog treated with t-PA
and ridogrel or in the other five dogs treated with t-PA, hirulog, and
ridogrel within 180 minutes after reperfusion. Hirulog prolonged and
maintained activated clotting times at a level twice that of baseline
values. Hirulog inhibited ex vivo platelet aggregation induced by thrombin,
and ridogrel inhibited platelet aggregation induced by U46619, a
thromboxane mimetic. CONCLUSIONS. Inhibition of thrombin in addition to
treatment with t-PA enhances thrombolysis. A combination of inhibition of
thrombin and thromboxane synthetase and blockade of thromboxane A2 receptor
enhances thrombolysis and delays or may prevent reocclusion of the
recanalized coronary arteries.
ARTICLES
Combination of inhibition of thrombin and blockade of thromboxane A2 synthetase and receptors enhances thrombolysis and delays reocclusion in canine coronary arteries
Cardiovascular Research Laboratory, Texas Heart Institute, Houston.
This article has been cited by other articles:
 |
|
 |
|
  D. R. Abendschein, P. K. Baum, P. Verhallen, P. R. Eisenberg, M. E. Sullivan, and D. R. Light A Novel Synthetic Inhibitor of Factor Xa Decreases Early Reocclusion and Improves 24-h Patency after Coronary Fibrinolysis in Dogs J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 567 - 572. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. D. White, P. E. Aylward, M. J. Frey, A. A. J. Adgey, R. Nair, W. S. Hillis, Y. Shalev, M. A. Brown, J. K. French, R. Collins, et al. Randomized, Double-blind Comparison of Hirulog Versus Heparin in Patients Receiving Streptokinase and Aspirin for Acute Myocardial Infarction (HERO) Circulation, October 7, 1997; 96(7): 2155 - 2161. [Abstract] [Full Text]
|
|
|
|
|
|
D. Pratico, N. P. Murphy, and D. J. Fitzgerald J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1178 - 1185. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. Li, D. Baykal, C. Horaist, C.-N. Yan, B. N. Carr, G. N. Rao, and M. S. Runge Cloning and Identification of Regulatory Sequences of the Human Thrombin Receptor Gene J. Biol. Chem., October 18, 1996; 271(42): 26320 - 26328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Shetler, V. G. Crowe, B. D. Bailey, and C. V. Jackson Antithrombotic Assessment of the Effects of Combination Therapy With the Anticoagulants Efegatran and Heparin and the Glycoprotein IIb-IIIa Platelet Receptor Antagonist 7E3 in a Canine Model of Coronary Artery Thrombosis Circulation, October 1, 1996; 94(7): 1719 - 1725. [Abstract] [Full Text]
|
|
|
|
|
|
D. R. Abendschein, Y. Y. Meng, S. Torr-Brown, and B. E. Sobel Maintenance of Coronary Patency After Fibrinolysis With Tissue Factor Pathway Inhibitor Circulation, August 15, 1995; 92(4): 944 - 949. [Abstract] [Full Text]
|
|
|
|
|
|
N. A. Prager, D. R. Abendschein, C. R. McKenzie, and P. R. Eisenberg Role of Thrombin Compared With Factor Xa in the Procoagulant Activity of Whole Blood Clots Circulation, August 15, 1995; 92(4): 962 - 967. [Abstract] [Full Text]
|
|
|
|
|
|
S.-K. Yao, S. Akhtar, T. Scott-Burden, J. C. Ober, P. Golino, L. M. Buja, W. Casscells, and J. T. Willerson Endogenous and Exogenous Nitric Oxide Protect Against Intracoronary Thrombosis and Reocclusion After Thrombolysis Circulation, August 15, 1995; 92(4): 1005 - 1010. [Abstract] [Full Text]
|
|
|
|
|
|
P. Theroux, F. Perez-Villa, D. Waters, J. Lesperance, F. Shabani, and R. Bonan Randomized Double-Blind Comparison of Two Doses of Hirulog With Heparin as Adjunctive Therapy to Streptokinase to Promote Early Patency of the Infarct-Related Artery in Acute Myocardial Infarction Circulation, April 15, 1995; 91(8): 2132 - 2139. [Abstract] [Full Text]
|
|
|
|
|
|
J. M. Stassen, A. Nystrom, M. Hoylaerts, and D. Collen Antithrombotic Effects of Thrombolytic Agents in a Platelet-Rich Femoral Vein Thrombosis Model in the Hamster Circulation, March 1, 1995; 91(5): 1330 - 1335. [Abstract] [Full Text]
|
|
|
|
|
|
J. S. Mruk, P. Zoldhelyi, M. W.I. Webster, M. Heras, D. E. Grill, D. R. Holmes Jr, V. Fuster, and J. H. Chesebro Does Antithrombotic Therapy Influence Residual Thrombus After Thrombolysis of Platelet-Rich Thrombus? : Effects of Recombinant Hirudin, Heparin, or Aspirin Circulation, February 15, 1995; 93(4): 792 - 799. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. V. Anderson and J. T. Willerson Thrombolysis in Acute Myocardial Infarction N. Engl. J. Med., September 2, 1993; 329(10): 703 - 709. [Full Text]
|
|