title: The effect of vasodilators on aspirin-induced antagonism of t-PA thrombolysis.
abstract: Although i.v. t-PA has proven successful in reducing neurologic deficits in acute ischemic stroke, the disadvantages of a narrow therapeutic time window and the failure of thrombolysis in more than 50% of patients treated have necessitated an examination of adjuvant therapies to improve the rate of thrombolysis. Experimentally, the combination of aspirin therapy with t-PA has resulted in a paradoxical antagonism of thrombolysis. Reversal of this antagonism with nitric oxide (NO) donors suggested that aspirin may inhibit/ antagonize NO-related mechanisms. Using this rabbit model of thromboembolic stroke, this hypothesis is now expanded to compare two clinically relevant anti-hypertensive agents, atenolol (NO-dependent) and hydralazine (NO-independent), for their ability to improve t-PA-mediated clot lysis following aspirin pre-treatment. Thirty rabbits (10 per group) were pre-treated with aspirin (20mg kg(-1), i.v.) and then randomized to receive either vehicle, atenolol (20 microg kg(-1) h(-1), i.v.) or hydralazine (10 microg kg(-1) min(-1), i.v.) beginning 30 min following autologous clot embolization. All rabbits then received t-PA (6.3 mg kg(-1), i.v.) beginning 1 h after embolization, with completion of the protocol 4 h after embolization. Aspirin therapy reduced regional cerebral blood flow (rCBF) from 82.8m +/- 4.7 to 62.5 +/- 6.6 (n = 30; p = 0.0005). In the aspirin control group only 30% (3 of 10) rabbits demonstrated complete clot lysis, whereas the combined atenolol (60%) and hydralazine (70%) groups experienced a clot lysis rate of 65% (13 of 20 rabbits), similar to clot lysis rates previously observed with t-PA alone. In a separate series of experiments, all agents able to reverse aspirin antagonism of thrombolysis demonstrated an improvement in rCBF, suggesting a common mechanism for this diverse group of agents in reversing aspirin's antagonism of thrombolysis.
authors.affiliation: Division of Neurosurgery, University of Vermont, Burlington 05405, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Bednar
authors.forename: C E
authors.initials: CE
authors.lastname: Gross
authors.forename: D B
authors.initials: DB
authors.lastname: Howard
authors.forename: S R
authors.initials: SR
authors.lastname: Russell
authors.forename: C
authors.initials: C
authors.lastname: Ellenberger
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001241:Aspirin / Q000037:antagonists & inhibitors*; D001262:Atenolol / Q000494:pharmacology / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D011817:Rabbits; D013923:Thromboembolism / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D005343:Fibrinolytic Agents; D020030:Nitric Oxide Donors; D011465:Prostaglandins, Synthetic; D014665:Vasodilator Agents; D006830:Hydralazine; D009569:Nitric Oxide; D001262:Atenolol; D010959:Tissue Plasminogen Activator; D001241:Aspirin