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 pretreatment. Thirty rabbits (10 per group) were pre-treated with aspirin (20 mg kg-1, i.v.) and then randomized to receive either vehicle, atenolol (20 µg kg-1 h-1, i.v.) or hydralazine (10 µg kg-1 min-1, i.v.) beginning 30 min following autologous clot embolization. All rabbits then received t-PA (6.3mg 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 82.8 ± 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. [Neurol Res 2001; 23: 745-750]

Keywords:

• STROKE
• ASPIRIN
• HYDRALAZINE
• ATENOLOL
• T-PA
• VASODILATORS
• ANTI-HYPERTENSIVES