Nitric oxide reverses aspirin antagonism of t-PA thrombolysis in a rabbit model of thromboembolic stroke.
Randomized trials of thrombolytic therapy in stroke have reported an improvement in neurologic outcome; however, the addition of aspirin has resulted in a significant increase in mortality and antagonism of clot lysis in clinical and animal studies, respectively. This finding is in contradistinction to the known synergy in mortality reduction for aspirin and thrombolytics in myocardial infarction. It is hypothesized that aspirin antagonism of clot lysis is related to inhibition of nitric oxide (NO) and may be reversed by providing a source of NO. Twenty rabbits were treated with aspirin (20 mg/kg, i.v.) prior to internal carotid clot embolization. One-half hour following embolization, rabbits were randomized to receive vehicle (n = 5), the NO precursor L-arginine (300 mg/kg, i.v. bolus at 0.5 and 2.5 h postembolus; n = 5), or a nitric oxide donor (nitroprusside, 1 mg/kg/h, i.a., or nitroglycerin, 10 microg/kg/min, i.v., n = 5 each agent). Tissue plasminogen activator (t-PA) (6.3 mg/kg) was administered from 1 to 3 h after embolization. Lysis of the tin-tagged clot was followed with serial X rays and gross examination. No rabbit in the control group experienced complete clot lysis. However, 2 of 5 rabbits in the L-arginine group and 6 of 10 rabbits in the nitric oxide donor (nitroprusside and nitroglycerin) groups noted complete clot lysis (P < 0.05, Fisher exact test). Thus, administration of an NO donor (nitroglycerin or nitroprusside) and, to a lesser extent L-arginine, reversed aspirin's antagonism of t-PA thrombolysis. This study may help explain the discrepant results seen with aspirin and thrombolytics.
Bednar
M M
MM
Division of Neurosurgery, University of Vermont, Burlington 05405, USA.
Gross
C E
CE
Howard
D B
DB
Russell
S R
SR
Thomas
G R
GR
D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002561:Cerebrovascular Disorders / Q000097:blood* / Q000209:etiology*; D005260:Female; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D011817:Rabbits; D013923:Thromboembolism / Q000150:complications*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000933:Antifibrinolytic Agents; D009569:Nitric Oxide; D010959:Tissue Plasminogen Activator; D001241:Aspirin