Abstract
OBJECTIVE: Tissue plasminogen activator (tPA) is administered to acute ischemic stroke victims in a vehicle formulation containing high concentrations of L-arginine (3.5g/100mg vial), a well-known nitric oxide synthase (NOS) substrate and precursor to nitric oxide (NO), as well as an enhancer of cerebral blood flow. METHODS: We studied the effects of tPA vehicle compared to tPA (3.3mg/kg) formulated in the same vehicle containing L-arginine, normal saline or normal saline containing L-arginine, on behavioral function following small clot embolic strokes in rabbits using clinical rating scores and quantal analysis curves as the primary end point. Treatments were administered intravenously (1ml/kg; 20% bolus/80% infused over 30min) starting 1h following the injection of small-sized blood clots into the brain vasculature and terminal behavior was measured 2days following embolization. Behavioral rating scores were used to calculate the effective stroke dose (P50 in mg) that produces neurological deficits in 50% of the rabbits. RESULTS: In this study, tPA significantly (p=0.001) improved behavior compared to all other treatments including tPA vehicle, saline and saline-L-arginine, increasing the P50 by 141% over tPA vehicle. Saline-L-arginine was not significantly different from either saline or tPA vehicle (p>0.05). CONCLUSION: This study demonstrates that the L-arginine component of the tPA vehicle does not contribute to the reproducible clinical improvement observed following tPA administration in rabbits. Moreover, the administration of L-arginine was not an effective method to promote behavioral recovery following embolic strokes in the stringent rabbit small clot stroke model, nor did L-arginine exacerbate behavioral deficits or intracerebral hemorrhage in embolized rabbits.