Intravenous infusion of calcium antagonist, nicardipine, does not increase intracranial pressure: evaluation in a rat model of transient cerebral ischemia and reperfusion.

OBJECTIVE AND METHOD: Early use of parenteral antihypertensive drugs is recommended in acute ischemic stroke patients suffering hypertensive emergencies. Calcium antagonist has been widely employed, although there is controversy as to whether calcium antagonist can be administered safely to patients with intracranial hypertension. In a rat model of transient cerebral ischemia and reperfusion, we evaluated the effect of the calcium antagonist, nicardipine, on intracranial pressure (ICP). Using spontaneously hypertensive rats (SHRs), focal cerebral ischemia was induced by an intraluminal thread method. ICP was monitored continuously employing an intraparenchymal catheter. The mean arterial blood pressure (MABP) was reduced by infusing nicardipine intravenously. RESULTS: Following 6 hours of transient ischemia and reperfusion, MABP was decreased by about 10 or 20% as compared to the baseline MABP with low-dose or high-dose nicardipine administration, respectively. ICP was significantly increased following reperfusion, although it did not increase further with nicardipine infusion. CONCLUSION: Under conditions where ICP was high following reperfusion, nicardipine reduced blood pressure safely without increasing ICP in rats.

Tissue plasminogen activator extravasated through the cerebral vessels: evaluation using a rat thromboembolic stroke model.

Neurotoxic effects of endogenous tissue plasminogen activator (tPA) have recently been reported. Employing a rat model of thromboembolic stroke, we evaluated the extent and degree of extravasation of exogenous tPA administered for the purpose of fibrinolysis. In a thromboembolic model using Sprague-Dawley rats, focal cerebral ischemia was induced at the territory of the middle cerebral artery (MCA). Early reperfusion was induced by administering tPA (10 mg/kg) intravenously at 30 minutes after the onset of ischemia. Extravasated tPA was evaluated by immunohistochemistry, and the concentration of tPA in the brain tissue was quantified by enzyme-linked immunosorbent assay methods. The integrity of the blood-brain barrier (BBB) was examined electronmicroscopically. In a thread model of transient ischemia, reperfusion was induced without tPA administration at 30 minutes or 2 hours after the onset of ischemia, and the tPA content of the brain was quantified. In the rats with thromboembolic stroke, extravasation of tPA was observed at the territory of the MCA. Both the endogenous and exogenous tPA contents were 3.5 +/- 1.6 ng/ml of homogenized brain in saline. Electronmicroscopically, mild ischemic changes were observed, although the integrity of the BBB was preserved. In the thread model rats, the endogenous tPA contents of the ischemic hemisphere were 0.9 +/- 0.1 and 1.0 +/- 0.2 ng/ml in the 30-minute and 2-hour ischemia groups, respectively, and were significantly lower than the tPA contents in the thromboembolic stroke rats (p<0.01). The present findings indicate that significant extravasation of exogenous tPA occurs through the cerebral vessels even though early reperfusion is induced.

Attenuation of extravasation of tissue plasminogen activator by the free radical scavenger, edaravone: evaluation in a rat thromboembolic stroke model.

OBJECTIVES AND METHODS: Deleterious effects of tissue plasminogen activator (tPA) have been described recently in experimental studies. For example, tPA can aggravate ischemic neuronal damage through its proteolytic activity. The present study was undertaken to examine whether or not the free radical scavenger, edaravone, could prevent the extravasation of tPA administered for the purpose of fibrinolysis in a rat model of thromboembolic stroke. RESULTS: Significant amounts of tPA were extravasated through the cerebral vessels even when early recanalization was induced by administering tPA at 30 minutes after the onset of schema. Edaravone significantly attenuated such extravasation of tPA. CONCLUSION: In acute ischemic stroke patients, combination therapy using tPA with edaravone appears to be a reasonable strategy for diminishing the negative effects of tPA.

Reduction of infarction volume by bolus injection of pamiteplase, a modified tissue plasminogen activator with a longer half-life.

Using a rat model of thromboembolic stroke we evaluated whether or not fibrinolysis by bolus injection of pamiteplase, a modified tissue plasminogen activator (tPA) with a longer half-life, reduces infarction volume. Infarction volume was significantly reduced by the early administration of pamiteplase at 2 h after the onset of ischemia. Hemorrhagic infarction was observed only in 3 of 10 rats (30%) treated at 6 h. Thus, bolus injection of pamiteplase can reduce infarction volume suppressing the incidence of hemorrhage.