Jerry S. Matsumura

Time- and pressure-dependent changes in blood-brain barrier permeability after temporary middle cerebral artery occlusion in rats.

SummaryAfter 180 min of temporary middle cerebral artery occlusion in rats, the affect of phenylephrine-induced hypertension on blood-brain barrier permeability was assessed. One of the following blood-pressure regimens was maintained during either a 30- or 120-min period of reperfusion: (a) 30/Norm, 30 min of normotensive reperfusion was allowed; (b) 30/HTN, mean arterial blood pressure was increased by 35 mm Hg during 30 min of reperfusion; (c) 120/Norm, 120 min of normotensive reperfusion was allowed; or (d) 120/HTN, mean arterial blood pressure was increased by 35 mm Hg during 120 min of reperfusion. Evans blue (30 mg/kg) was given, and brains were analyzed for Evans blue by spectrophotometry. Evans blue (μg/g brain tissue, mean ± SD) was greater (P<0.05) in both hypertensive groups versus their time matched normotensive groups (30/HTN: 80±16 versus 18±6 in the 30/Norm group; 120/HTN: 17±6 versus 8±3 in the 120/Norm group). In addition, Evans blue was greater (P<0.05) in both 30-min groups versus their pressure matched 120-min groups (30/Norm: 18±6 versus 8±3 in the 120/Norm group; 30/HTN: 80±16 versus 17±6 in the 120/HTN group). The data are consistent with previous studies which have demonstrated an opening of the blood-brain barrier at the onset of reperfusion. In addition, the data support a hypothesis that changes in blood-brain barrier permeability are more sensitive to hypertension in the early period of reperfusion.

Focal Cerebral Ischemia in Rats: Effects of Induced Hypertension, during Reperfusion, on CBF:

The effect of phenylephrine-induced hypertension on CBF was investigated after 120 min of middle cerebral artery occlusion in rats. Blood pressure was manipulated by one of the following schedules during a 90-min period of reperfusion: 90/NORM, 90 min of normotensive reperfusion; 90/HTN, 90 min of hypertensive reperfusion (MABP increased by 30 mm Hg); or 15/HTN, the 90-min period of reperfusion was divided into 30 min of normotension, followed by 15 min of hypertension and 45 min of normotension. At the end of reperfusion, 100 μCi kg−1 of [14C]iodoantipyrine was given and an autoradiographic analysis of CBF performed. In the coronal brain section at the center of middle cerebral artery distribution, the area (percentage of hemisphere, mean ± SD) with a CBF of 0–20 or 21–40 ml 100 g−1 min−1 was less (p < 0.05) in the 15/HTN group (1 ± 2 and 5 ± 3%, respectively) versus the 90/HTN group (12 ± 4 and 10 ± 4%), which was in turn less than in the 90/NORM group (18 ± 5 and 22 ± 6%). These data are consistent with the hypothesis that during reperfusion a short interval of hypertension effectively augments CBF via an abrupt opening of collapsed vessels and that a more sustained interval of hypertension conveys no added benefit.

Hypervolemic-hemodilution and hypertension during temporary middle cerebral artery occlusion in rats: the effect on blood-brain barrier permeability.

The effect of hypervolemic-hemodilution, with and without hypertension, on blood-brain barrier permeability was investigated in rats, after 180 minutes of middle cerebral artery occlusion (MCAo), and 60 minutes of reperfusion. One of the following conditions was maintained during MCAo: 1) Control--hematocrit and blood pressure were not manipulated; 2) Hypervolemic-Hemodilution/Normotension--the hematocrit was decreased to 30%; 3) Hypervolemic-Hemodilution/Hypertension--the hematocrit was decreased to 30% and mean arterial pressure increased by 30 mmHg with phenylphrine. In all groups, Evans Blue was administered, and its concentration determined by spectrophotometric assay. Evans Blue (micrograms (g-1 of brain tissue [mean +/- SD]) was greater in the Hypervolemic-Hemodilution/Hypertension group (71 +/- 20) versus the Control (13 +/- 9) and Hypervolemic-Hemodilution/Normotension (17 +/- 10) groups (p less than 0.05). No other differences were present. These results support the hypothesis that during MCAo, hypervolemic-hemodilution/hypertensive therapy effects an increase in blood-brain barrier permeability in the early period of reperfusion.

Nitrendipine and Superoxide Dismutase in Ischemic Renal Injury

The effect of the Ca entry blocker nitrendipine, the antioxidant superoxide dismutase (SOD), and a combination of nitrendipine and superoxide dismutase on postischemic renal function was studied in four groups (n = 24) of rats. The rats in group 1 (n = 6) were the ischemic control and received 10 mL of 0.9% NaCl. Group II (n = 6) received SOD 7.0 mg/kg. Group III (n = 6) received nitrendipine 1 mg/kg. Group IV (n = 6) received nitrendipine 1 mg/kg and SOD 7 mg/kg. After administration, both kidneys were rendered ischemic by cross-clamping the renal vessels for 60 min. Comparison of 24-h creatinine clearance (CCr) for 3 days after reversal of ischemia revealed: (a) nitrendipine alone was the most effective in preserving renal function (p < .05); (b) SOD provided some degree of improvement, but only on day 3 (p < .05); (c) a similar result was detected using a combination of nitrendipine and SOD (p < .05); (d) there was no significant difference between SOD and nitrendipine nor between SOD and the combination of nitrendipine/SOD; (e) there was a significant improvement with nitrendipine when compared to the combination of nitrendipine/SOD (p < .05).

L-644,711, A NOVEL ANION TRANSPORT INHIBITOR, INCREASES ISOFLURANE MAC IN RATS

The effect of the anion transport inhibitor L-644,711 on isoflurane MAC was determined in rats (n=24). After baseline MAC determination, each rat received one of the following drug protocols: (a) control, vehicle only; (b) L-M4,7llrr, a 3-mg/kg intrathecal bolus of L-644,711 followed by an infusion at 1.5 mg·kg−1·h−1; or (c) L-644,711Iv, a 6-mg/kg intravenous bolus of L-644,711 followed by an infusion at 3 mg·kg−1-h−1. MAC was again determined. The baseline isoflurane MAC was not different between groups (control, 1.52% ± 0.15%; L-644,711IT, 1.51% ± 0.24%; L-644,711IV, 1.54% ± 0.13% [mean ± SD]). After drug or vehicle administration, isoflurane MAC was larger for the L-644,711,IT group (2.25% ± 0.17%) versus the control (1.38% ± 0.13%) and L-644,711IV (1.39% ± 0.15%) groups (P < 0.05). These data are consistent with the hypothesis that isoflurane anesthesia is influenced by anion channels and that blocking these channels may reduce the pharmacodynamic potency of isoflurane.