Oak Z. Chi

Effects of Mild Hypothermia on Blood–Brain Barrier Disruption during Isoflurane or Pentobarbital Anesthesia

BackgroundThis study was performed to determine whether mild hypothermia (32°C) could attenuate the degree of blood–brain barrier (BBB) disruption caused by a hyperosmolar solution and whether the degree of disruption would vary depending on anesthetic agents. MethodsRats were assigned to one of four groups: normothermic isoflurane, normothermic pentobarbital, hypothermic isoflurane, and hypothermic pentobarbital. During isoflurane (1.4%; normothermic or hypothermic) or pentobarbital (50 mg/kg administered intraperitoneally; normothermic or hypothermic) anesthesia, the external carotid artery and the femoral artery and vein were catheterized. Body temperature was maintained at 37 and 32°C for the normothermic and hypothermic groups, respectively. To open the BBB, 25% mannitol was infused through the right carotid artery at the rate of 0.25 ml · kg−1 · s−1 for 30 s. The transfer coefficient of 14C-&agr;-aminoisobutyric acid was determined. ResultsBlood pressure was similar among the four groups of animals. The degree of the BBB disruption by hyperosmolar mannitol was less with isoflurane than pentobarbital anesthesia in the normothermic groups (transfer coefficient: 29.9 ± 17.1 and 50.4 ± 17.5 &mgr;l · g−1 · min−1 for normothermic isoflurane and pentobarbital, respectively;P < 0.05). Mild hypothermia decreased the BBB disruption during anesthesia with both anesthetic agents (hypothermic isoflurane: 9.8 ± 8.3 &mgr;l · g−1 · min−1, P < 0.05 vs. normothermic isoflurane; hypothermic pentobarbital: 30.2 ± 13.9 &mgr;l · g−1 · min−1, P < 0.05 vs. normothermic pentobarbital), but the disruption was less during isoflurane anesthesia (hypothermic isoflurane vs. hypothermic pentobarbital, P < 0.005). In the contralateral cortex, there were no significant differences among these four experimental groups. ConclusionsThe data demonstrated that hypothermia was effective in attenuating BBB disruption by hyperosmolar mannitol during isoflurane as well as pentobarbital anesthesia. The degree of disruption appeared smaller during isoflurane than during pentobarbital anesthesia in both the normothermic as well as the hypothermic groups.

Effects of anti-VEGF antibody on blood-brain barrier disruption in focal cerebral ischemia.

Since cerebral ischemia increases expression of vascular endothelial growth factor (VEGF) and exogenous VEGF can aggravate BBB disruption in cerebral ischemia, we hypothesized that inhibition of endogenous VEGF would attenuate BBB disruption. To test this hypothesis, rats were mechanically ventilated with isoflurane and a craniotomy (5 mm in diameter) was performed to expose the cerebral cortex. Anti-VEGF antibody was applied topically (75 mug) 1 h before middle cerebral artery (MCA) occlusion and additional anti-VEGF antibody was applied (25 mug) immediately after MCA occlusion (anti-VEGF group). For the control animals, normal saline was applied instead of anti-VEGF antibody on the surface of the cortex (control group). One hour after MCA occlusion, the transfer coefficient (K(i)) of (14)C-alpha-aminoisobutyric acid and volume of (3)H-dextran (70,000 Da) distribution were determined to measure the degree of BBB disruption. There was no significant difference in vital signs, blood gases, and pericranial temperature between the control and the anti-VEGF group. In both of the groups, the K(i) of the ischemic cortex (IC) was higher than that of the corresponding contralateral cortex (CC) (p<0.05). The K(i) of the IC of the anti-VEGF group was significantly lower than that of the IC of the control group (-34%, p<0.05). The K(i) of the CC and pons were similar between these two groups. The data of volume of dextran distribution followed the same pattern as that of K(i) but without a statistical significance. Our data demonstrated that inhibition of endogenous VEGF by topical application of anti-VEGF antibody in the ischemic cortex decreased the K(i) of (14)C-AIB and suggest that endogenous VEGF is in part responsible for the BBB disruption during the early stage of focal cerebral ischemia.

Effects of Inhibition of Nitric Oxide Synthase on Blood-Brain Barrier Transport in Focal Cerebral Ischemia

This study was performed to determine whether nitric oxide (NO) alters the transport of small hydrophilic molecules across the blood-brain barrier in focal cerebral ischemia by administering an NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) and by measuring the blood-brain barrier transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid (14C-AIB) in the rats with middle cerebral artery occluded under isoflurane anesthesia. L-NAME increased the mean arterial blood pressure from 91 +/- 9 to 134 +/- 13 mm Hg. The Ki of the ischemic cortex (ICO) was 26% higher than that of the contralateral cortex (CCO) in the control animals without the L-NAME treatment. However, in the L-NAME-treated animals, Ki was 33% lower in the ICO than in the CCO. The Ki of ICO in the L-NAME group was significantly lower (-54%) than that of the control group. L-NAME did not affect Ki significantly in the nonischemic brain regions. Our data demonstrate that focal ischemia increased Ki of 14C-AIB, but L-NAME significantly decreased the Ki in the focal ischemic area of the brain without causing significant changes in the nonischemic tissue. Our results suggest that NO may participate in increasing transport of small hydrophilic molecules across the blood-brain barrier in focal ischemia.

Effects of isoflurane on transport across the blood-brain barrier

The blood-brain barrier (BBB) plays an important role in regulating and restricting transfer of molecules into the interstitial space of the brain. Anesthetic agents may affect the permeability of the BBB. In this investigation, the effect of isoflurane on the transport of small hydrophilic molecules across the BBB was studied in rats by measuring the blood-brain transfer coefficient (Ki) and the regional cerebral blood flow (rCBF) and by calculating the capillary permeability-surface area (PS) product. In the control group, after a femoral artery and vein were catheterized under isoflurane anesthesia, rats were allowed to remain awake for 2 h before measuring Ki (n = 6) or rCBF (n = 11). In the two experimental groups, rats were anesthetized with 1% and 2% isoflurane respectively, and their lungs were mechanically ventilated through a tracheal tube. Ki was measured (1% n = 6, 2% n = 7) using 14C-alpha-aminoisobutyric acid, and rCBF was measured (2% n = 7) using 14C-iodoantipyrine. Two percent isoflurane did not affect rCBF in 9 of 13 brain regions. Blood flow was less in the lateral and posterior cortex and greater in the medulla and pons when compared with the control group. Ki was less in 11 of 13 brain regions in both the 1% and 2% isoflurane groups than in the control group. There was no significant difference between 1 and 2% isoflurane in any brain region.(ABSTRACT TRUNCATED AT 250 WORDS)

Power spectral analysis of EEG during sufentanil infusion in humans

The purpose of this study was to examine the relationship of continuous sufentanil infusion (0.71 μg · kg−1 · min−1 for 14 min) and the response of the power spectrum of the electroencephalogram (EEG) performed during the induction of anaesthesia in 12 patients undergoing CABG surgery. Data were collected at various times including the preinduction period, every minute during the infusion period (minute 0 to 14), and 15, 20 and 25 min after the start of the infusion (1,6 and 11 min respectively after completion of the infusion). Within three minutes of the sufentanil infusion, the total power and the relative power of delta increased to near maximum, while the 95% spectral edge and the mean frequency decreased markedly. In spite of the continued infusion of sufentanil, there were very little further changes in the EEG activity. This ceiling effect for the EEG changes appear to coincide with the failure to respond to verbal command. We conclude that the power spectrum of the EEG failed to respond to increasing doses of sufentanil during its infusion after the rapid initial changes.RésuméLe but de cette étude était d’examiner la relation d’une perfusion continue de sufentanil (0.71 μg · kg−1 · min−1 pour 14 min) et la réponse du spectre de puissance de l’ électroencéphalogramme (EEG) obtenue durant l’induction de l’anesthésie chez douze patients devant subir un pontage aortocoronarien. Les données furent obtenues à des temps differents incluant la période de préinduction, chaque minute durant la perfusion (minute 0 à 14), et 15, 20 et 25 minutes après le debut de la perfusion (1, 6 et 11 minutes respectivement apres la cessation de la perfusion). En dedans de trois minutes de la perfusion de sufentanil, la puissance totale et la puissance relative de l’onde delta augmenta pour presqu’ atteindre le maximum, alors que la crête spectrale de 95% et la fréquence moyenne out diminué d’une façon marquée. Malgré la perfusion continue de sufentanil, il n’y avait que tres peu d’altération dans l’activité de l’EEG. Cet effet de plafonnement pour les alterations de l’EEG coïncide approximativement avec la non-réponse à la commande verbale. On conclut que la spectre de puissance de l’EEG a manqué de répondre à l’augmentation de la dose de sufentanyl lors de sa perfusion après les changements rapides initianx.

Effects of VEGF and nitric oxide synthase inhibition on blood–brain barrier disruption in the ischemic and non-ischemic cerebral cortex

Abstract Objectives: This study was performed to compare the effects of exogenous vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) inhibition on blood–brain barrier (BBB) disruption in the ischemic cortex (IC) and non-ischemic contralateral cortex (CC) during the early stage of focal cerebral ischemia in rats. Methods: A middle cerebral artery (MCA) was occluded after a craniotomy in each rat under isoflurane anesthesia. Two more craniotomies were performed over the contralateral non-ischemic hemisphere to expose cerebral cortex. For the control rats, the normal saline patches were applied to all three craniotomy holes (control group). To inhibit NOS, NG-nitro-L-arginine-methyl ester (L-NAME) (10 mg/kg) was administered i.v. 20 minutes after MCA occlusion (L-NAME group). In another group, VEGF (10−10 M) was topically applied 30 minutes after MCA occlusion on the IC as well as one of the holes of the contralateral cortex (VEGF group). To investigate the effects of the combination of VEGF and L-NAME, both L-NAME and VEGF were administered as described above (L-NAME+ VEGF group). The transfer coefficient (Ki) of 14C-α-aminoisobutyric acid and the volume of 3H-dextran (70000 Da) distribution were determined to measure the degree of BBB disruption at 1 hour after MCA occlusion. Results: In the control group, Ki of the IC was significantly higher than the contralateral cortex (CC) (p<0.005). VEGF application increased the Ki of the IC further when compared with the control group (+51%, p<0.05%). L-NAME administration produced no significant decrease in the Ki of the IC when compared with the control group. With L-NAME+ VEGF administration, the Ki of the IC became significantly lower than that of the VEGF alone (−38%, p<0.005). Thus, L-NAME produced a much greater decrease in the Ki of the IC in the VEGF treated than the control animals (p<0.05). In the non-IC, VEGF, L-NAME, or their combination did not affect BBB disruption. The volume of dextran distribution followed a similar pattern to Ki. Discussion: Our data suggest that even in the early stage of focal cerebral ischemia, the degree of BBB disruption in response to the exogenous VEGF is much greater in the ischemic than in the non-IC and that the mechanism of the increase of BBB disruption by VEGF in the IC involves the NOS pathway.

Effects of nitric oxide synthase inhibition on regional cerebral blood flow and vascular resistance in conscious and isoflurane-anesthetized rats

Nitric oxide is an important regulator of the regional cerebral vascular tone. We compared the magnitude of nitric oxide-related changes in the vascular tone by studying the regional cerebral blood flow (rCBF) and vascular resistance in conscious and isoflurane-anesthetized rats by using a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). In the conscious group (n = 12), after cannulation of a femoral artery and two veins under isoflurane anesthesia, rats were allowed to remain awake for 90 min. In the anesthetized group (n = 18), rats were anesthetized with 2% isoflurane and mechanically ventilated. Six rats in each group were treated with L-NAME (2 mg.kg-1 x min-1 for 30 min) or saline. For the remaining rats in the isoflurane-anesthetized group (n = 6), arterial blood pressure was increased by phenylephrine infusion to the same level as that in the L-NAME-treated, isoflurane-anesthetized rats. Regional vascular resistance was determined by the ratio of mean arterial blood pressure and rCBF which was measured by [14C]iodoantipyrine. L-NAME significantly increased mean arterial blood pressure in both the conscious (123 to 158 mm Hg) and anesthetized (82 to 144 mm Hg) rats. Regional vascular resistance increased significantly in all 12 brain regions studied with the average value increasing from 1.19 +/- 0.33 mm Hg.mL-1 x min x 100 g to 2.22 +/- 0.48 (P < 0.0001) in the conscious and from 0.78 +/- 0.27 to 1.61 +/- 0.48 (P < 0.0001) in the isoflurane-anesthetized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of MK-801 on cerebral regional oxygen consumption in focal cerebral ischemia in rats.

This investigation tested in rats whether MK-801, an N-methyl-D-aspartate receptor antagonist, would improve the balance of oxygen supply and consumption in the focal ischemic area of the brain induced by occlusion of the middle cerebral artery. Fifteen minutes after middle cerebral artery occlusion, 5 mg/kg MK-801 was administered intravenously to the MK-801 group (n = 12), and normal saline was given to the control group (n = 12). One hour after the occlusion in each group, regional cerebral blood flow was determined in six rats using [14C]iodoantipyrine, and regional arterial and venous oxygen saturations were determined using a microspectrophotometric technique in the other six rats. In both groups of animals, the cerebral blood flow of the ischemic cortex was significantly lower than that of the contralateral cortex (36 +/- 16 [SD] and 67 +/- 14 ml/min/100 g for the control group; 33 +/- 10 and 58 +/- 11 ml/min/100 g for the MK-801 group, respectively). Oxygen extraction was significantly higher in the ischemic cortex (8.8 +/- 2.1 ml O2/100 ml blood) than in the contralateral cortex (5.6 +/- 0.3) for the control group. However, for the MK-801 group, there was no significant difference between the ischemic cortex (6.1 +/- 1.0) and the contralateral cortex (5.7 +/- 1.1). Oxygen extraction in the ischemic cortex of the MK-801 group was significantly lower than that of the control group. Calculated ischemic regional oxygen consumption was similar to the nonischemic values in the control group, whereas the ischemic value was reduced to 61% of the value of the contralateral cortex in the MK-801 group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of isoflurane pretreatment on cerebral blood flow, capillary permeability, and oxygen consumption in focal cerebral ischemia in rats.

BACKGROUND: We performed experiments to test whether isoflurane pretreatment produces vascular effects, especially at the levels of arterioles and capillaries affecting regional cerebral blood flow (rCBF), O2 supply and consumption, or capillary permeability in focal cerebral ischemia. Because inducible nitric oxide synthase (iNOS) was implicated as one of the mechanisms of isoflurane preconditioning, the effect of iNOS inhibition on rCBF was also studied. METHODS: Twenty-four hours before middle cerebral artery (MCA) occlusion, rats were pretreated with 2% isoflurane for 30 minutes using an endotracheal tube and mechanical ventilation for the isoflurane preconditioned (IsoPC) group. For the group of iNOS inhibition, aminoguanidine 200 mg/kg was injected IP 30 minutes before isoflurane pretreatment. One hour after MCA occlusion, rCBF was measured using 14C-iodoantipyrine autoradiography. Alternate slices of the tissue were used to determine arteriolar and venular O2 saturation using cryo microspectrophotometry. Capillary permeability was determined by measuring the transfer coefficient (Ki) of 14C-&agr;-aminoisobutyric acid. Additional measurements of rCBF were performed at 3 hours after MCA occlusion. RESULTS: MCA occlusion decreased rCBF and O2 consumption and increased Ki in both the control and the IsoPC groups at 1 hour after MCA occlusion. In the ischemic cortex (IC), the rCBF and O2 consumption were significantly greater in the IsoPC group than in the control group (+40% and +41%, respectively), but they were similar in the contralateral cortex between the 2 groups. There was no difference in Ki between the groups in the IC or in the contralateral cortex. The increase of rCBF in the IC (+50%) was sustained in the IsoPC group at 3 hours after MCA occlusion. With iNOS inhibition, the increase of rCBF in the IC with isoflurane pretreatment became insignificant. CONCLUSIONS: Our data demonstrate that isoflurane pretreatment improved rCBF and increased the regional O2 supply and consumption in the focal ischemic area but did not affect capillary permeability during the early stage of focal cerebral ischemia. The isoflurane-induced increase in rCBF in the ischemic area became insignificant with inhibition of iNOS.

The effects of pentobarbital on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats

This study was performed to evaluate both the effects of pentobarbital on disruption of the blood-brain barrier (BBB) by hyperosmolar mannitol and the relationship between its effect on blood pressure and the integrity of the BBB. Under isoflurane anesthesia, rats in the control group were infused with 25% mannitol into the internal carotid artery before measuring the transfer coefficient (Ki) of14 C alpha-aminoisobutyric acid. Ten minutes before the administration of mannitol, rats received an infusion of pentobarbital: 20 mg/kg in the small-dose group and 50 mg/kg in the large-dose group. In another group of animals (hydralazine group), hydralazine was administered to maintain the mean arterial blood pressure (MAP) at 65 mm Hg during the experimental period. The MAP of the control group (113 +/- 14 mm Hg) was significantly higher (P < 0.002) than that of the small-dose pentobarbital group (78 +/- 13 mm Hg) or the large-dose pentobarbital group (68 +/- 14 mm Hg). In the control group, the K (i) of the cortex ipsilateral to the mannitol injection was increased to 4.5 times that of the contralateral cortex (14.5 +/- 7.7 vs 3.2 +/- 0.6 [micro sign]L [center dot] g-1 [center dot] min-1; P < 0.002). The Ki of the ipsilateral cortex of the small-dose pentobarbital group was 9.7 +/- 5.6 [micro sign]L [center dot] g-1 [center dot] min-1. The Ki of the ipsilateral cortex of the large-dose pentobarbital group was 5.5 +/- 2.9 [micro sign]L [center dot] g-1 [center dot] min-1, and lower (-9.0 [micro sign]L [center dot] g-1 [center dot] min-1) than that of the control animals (P < 0.05). There was no significant difference in the Ki of the contralateral cortex among any of the three groups of animals. At the same MAP, the Ki of the ipsilateral cortex of the large-dose pentobarbital group was lower (-4.3 [micro sign]L [center dot] g-1 [center dot] min-1) than that of the hydralazine group (9.8 +/- 4.6 [micro sign]L [center dot] g-1 [center dot] min-1) (P < 0.05). Pentobarbital attenuated the BBB disruption induced by hyperosmolar mannitol. This may be attributed, at least in part, to the blood pressure effect of pentobarbital. Implications: When the blood-brain barrier (BBB) was disrupted by a hyperosmolar solution, pentobarbital attenuated the degree of leakage of the BBB. Systemic hypotension caused by pentobarbital played a significant role in decreasing the leakage. Our study suggests that when the BBB is disrupted, pentobarbital may be effective in protecting the BBB. Furthermore, systemic blood pressure plays an important role in determining the degree of disruption. (Anesth Analg 1998;86:1230-5)