Cerebral ischemia remains a major problem for patients requiring anesthesia and surgery. Our work is devoted to understanding the effects of anesthesia on ischemic brain damage.We have shown that rats anesthetized with halothane have reduced injury when compared to rats undergoing ischemia while awake. This protection is not attributable to effects on brain temperature, plasma glucose, perfusion pressure, or cerebral metabolic rate. We postulate that the protective effect may, in part, be attributable to reduction of adrenergic responses to ischemia. We will first extend the halothane protection observation to a more commonly used anesthetic agent, isoflurane. Effects of both of these drugs on the frequency of spontaneous depolarizations and tissue PO2 in the focal ischemic penumbra will be defined. We will then compare effects of different anesthetic states, which produce known differences in circulating catecholamine concentrations, on histologic outcome from near- complete (isoelectric EEC) and incomplete (attenuated EEC) global ischemia. We expect differences in outcome to occur only during incomplete ischemia. We speculate that anesthetic effects on brain extracellular adrenergic neurotransmitter concentrations will be of importance only when ischemia induced changes in brain catecholamine concentrations are small (i.e., incomplete ischemia). During more severe (near-complete) ischemia, anesthetic effects are expected to be inconsequential given massive release of endogenous catecholamine stores. To verify this we will correct for anesthetic differences by administration of exogenous catecholamines or by sympathetic ganglionic blockade. Corollary studies will use microdialysis to associate plasma and brain extracellular catecholamine concentrations to histologic outcome as a function of severity of the ischemic insult. To specifically examine effects of endogenous brain catecholamine concentrations on anesthetic differences in outcome, lesions of the locus coeruleus and substantia nigra will be used to inhibit ischemia induced release of norepinephrine and dopamine. Corollary in vitro studies using primary neuronal cultures will examine adrenergic neurotransmitters as neurop rotectants against glutamatergic excitotoxicity and how these adrenergic neurotransmitters modulate neuroprotection provided by volatile anesthetic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039771-13
Application #
2900679
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1988-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2001-03-31
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Kudo, M; Aono, M; Lee, Y et al. (2001) Absence of direct antioxidant effects from volatile anesthetics in primary mixed neuronal-glial cultures. Anesthesiology 94:303-212
Kudo, M; Aono, M; Lee, Y et al. (2001) Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures. Anesthesiology 95:756-65
Mackensen, G B; Nellgard, B; Sarraf-Yazdi, S et al. (2000) Post-ischemic RSR13 amplifies the effect of dizocilpine on outcome from transient focal cerebral ischemia in the rat. Brain Res 853:15-21
Sheng, H; Kudo, M; Mackensen, G B et al. (2000) Mice overexpressing extracellular superoxide dismutase have increased resistance to global cerebral ischemia. Exp Neurol 163:392-8
Nellgard, B; Mackensen, G B; Massey, G et al. (2000) The effects of anesthetics on stress responses to forebrain ischemia and reperfusion in the rat. Anesth Analg 91:145-51
Nellgard, B; Mackensen, G B; Pineda, J et al. (2000) Anesthetic effects on cerebral metabolic rate predict histologic outcome from near-complete forebrain ischemia in the rat. Anesthesiology 93:431-6
Mackensen, G B; Nellgard, B; Kudo, M et al. (2000) Periischemic cerebral blood flow (CBF) does not explain beneficial effects of isoflurane on outcome from near-complete forebrain ischemia in rats. Anesthesiology 93:1102-6
Sheng, H; Brady, T C; Pearlstein, R D et al. (1999) Extracellular superoxide dismutase deficiency worsens outcome from focal cerebral ischemia in the mouse. Neurosci Lett 267:13-6
Miura, Y; Mackensen, G B; Nellgard, B et al. (1999) Effects of isoflurane, ketamine, and fentanyl/N2O on concentrations of brain and plasma catecholamines during near-complete cerebral ischemia in the rat. Anesth Analg 88:787-92
Sheng, H; Laskowitz, D T; Pearlstein, R D et al. (1999) Characterization of a recovery global cerebral ischemia model in the mouse. J Neurosci Methods 88:103-9

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