Regional Cerebral and Neural Lobe Blood Flow during Insulin-Induced Hypoglycemia in Unanesthetized Rats

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1 Journal of Cerebral Blood Flow and Metabolism 7: Raven Press, New York Regional Cerebral and Neural Lobe Blood Flow during nsulin-ndued Hypoglyemia in Unanesthetized Rats *trobert M. Bryan, Jr., Bryan R. Hollinger, *Kerry A. Keefer, and *:l:robert B. Page *Departments of Surgery (Division of Neurosurgery), tphysiology, and :j:anatomy, M, S. Hershey Medial Center, Pennsylvania State University, Hershey, Pennsylvania, U.S.A. Summary: The effets of hypoglyemia on regional erebral blood flow (rcbf) were studied in awake restrained rats. The rats were divided into three groups onsisting of (1) a normoglyemi ontrol group that reeived only saline, (2) a hypoglyemi group A, whih was given insulin 3 min before flow was measured, and (3) a hypoglyemi group B, whih was given insulin 9 and 3 min before flow was measured. Regional CBF was measured using 14C-iodoantipyrine. Mean plasma gluose was 8.76 f.lmollml in the ontrol group, 2.63 f.lmollml in hypoglyemi group A, and 1.51 f.lmollml in hypoglyemi group B. Plasma epinephrine and norepinephrine onentrations inreased to approximately 375% and 16%, respetively, of ontrol values in hypoglyemi groups A and B. n the hypoglyemi group A, rcbf signifiantly inreased in three brain regions. n the hypoglyemi group B, rcbf inreased signfiantly in all brain regions measured, with the exeption of the neural lobe, in whih it dereased. The inrease in rcbf ranged from 38% in the hypothalamus to 138% in the thalamus. Neural lobe blood flow signifiantly dereased by 31%. The neural lobe was the only brain region studied that is not proteted by a blood-brain barrier. t may be sensitive to hanges in the onentration of vasoative agents in blood, suh as epinephrine and norepinephrine. Key Words: Cerebral blood flow-hypoglyemia-rats Neural lobe blood flow-nsulin-indued hypoglyemia -odoantipyrine. nsulin-indued hypoglyemia has been an important model in the study of erebral energy metabolism (Siesjo, 1978). t has been used as a means to study arbohydrate metabolism in brain, alternate substrates for erebral energy metabolism, and the pathophysiology of oma. However, during the ourse of these studies, there has been disagreement as to the effets of hypoglyemia on erebral blood flow (CBF). Some studies have reported that hypoglyemia had no effet on CBF, even when hypoglyemia was severe enough to produe oma (Kety et a., 1948; Eisenberg and Seltzer, 1962; Ghajar et a., 1982), whereas other studies have reported that CBF inreased prior to or during hy- Reeived June 25, 1986; aepted September 16, Address orrespondene and reprint requests to Dr. Robert M. Bryan, Jr. at Division of Neurosurgery. M. S. Hershey Medial Center, P. O. Box 85, Hershey, PA 1733, U.S.A. Preliminary results of this study were presented at the annual meeting of the Soiety for Neurosiene, Washington, D.C., November 1986, (Hollinger et a., 1986). Abbreviations used: rcbf, regional erebral blood flow; MABP, mean arterial blood pressure; lap, 4-iodo-(N-methyl- 14C)antipyrine. poglyemi oma (Della Porta et a., 1964; Norberg and Siesjo, 1976; Abdul-Rahman et a., 198). Two studies in neonates reported that CBF did not hange during hypoglyemia (Gardiner, 198; Hernandez et a., 198). The reason for the disordant results may be due to differenes in speies used in the studies, the presene or absene of anesthesia in the experimental animals, or the nutritional state of the animals. n an attempt to resolve the disrepany, Ghajar et ai. (1982) studied CBF in awake rats (i.e., free of anesthesia). The authors reported that hypoglyemia had no effet on blood flow measured in two ortial regions. CBF in other brain regions was not measured. n another study, Abdul-Rahman et a. (198) measured regional CBF (rcbf) in rats that were paralyzed and artifiially ventilated with nitrous oxide/oxygen. The authors reported that individual brain regions were affeted differently by insulinindued hypoglyemia. When blood gluose dereased from the normal level of 6 flmol/ml to 1.26 flmollml (orresponding to 8.4 and 1.76 flmollml plasma gluose), rcbf signifiantly inreased in all 96

2 CBF DURNG HYPOGLYCEMA 97 brain regions studied. The inreases ranged from 1.4 to 3.2 times the flow in normoglyemi ontrol rats. When blood gluose dereased to.73 f.lmol/ ml (1 f.lmol/ml plasma gluose) (orresponding to essation of EEG ativity), rcbf in some strutures further inreased to 4-5 times that of the ontrol rats. Studies from the same laboratory reported that interpretation of the results was onfounded by the animal model used in the studies (Siesjo et a., 1983). Rats that are paralyzed and ventilated with nitrous oxide have an elevated mean arterial blood pressure (MABP) (Siesjo et ai., 1983). During hypoglyemia, autoregulation was lost in some brain regions, partially lost in others, and preserved in still other regions (Siesjo et a!., 1983). Those regions in whih autoregulation was lost or partially lost had rates of flow that were affeted by the elevated MABP. n this artile, we report rates for rcbf during insulin-indued hypoglyemia in awake rats. MABP is not elevated in awake rats during hypoglyemia (Bryan et a!., 1986) and thus, would not be responsible for inreasing rcbf. Regional CBF inreased in every brain region measured when plasma gluose fell below f.lmol/ml, with the exeption of the neural lobe of the pituitary, whih dereased by approximately 3 1%. METHODS General Experiments were performed on 21 male Long-Evans rats (Charles River, Wilmington, MA, U.S.A.) with a mass between 26 and 37 g. All rats were fasted for 18 h before surgery, but were allowed free aess to water. Animal preparation Anesthesia was indued with 4% halothane in nitrous oxide/oxygen (7%/3%). After indution, the halothane was redued to 1.5%. Catheters were plaed in the left femoral artery and vein. The surgial wounds were infiltrated with lidoaine hydrohloride and losed. A plaster ast was fitted around the lower quarter of eah rat to immobilize the hindlimbs and protet the atheters. Body temperature was monitored and maintained at 37 C. Anesthesia was disontinued, and eah rat was allowed 5 h to reover before rcbf was measured. Experimental proedure Rats were divided into a normoglyemi ontrol group and two hypoglyemi groups, whih were designated as hypoglyemi groups A and B. The normoglyemi ontrol rats reeived an i. v. injetion of saline 9 min and 3 min before rcbf was measured. The hypoglyemi group A reeived i. v. saline 9 min before rcbf was measured and insulin at 15 U/kg body weight 3 min before rcbf was measured. The hypoglyemi group B reeived insulin at 15 U/kg body weight, i. v., 9 min before rcbf was measured and an additional 5 U/kg body weight, i.v., 3 min before rcbf was measured. mmediately before the rcbf measurement, hematorit, heart rate, and MABP were measured, and arterial blood samples were withdrawn from the femoral artery for the determination of blood gasses and pha, plasma gluose, and plasma ateholamines. Plasma gluose was measured using a Bekman Gluose Analyzer (Bekman nstruments Co., Brea, CA, U.S.A.). Plasma ateholamines (epinephrine and norepinephrine) were measured using a radioenzymati assay desribed by Peuler and Johnson (1977). Measurement of rcbf Regional CBF was measured using the diffusible indiator, 4-iodo-(N-methyl-14C) antipyrine (lap) (Sakurada et a., 1978). Approximately 4 j-lci lap in.7 ml of physiologial saline was infused into the femoral vein atheter over 3 s. Nine arterial blood samples were taken at predetermined time intervals during the lap infusion by allowing blood to drip into tubes from the arterial atheter (approximately 5 m). Thirty seonds after beginning the lap infusion, eah rat was killed by deapitation. After death, the brain was rapidly removed and disseted. Tissue samples from 17 brain regions were weighed, solubilized, and ounted in a liquid sintillation ounter. The pituitary was immediately frozen in liquid Freon and plaed in a freezer at -7 C. Eah pituitary was ut into 2-j-lm thik setions with a ryostat (AO Reihart, Buffalo, NY, U.S.A.). Representative setions were plaed on glass slides and dried at 5 C. The glass slides ontaining the pituitary setions were paked with 14C_ methyl metharylate standards (Amersham, Arlington Heights, L, U.S.A.) in light-tight assettes for the autoradiographi determination of the traer in the neural lobe. The traer onentration was determined by omparing the optial densities of the neural lobe images to the optial densities produed by the alibrated standards (Reivih et a., 1969). An aliquot from eah blood sample was solubilized, deolorized, and ounted in a liquid sintillation ounter. Regional CBF was alulated by the method of Sakurada et al. (1978), using a brain-to-blood partition oeffiient of.8 for all regions. Statistial analysis For physiologial parameters, the signifiane of differenes between means of the hypoglyemi groups and the normoglyemi ontrol group was determined using the t test for pooled samples, with a Bonferroni orretion for multiple omparisons. The rates of rcbf were logarithmially transformed and analyzed by repeated measures analysis of variane (Winer, 1971), using the SAS General Linear Models Analysis. The aeptable level of signifiane was 5% (p <.5). RESULTS All rats were onsious at the time rcbf was measured. Some of the hypoglyemi rats, espeially those in group B, showed depressed motor ativity, but responded to tatile stimulation. Many of the rats in group A ould not be distinguished by observing their behavior from the rats in the normoglyemi ontrol group. Mean plasma gluose was 8.76 f.lmol/ml in the normoglyemi ontrol group, 2.63 f.lmol/ml in the J Cereb Blood Flow Metab, Vol. 7, No. 1, 1987

3 98 R. M. BRYAN, JR., ET AL. hypoglyemi group A, and flmollml in hypoglyemi group B (Table 1). MABP dereased in hypoglyemi group A, but was not signifiantly different from ontrol in hypoglyemi group B. P ao2 inreased and pha dereased from the ontrol values in both of the hypoglyemi groups. Plasma epinephrine and norepinephrine onentrations inreased to approximately 375% and 16%, respetively, of the ontrol levels in both hypoglyemi groups. Mean rates of rcbf in the three groups are shown in Table 2. Regional CBF in hypoglyemi group A inreased in all brain regions measured, with the exeption of the neural lobe. Twelve of the 18 regions measured showed a statistially signifiant inrease in rcbf ompared to the normoglyemi ontrol group. n the hypoglyemi group B, rcbf in all regions measured inreased signifiantly ompared to the normoglyemi ontrols, with the exeption of the neural lobe, in whih it signifiantly dereased. Regional CBF in the hypoglyemi group B was signifiantly greater in 14 regions ompared to hypoglyemi group A. Table 3 shows rates for rcbf in the normoglyemi ontrol group and the two hypoglyemi groups after rcbf was orreted for hanges in P ao2' The orretion assumed a 5% inrease in rcbf for eah mm Hg that Pao2 inreased (Hernandez et a., 1978). Nilsson et al. (1981) demonstrated that although autoregulation was lost during hypoglyemia, the CO2 response of the irulation was retained. After orreting for Pao2, only the olfatory bulb, audate-putamen, and thalamus showed a signifiant inrease in rcbf for hypoglyemi group A when ompared to the normoglyemi ontrol group. n hypoglyemi group B, rcbf was signifiantly greater in all regions ompared to the normoglyemi ontrols, with the exeption the neural lobe. Regional CBF was signifiantly greater in 13 brain regions in hypoglyemi group B ompared to hypoglyemi group A. The neural lobe was not orreted for hanges in Pao2 in the hypoglyemi groups and is not inluded in Table 3, as the orretion fator for the neural lobe may be different than in other brain regions (Page et a., 1981) and is not known for the rat. However, the derease in blood flow in the neural lobe would be aentuated rather than diminished after orreting for altered Pao2 (see Disussion). Figure 1 shows rcbf, orreted for Pao2, in the two hypoglyemi groups as a perent of rcbf in the normoglyemi ontrols. As the neural lobe was not orreted for Pao2, it is shown separately in Fig. 2. As demonstrated by the bar graphs, hypoglyemia affeted different brain regions to different degrees. n hypoglyemi group B (dark bars), the thalamus showed the greatest inrease (238% of ontrol), and the hypothalamus showed the least inrease (138% of ontrol). Neural lobe blood flow in hypoglyemi groups A and B was 85% and 69% of the normoglyemi ontrols, respetively. A plot of rcbf (orreted for Pao2) as a funtion of plasma gluose is shown in Fig. 3 for four representative brain regions. The irles represent individual rates of rcbf for rats in the normoglyemi ontrol group, the squares represent individual rates for rats in hypoglyemi group A, and the diamonds represent individual rates for rats in hypoglyemi group B. Regional CBF inreased in all brain regions, with the exeption of the neural lobe, when plasma gluose fell below flmollml. DSCUSSON Our results show that rcbf inreased during hypoglyemia in all brain regions, with the exeption of the neural lobe. The inrease was greater than ould be explained by hanges in Pao2 alone. Furthermore, a loss of autoregulation ould not be re- TABLE 1. Physiologial measurements in the normoglyemi ontrol group, hypoglyemi group A, and hypoglyemi group B (mean ± SE) Plasma Plasma Plasma gluose MABP Heart rate Pao, Pao, epinephrine norepinephrine (flmollml) (mm Hg) (beat/min) (mm Hg) (mm Hg) pha (pg/ml) (pg/ml) Normoglyemi ontrol (n = 6) 8.76 ± ± 2 Hypoglyemi group A (n = 7) 2.63 ±.18b 18 ± 2a Hypoglyemi group B (n = 8) 1.51 ±.32b 119 ± ± ± 18a 35 ± 19b 9 ± ± ± ± ± ± ±.7a 7.36 ±.17b 1744 ± 199b 752 ± 7b 15 ± 3a 43.7 ± 1.3a ±.13a 1749 ± 127b 758 ± 82a a p <.5 ompared to normoglyemi rats. b p <.1 ompared to normoglyemi rats. J Cereb Blood Flow Metab, Vol. 7, No.1, 1987

4 CBF DURNG HYPOGLYCEMA 99 TABLE 2. Regional erebral blood flow (mioo g- min-) in the normoglyemi ontrol group, hypoglyemia group A, and hypoglyemia group B TABLE 3. Regional erebral blood flow (ml 1 g- min-) in the normoglyemi ontrol group, hypoglyemia group A, and hypoglyemia group B Normoglyemia Hypoglyemia A Hypoglyemia B N ormoglyemia Hypoglyemia A Hypoglyemia B mean ± SE mean ± SE mean ± SE mean ± SE mean ± SE mean ± SE (n = 6) (n = 7) (n = 8) (n = 6) (n = 7) (n = 8) Olfatory bulb 114 ± ± 22' 243 ± 1' Visual ortex 143 ± ± 32' 389 ± 47',e Auditory ortex 166 ± ± 19' 373 ± 37',d Sensory ortex 155 ± ± 25' 39 ± 54' Motor ortex 137 ± ± 32a 344 ± 43',e Subortial white 81 ± ± 11' 179 ± 17"d Caudate-putamen 121 ± ± 23' 272 ± 23' Hippoampus 11 ± ± loa 22 ± 19', Thalamus 12 ± ± 23b 378 ± 36',d Hypothalamus 113 ± ± ± 19',d Superior olliulus 12 ± ± 16" 363 ± 5',d nferior olliulus 157 ± 9 2 ± ± 4',d Cerebellum 9 ± 2 17 ± ± 36b,d Pyramidal trat 99 ± ± ± 29b, Mesenephalon 117 ± 4 27 ± 21b 323 ± 47', Pons 19 ± ± 18a 289 ± 39b,d Medulla 12 ± ± ± 44b, Neural lobe 581 ± ± ± 55a Physiologial values for eah group are given in Table. Regional CBF has not been orreted for hanges in Pao, in the hypoglyemi groups, a p <,5 ompared to normoglyemi rats, b p <.1 ompared to normoglyemi rats. e p <,5 hypoglyemi group B ompared to hypoglyemi group A, d P <.1 hypoglyemi group B ompared to hypoglyemi group A. Olfatory bulb 116 ± ± 14' 193 ± 15' Visual ortex 145 ± ± ± 46', Auditory ortex 169 ± ± ± 39',e Sensory ortex 158 ± ± ± 55' Motor ortex 139 ± ± ± 4a Subortial white 82 ± 6 96 ± ± 14',d Caudate-putamen 124 ± ± 16a 214 ± 21b Hippoampus 112 ± ± ± 16a, Thalamus 122 ± ± 14a 291 ± 23b,d Hypothalamus lis ± 1 14 ± ± 17a,d Superior olliulus 122 ± ± ± 39b,d nferior olliulus 161 ± ± S 269 ± 28b,d Cerebellum 91 ± 6 84 ± ± 21',d Pyramidal trat 11 ± 8 15 ± ± 17',d Mesenephalon 119 ± ± ± 32b, Pons ± ± ± 25',d Medulla 13 ± 9 17 ± ± 3a, Physiologial values for eah group are given in Table 1. Regional CBF has been orreted to 38.5 mm Hg for Pao, (mean Pao, for normoglyemi ontrol rats) using a orretion of 5% hange in rcbf for eah mm Hg (Hernandez et al, 1978), a p <,5 ompared to normoglyemi rats. b p <.1 ompared to normoglyemi rats. e p <,5 hypoglyemi group B ompared to hypoglyemi group A. d P <,1 hypoglyemi group B ompared to hypoglyemi group A, sponsible for the inrease in rcbf during hypoglyemia, as MABP in the normoglyemi ontrols and the hypoglyemi group B was not different. The effet of hypoglyemia on rcbf varied depending on the brain region. n hypoglyemi group B, rcbf in the hypothalamus inreased to 138% of ontrol and rcbf in the thalamus inreased to 238%. Other brain regions showed an inrease in rcbf that ranged between the hypothalamus and thalamus (see Fig. 1). Our results agree with the earlier results of Abdul-Rahman et al. (198), who measured rcbf in anesthetized, paralyzed, and artifiially ventilated rats. Both studies found that rcbf inreased before the onset of oma and that the inrease was not uniform, but rather varied among brain regions. Abdul-Rahman et al. (198) reported that the elevation in rcbf persisted during oma, with an additional inrease in blood flow in some brain regions. U sing a venous outflow method for measuring CBF, Nilsson et al. (1981) showed that autoregulation was lost during hypoglyemia. Siesjo et al. (1983) furthered this study by showing that during hypoglyemia, autoregulation was lost in some brain regions, partially lost in others, and preserved in still other brain regions. n the study by Abdul Rahman et al. (198), rcbf in some brain regions was affeted during hypoglyemia by an elevated MABP of their animal model. However, Siesjo et al. (1983) showed that even when MABP was ontrolled during hypoglyemi oma by bleeding the rats, rcbf inreased signifiantly in 16 of the 24 brain regions studied. Three brain regions (parietal, auditory, and ingulate orties) showed a signifiant derease in rcbf when MABP was prevented from inreasing. Comparison of our study to that reported by Siesjo et al. (1983) is not pratial, as the two studies looked at different levels of hypoglyemia, and we did not measure as many brain regions as Siesjo et al. (1983). There has been only one previous study where CBF was measured during hypoglyemia in awake rats (Ghajar et al., 1982). Contrary to our results, these authors reported that CBF did not hange during hypoglyemia at plasma gluose levels omparable to those in our study. Furthermore, Ghajar et al. (1982) found that CBF did not hange even after the essation of EEG ativity. However, there were several differenes between the two studies. First, the strain and sex of the rats were different in the two studies. Seond, Ghajar et al. (1982) measured CBF in the frontal and parieto-oipital orties using a 14C-butanol indiatofrationation tehnique, whereas we used 14C-iodoantipyrine. Third, although rats in our study were restrained by plaster asts fitted around the groin and hip area, Ghajar et al. (1982) additionally restrained the head J Cereb Blood Flow Metab, Vol. 7, No. 1, 1987

5 1 R. M. BRYAN, JR., ET AL. RCBF AS PER CENT OF CONTROL OLFACTORY LOBE -- :,. HYPOTHALAMUS t-- VSUAL CORTEX Avn!TORY CORTEX..,. SENSORY [ORTEX -- MOTOR CORTEX SUBCORTCAL WHTE,.,. CAUDATE - PUT AMEN f-..,.,. ;< : SUPEROR (OLLCVlUS NFEROR COlLCUlUS CEREBELLUM PYRAMDAL TRACT MESENCEPHALON HPPOCAMPUS - PONS,. THALAMUS,. MEDULLA FG. 1. Regional erebral blood flow in hypoglyemi group A (open bars) and hypoglyemi group B (filled bars) expressed as a perent of ontrol values. Regional CBF has been orreted to 38.5 mm Hg for P aco2 (mean P ac2 for normoglyemi ontrols) using a orretion of 5% hange in rcbf for eah mm Hg (Hernandez et a., 1978). Error bars = 1 SE; *p <.5 ompared to normoglyemi rats; **p <.1 ompared to normoglyemi rats; #p <.5 hypoglyemi group B ompared to hypoglyemi group A; up <.1 hypoglyemi group B ompared to hypoglyemi group A. 3:.&.. C m m a: ::: :::> :z ::: - :z U.&.. - :z U ::: Q.. V a: L...-_-L-_ A B HYPOGLYCEMA FG. 2. Neural lobe blood flow in the hypoglyemi group A (open bar) and hypoglyemi group B (filled bar) expressed as a perent of the ontrol value. Neural lobe blood flow was not orreted for hanges in P ao2 in the hypoglyemi groups (see Disussion). Error bars = 1 SE; *p <.5 ompared to normoglyemi rats. by seuring the nose between a bar and nose brae. Other than the possibility of the differenes noted above, we have no explanation as to the different effets of hypoglyemia on CBF in the two studies. Previous work from this laboratory demonstrated that f.lmol/ml is a ritial level for plasma gluose. Below this level, regional erebral gluose utilization dereased (Bryan et a., 1986), other substrates were utilized as a soure of energy (Bryan and Jobsis, 1986), and the respiratory hain beame oxidized due to a derease in reduing equivalents from gluose (Bryan and Jobsis, 1983, 1986). n the present study, we have demonstrated that rcbf inreased in all brain regions, exept the neural lobe, when plasma gluose values fell below f.lmol/ml (Fig. 3). Perhaps the inrease in rcbf during hypoglyemia was an attempt to maintain the gluose supply to the brain when plasma gluose dereased below this ritial level. Studies in anesthetized sheep indiate that the neural lobe and median eminene are not as sensitive to hanges in Pao2 as other brain regions are (Page et a., 1981). Blood flow in sheep brain inreased 4% for eah mm Hg that Pao2 inreased, exept for the neural lobe and median eminene, where blood flow inreased by 1.5%/mm Hg for Pao2 values below 4 mm Hg. Above 4 mm Hg, J Cereb Blood Flow Metab. Vol. 7. No. 1, 1987

6 CBF DURNG HYPOGLYCEMA 11 SUPEROR COLLCULUS VSUAL CORTEX " u 5 <> OB \, 8 THALAMUS 4 3 o goo O 2 <a a PONS FG. 3. Regional erebral blood flow (ml 1 g 1 min 1) plotted as a funtion of plasma gluose onentration (flmol/ml) in four brain regions. The irles represent values for the normoglyemi ontrol rats, the squares represent values for the hypoglyemi group A, and the diamonds represent values for the hypoglyemi group B. Regional CBF has been orreted to 38.5 mm Hg for P.o2 (mean P.o2 for normoglyemi ontrols) using a orretion of 5% hange in rcbf for eah mm Hg (Hernandez et a., 1978). 1 a < PLASMA GLUCOSE ( UM/MU flow was independent of PaCOZ' Unlike the other brain regions in our experiment, orreting neural lobe blood flow for hanges in PaCOZ would aentuate the differenes between flow in the hypoglyemi groups and the normoglyemi ontrol group. The neural lobe was the only brain region where blood flow dereased during hypoglyemia. t is interesting that this is the only brain region studied that is laking a blood-brain barrier (Wisloki and King, 1936). Vasoative agents in blood should readily gain aess to this tissue and ould have altered blood flow, whereas other brain regions were proteted from these agents by the blood-brain barrier. t is interesting to note that in hypoglyemi group B, MABP was not different from the normoglyemi ontrols while heart rate signifiantly dereased. This indiates an overall vasoonstrition during hypoglyemia. Epinephrine and norepinephrine, whih have vasoative effets, were elevated during hypoglyemia. Perhaps one of these ateholamines was responsible for the vasoonstrition in the neural lobe and peripheral tissues. Aknowledgment: This researh was supported by a Grant-in-aid from the Amerian Heart Assoiation and with funds ontributed in part by the Amerian Heart Assoiation, Palm Beah County Chapter, Florida (R.M.B.), and Grants NS19341 (R.M.B.) and NS5926 (R.B.P.) from the National nstitute of Neurologial, Communiative Diseases, and Stroke. Bryan Hollinger was supported by a Professional Student Short Term Fellowship from the National Heart, Lung, and Blood nstitute (PHS 2T 35HL7477). REFERENCES Abdul-Rahman A, Agardh CD, Siesjo BK (198) Loal erebral blood flow in the rat during severe hypoglyemia, and in the reovery period following gluose injetion. Ata Physiol Sand 19: Bryan RM, obsis FF (1983) The erebral redox state in ats during severe insulin indued hypoglyemia. Brain Res 279: Bryan RM, obsis FF (1986) nsuffiient supply of reduing equivalents to the respiratory hain in erebral ortex during severe insulin-indued hypoglyemia in ats. J Cereb Blood Flow Metabol 6: Bryan RM, Keefer KA, MaNeill C (1986) Regional erebral gluose utilization during insulin-indued hypoglyemia in unanesthetized rats. J Neurohem 46: Della Porta P, Maiolo AT, Negri VU, Rossella E (1964) Cerebral blood flow and metabolism in therapeuti insulin oma. Metabolism 13: Eisenberg S, Seltzer HS (1962) The erebral metaboli effets of autely indued hypoglyemia in human subjets. Metabolism 11: Gardiner RM (198) The effets of hypoglyemia on erebral blood flow and metabolism in the new-born alf. J Physiol 298:37-51 Ghajar JBG, Plum F, Duffy TE (1982) Cerebral oxidative metabolism and blood flow during aute hypoglyemia and reovery in unanesthetized rats. J Neurohem 38: Hernandez M, Brennan RW, Bowman GS (1978) Cerebral blood flow autoregulation in the rat. Stroke 9: Hernandez MJ, Vannui RC, Saledo A, Brennan RW (198) Cerebral blood flow and metabolism during hypoglyemia in newborn dogs. J Neurohem 35: Hollinger BR, Page RB, Bryan RM (1986) Regional erebral and neural lobe blood flow during insulin-indued hypoglyemia in unanesthetized rats. Abstrats Soiety for Neurosiene 12: 144 J Cereb Blood Flow Me/ab, Vol. 7, No. 1, 1987

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