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New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, U.S.A.. Summary: We determined the effects of spreading de pression on local ...
Journal of Cerebral Blood Flow and Metabolism 11:829-836 © 1991 The International Society of Cerebral

Blood Flow and Metabolism

Published by Raven Press. Ltd .. New York

Cerebral Blood Flow and Oxygen Consumption in Cortical Spreading Depression

Avraham Mayevsky and *Harvey R. Weiss Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, and *Heart and Brain Circulation Laboratory, Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, U.S.A.

Summary: We determined the effects of spreading de­ pression on local cerebral O2 supply, oxygenation, and O2 consumption in the anesthetized rat. Spreading depres­ sion was induced by application of 0 . 5 M KCI to the fron­ tal cortex. Regional cerebral blood flow was determined with [14CJiodoantipyrine and regional O2 extraction was determined microspectrophotometrically. The passage of the spreading depression wave was determined with a multiprobe assembly that recorded NADH redox state (surface fluorometry), extracellular K + activity, and DC steady potential (surface minielectrodes). As the wave of spreading depression passed, there was an increase in extracellular K + and a decrease in NADH . Cerebral blood flow was significantly increased (1 20 ± 51 mIl min/tOO g, mean ± SD) during the wave as compared with other regions. In the affected cortex, blood flow was not different from that in the contralateral cortex (69 ± 28 mllmin/1 00 g) either before or after the wave of spreading

depression passed. Arterial and venous O2 saturation were unaffected by the wave and the histogram of O2 saturations of examined veins followed a similar normal distribution in all regions. Oxygen extraction was not al­ tered by the wave of spreading depression. Oxygen con­ sumption was significantly increased during the wave to 7 . 4 ± 3.7 ml 02/min/1 00 g compared with the contralateral cortex (5. 1 ± 2.6 mllmin/loo g) and other regions. It can be concluded that spreading depression caused an in­ crease in cerebral O2 consumption that was adequately matched by an increase in local blood flow. Oxygen de­ livery was not limited during spreading depression and its effects were quickly over as evidenced by the lack of alteration in oxygenation after the wave of spreading de­ pression passed. Key Words: Cerebral blood flow­ Cerebral O2 consumption-Cerebral O2 extraction­ NADH redox state-Spreading depression.

The depolarization caused by the spreading de­ pression of Leao (l944a) is a response of the brain to various stimuli imposed as well as secondary metabolic and hemodynamic effects. Leao (l944b) found in rabbit a marked dilation and increased ce­ rebral blood flow in pial vessels. He concluded that the vascular response was secondary to the local change in the activity of neural elements. The re­ sponses of cerebral blood flow (CBF) before, dur­ ing, and after the spreading depression wave were

described by various investigators (Van Harreveld and Stamm, 1952; Van Harreveld and Ochs, 1 957; Buresova, 1957; Hansen et aI., 1980; Lauritzen et aI. , 1982; Mies and Paschen, 1984; Lauritzen, 1 984; Lauritzen and Diemer, 1986) and have been re­ viewed by Lauritzen (l987a,b). In all studies, a large increase in cerebral blood flow was recorded during the wave. Lauritzen and collaborators de­ scribed a post-spreading depression wave hypoper­ fusion, while a preceding vasoconstriction was not established or proved. The effect of the spreading depression wave on O2 consumption has been reported by very few groups owing to the lack of reliable techniques. Leao and Morrison (1945) found a decreased O2 concentration in sagittal sinus during spreading de­ pression. A fall in P02 during the spreading depres­ sion wave was described (Van Harreveld and Stamm, 1952; Marshall, 1 959; Lukyanova and

Received December 12. 1990; revised March 19, 1991; ac­ cepted March 28, 1991. Address correspondence and reprint requests to Dr. H. R. Weiss at Heart and Brain Circulation Laboratory, Department of Physiology and Biophysics, University of Medicine and Den­ tistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, U.S. A. Dr. A. Mayevsky's permanent address is Department of Life Sciences, Bar IIan University, Ramat Gan 52900, Israel. Abbreviation used: MPA, multiprobe assembly.

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A. MAYEVSKY AND H. R. WEISS

Bures, 1967). Those indirect measurements of in­ creased O2 consumption implied that the increased pumping activity stimulated mitochondrial activity to produce more ATP (Erecinska and Silver, 1989). A linkage between pumping activity and increased O2 consumption was shown in 1973 by monitoring the NADH redox state using the surface fluorome­ try approach (Mayevsky and Chance, 1973; Rosenthal and Somjen, 1973). Mayevsky et al. (1974) were able to combine the measurements of extracellular K + with the NADH redox state show­ ing an increased energy utilization during the pas­ sage of a spreading depression wave. To the best of our knowledge, no one has reported a direct mea­ surement of cortical O2 consumption and cerebral blood flow changes in the same brain during spread­ ing depression. The aim of the present study was to determine the local changes in O2 supply, O2 consumption, and oxygenation during the passage of a wave of spread­ ing depression. We combined in vivo monitoring techniques (NADH redox state, extracellular K + , and DC potential) with single-point measurements (cerebral blood flow and O2 consumption) to assess the effect of spreading depression waves in anes­ thetized rats. We continuously monitored the NADH redox state as well as extracellular K + and DC potential from three cortical regions. After iden­ tification of the spreading depression wave, we de­ termined cerebral blood flow. We used a mi­ crospectrophotometric technique to measure re­ gional cerebral arterial and venous O2 saturation. Using this approach, we were able to calculate O2 consumption and cerebral blood flow in different brain regions representing the before, during, and after spreading depression wave areas and com­ pared them with a contralateral control area. The in vivo monitoring was used to localize the spreading depression wave in real time throughout the cere­ bral cortex.

the modified (described below) multiprobe assembly (MPA) shown in Fig. IA. A small push-pull cannula was placed epidurally, anterior to the MPA, to elicit waves of spreading depression to propagate posteriorly (Fig. lB). The dura mater was partially removed from the exposed cortex to measure K + . Each animal was exposed to a set of spreading depres­ sion cycles induced by application of 0.5 M KCI through the push-pull cannula. The brain was allowed to recover (K + back to normal and NADH to the prewave steady state) for 20 min. After a new spreading depression wave reached the second K + electrode, i.e. , at the beginning of the steep rise of K + , the rat was infused (venous cathe­ ter) with 50 f.1Ci of 4-iodo-[N-methyl-14C]antipyrine (Am-

(A)

DC

NADH

METHODS Male Long-Evans rats (250-300 g) were used in this study. They were anesthetized with sodium pentobarbital (50 mg/kg) and the femoral artery and vein were cathe­ terized with polyethylene catheters. The femoral artery catheter was attached to a Statham P23Db pressure trans­ ducer connected to a Beckman R-411 recorder to obtain blood pressure. The venous catheter was used for the administration of [14C]iodoantipyrine and supplemental anesthetic. Eleven rats were studied, although in only eight were complete data obtained. After the animal was connected to a head holder, the skull was exposed by a midline incision of the skin and removal of the connective tissue. A 5 x II-mm hole was drilled in the frontoparietal bone area to accommodate J

Cereb Blood Flow Metab, Vol. 11, No.5, 1991

Q

KCI

FIG. 1. Schematic presentation of the multiprobe assembly

(A)

and its location on the rats' brain during the monitoring phase (B), NADH1-NADH3, light guides for NADH monitoring; K;t- -K;, minielectrodes for extracellular K+, DCcDC3, DC steady potential electrodes; KCI, application of KCI for spreading depression initiation,

CEREBRAL O2 CONSUMPTION AND SPREADING DEPRESSION

ersham) for the determination of cerebral blood flow. When the isotope entered the venous circulation, the ar­ terial catheter was cut to a length of 20 mm to minimize smearing in the sampling catheter. Twenty-microliter blood samples were obtained from the arterial catheter every 3 s during the next 30 s. At the moment the last sample was obtained, the animal was decapitated and its head was frozen in liquid N2• While frozen, the brain was sampled for four cortical regions representing areas from before the spreading depression wave, during the wave, after recovery, and the middle of the contralateral cere­ bral hemisphere (control) . The aim of the MPA monitor­ ing in the present study was to improve the tissue sam­ pling-wave location relationship in each animal. This helped to make the variation between animals smaller. Blood and tissue samples were then placed in a tissue solubilizer (Soluene; Packard), and 24 h later, they were put in a counting fluid (Dimiscint; National Diagnostic) and agitated. These samples were counted on a Beckman LS-230 liquid scintillation counter. Quench curves were prepared using carbon tetrachloride while the isotope counts were adjusted for color and quench correction. Regional blood flow determinations were made using a computer program based on the equation

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three brain regions, we constructed a special MPA shown schematically in Fig. lAo The Plexiglas holder contained the following holes: three holes of 1. 2-mm diameter for the common part of the light guide; three holes of 1. 5-mm diameter for the 1. 2-mm diameter K + electrodes. The clearance between the K + electrode and the hole con­ tained physiological saline and was connected to the DC potential electrodes. The K + and DC electrodes were connected to an electrode holder containing an Ag/AgCI pellet (WPI, New Haven, CT, U . S . A . ) and was sealed with epoxy glue. The electrodes as well as the light guides were cemented to the Plexiglas holder with epoxy glue. The testing and calibration of the electrodes were similar to those published previously (Crowe et aI . , 1977; Friedli et aI . , 1982) . A factorial analysis of variance was employed to assess differences between the various regions examined (be­ fore, during, and after the wave as well as contralateral cortex) for cerebral blood flow, O2 extraction, and O2 consumption. The statistical significance of differences was determined by Duncan's procedure. A p value of