414 Effects of MK- 801 on Cerebral Regional Oxygen Consumption in Focal Cerebral Ischemia in Rats Oak Za Chi, Mujahid Anwar, Arabinda K. Sinha, and Harvey R. Weiss This investigation tested in rats whether MK-801, an N-methyl-D-aspartate receptor antago- nist, 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±t10 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 02/100 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 extrac- tion 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. Thus, MK-801 improved the ratio of oxygen supply to consumption by decreasing the oxygen consumption without a significant change in the oxygen supply of the ischemic region. Inhibition of the increase of oxygen extraction in the ischemic cortex of the MK-801 group may be related to the ability of MK-801 to block the N-methyl-D-aspartate receptors. (Circulation Research 1991;69:414-420) R ecently, the role of excitatory amino acid neurotransmitters in producing neuronal damage in cerebral ischemia has been in- creasingly emphasized.12 However, the mechanism of the neurotoxicity has not been determined. In vitro studies suggest that an imbalance of the cerebral energy metabolism between supply and demand may be one of the factors responsible for the neurotoxicity of glutamate, one of the excitatory amino acid neu- From the Departments of Anesthesia (O.Z.C.) and Pediatrics (M.A.), and the Heart and Brain Circulation Laboratory (A.K.S., H.R.W.), Department of Physiology and Biophysics, the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, N.J. Supported by grants from the American Heart Association, New Jersey Affiliate (451390026), and the US Public Health Service (NS25100). Address for correspondence: Oak Za Chi, MD, Department of Anesthesia, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School-CN19, New Brunswick, NJ 08903. Received October 17, 1990; accepted April 15, 1991. rotransmitters.3,4 Application of a low concentration of excitatory amino acid neurotransmitters such as glutamate and aspartate or their receptor agonists on hippocampal slices elevated the amplitude of the postsynaptic potential and increased oxygen con- sumption. Application of antagonists inhibited the increase in neuronal activity and oxygen consumption induced by the excitatory amino acids.4 MK-801 is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of excitatory amino acid receptors. Its pro- tective effects have been demonstrated in some of the animal models of focal cerebral ischemia.5-7 How- ever, the mechanism of this protective effect on ischemia has not been clarified. Because some inves- tigators demonstrated that MK-801 may not signifi- cantly affect the oxygen supply in the ischemic area of the brain,8 we hypothesized that MK-801 would improve the ratio of oxygen supply to consumption by decreasing oxygen consumption in the ischemic area of the brain, thus potentially improving the outcome of the stroke. by guest on November 12, 2016 http://circres.ahajournals.org/ Downloaded from