The effect of the excitatory amino acid receptor antagonist dizocilipine maleate (MK-801) on hemispheric cerebral blood flow and metabolism in dogs: modification by prior complete cerebral ischemia

Abstract

The effect of the N-methyl- d-aspartate (NMDA) receptor antagonist dizocilipine maleate (MK-801) on cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO 2), intracranial pressure and systemic variables was examined in 6 normal dogs (Group I). In 6 additional dogs (Group II), the effects of a prior 11 min episode of complete cerebral ischemia on the response to dizocilipine was studied. CBF was measured with a sagittal sinus outflow technique and CMRO 2 was calculated as the product to CBF and the arterial to sagittal sinus O 2 content difference. Dizocilipine was administered as a 150 μg/kg i.v. bolus followed by a 75 μg·kg −1·h −1 infusion for 90 min. Plasma dizocilipine levels were >25 ng/ml for the duration of the infusion. The CSF levels were approximately half the plasma levels. Five minutes after initiation of dizocilipine treatment, Group I dogs experienced a 63% increase in heart rate ( P < 0.01) and an 8% decrease in the mean arterial blood pressure ( P < 0.05). Over the same time interval, CBF increased by 85% ( P < 0.01) and intracranial pressure nearly doubled ( P < 0.05). In addition, dizocilipine treatment in all Group I animals resulted in EEG quasiperiodic bursts of δ-waves and polyspikes on a background of β-activity. With the exception of the intracranial pressure, the above changes in systemic and cerebral variables persisted for the duration of the drug infusion. Intracranial pressure was no longer significantly elevated after 80 min of drug infusion. Hemispheric CMRO 2 was unchanged by dizocilipine in Group I dogs. There was a decrease in the cortical glucose level the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with 6 laboratory normals. An identical dose of dizocilipine administered after an 11 min episode of complete cerebral ischemia resulted in no significant changes in either cerebral or systemic variables. The absence of systemic effects in Group II dogs suggests that dizocilipine administration in normal dogs results in a centrally mediated activation of the peripheral sympathetic nervous system. The uncoupling of CBF and CMRO 2 observed following dizocilipine treatment is similar to that reported for two other known NMDA antagonists, ketamine and phencyclidine. If administration of dizocilipine results in improved histopathological and neurological outcome following an episode of complete cerebral ischemia, this improvement is unrelated to changes in postischemic CBF or hemispheric CMRO 2.