MK-801 Prevents the Post-Ischemic Cerebral Hypoperfusion, but Not the Dysfunction of the Vagal Baroreflex in Dogs

Abstract

Pretreatment with MK-801, a non-competitive N-methyl-D-aspartate (NMDA) antago nist, failed to protect the vagal component of reflex bradycardia from 5-min global cerebral ischemia in dogs under pentobarbital anesthesia. On the other hand, MK-801 completely prevented the develop ment of the post-ischemic cerebral hypoperfusion without affecting the cerebral blood flow in sham operated animals. The results suggest that NMDA receptors may participate in the development of the secondary disturbance of the cerebral circulation, but are not involved in the post-ischemic dysfunction of the baroreflex system.The non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 has been used to investigate the pathological role of excitatory amino acid in ischemic neuronal injury (1). In the present study, we examined the effect of MK-801 on the post-ischemic dysfunction of the vagal baroreflex and the secondary cerebral hypoperfusion in a canine model of transient global cerebral ischemia (2, 3).Mongrel dogs of either sex, weighing about 7 to 15 kg, were anesthetized with sodium pentobarbital (32 mg/kg, i.v. followed by an infusion of 3.2 mg/kg/hr, i.v.). The animals were artificially ventilated (a tidal volume of 20 ml/kg at a rate of 20 breaths/min) and immobilized with suxamethonium chloride (2 mg/kg, i.v., followed by an infusion of 1 mg/kg/hr, i.v.). Arte rial Pot and Pco2 were maintained at about 100 and 35 mmHg, respectively, providing an appropriate volume of 02 and CO2 gasses via a respirator. The rectal temperature was maintained at about 38°C using a heat ing pad and lamp.Arterial blood pressure was measured from the left femoral artery by means of a pressure transducer (Nihon Kohden, TP-200T), and heart rate was meas ured by a heart rate counter (Nihon Kohden, AT 600G) triggered by the lead II ECG. The cortical EEG was continuously monitored from the parietal skull us ing a frequency analyzer (Nihon Kohden, OEE-7102). The reflex increase in pulse interval by 1-phenylephrine hydrochloride (0.3 to 10 ,ug/kg injected into the left cephalic vein) was correlated with the increase in mean blood pressure by a method of least squares. The slope of the regression line (msec/mmHg) was used as a meas ure of baroreflex sensitivity (BRS).Incomplete global cerebral ischemia was produced by a 5-min occlusion with clamps of the brachiocephalic artery and the left subclavian artery following ligations of about 14 intercostal arteries. Regional cerebral blood flow (rCBF) in the dorsal medulla oblongata was con tinuously measured by a tissue flow monitor (Unique Medical, UMW-101) using a plate-type thermocouple electrode, and the mean residual blood flow during ischemia was calculated as an index of the severity of ischemia (2). Furthermore, the absolute value of rCBF in the dorsal medulla oblongata was obtained by a hy drogen clearance method (4).MK-801 (Research Biochemical, Inc.) was dissolved in saline and infused according to the dosage regimen by Michenfelder et al. (5), which produces the steady plasma concentrati...

Transient NMDA receptor‐mediated hypoperfusion following umbilical cord occlusion in preterm fetal sheep

“…These data suggest the possibility that abnormal central excitatory activity may contribute to delayed hypoperfusion. Supporting this hypothesis, preinsult treatment with the highly selective non-competitive NMDA receptor antagonist dizocilpine has been shown to attenuate delayed cerebral hypoperfusion after cerebral ischaemia and traumatic injury in adult animals (Meyer et al 1990;Stevens & Yaksh, 1990;Kurihara et al 1992). However, these effects may have been related, at least in part, to reduced neural injury owing to pretreatment with dizocilpine (Stevens & Yaksh, 1990).…”