Neuroprotective, anesthetic, and cardiovascular effects of the NMDA antagonist, CNS 5161A, in isoflurane-anesthetized lambs

Background: N-methyl-o-aspartate (NMDA) receptor antagonists are neuroprote ctive in animal models of cerebral ischemia, but adverse cardiovascular and neurobehavioral effects have precluded their clinical use. The authors pre sent the neuroprotective, anesthetic, and cardiovascular effects of a novel NMDA antagonist, CNS 5161A. Methods: Lambs, 4.0-6.5 kg, were anesthetized with isoflurane, intubated an d ventilated and had thermodilution catheters placed in the pulmonary arter y and 20-g catheters placed in the femoral artery. The minimum alveolar con centration (MAC) of isoflurane was determined using the "bracketing techniq ue." CNS 5161A was given as a bolus and then as an infusion at three doses. Cardiovascular measurements were determined every 15 min. Other lambs (n = 25) were subjected to cardiopulmonary bypass (CPB) with hypothermic circul atory arrest (HCA) for 120 min Eighteen received CNS 5161A, and seven recei ved saline vehicle. One hour after CPB, brains were perfusion-fixed and rem oved for in situ hybridization and immunohistochemistry analysis in half of the animals. The other half survived 48 h before their brains were examine d for neuronal degeneration. Results: Isoflurane at MAC significantly decreased blood pressure, heart ra te, cardiac output, and systemic vascular resistance by 30-48% (n = 16; P < 0.05). CNS 5161A (n = 12) had no significant cardiovascular effects. All c oncentrations of CNS 5161A caused a significant reduction (21-29%) of the M AC of isoflurane (n = 12; P < 0.05). CNS 5161A, at serum concentrations gre ater than 25 ng/ml, completely inhibited c-fos mRNA and c-FOS protein expre ssion in hippocampal neurons after 120 min of HCA, attenuated neuronal dege neration, and improved functional outcome by 47% (P < 0.05). Conclusions: CNS 5161A at neuroprotective concentrations before CPB-HCA sig nificantly; reduces the MAC of isoflurane without cardiovascular effects.