Neuroprotective, anesthetic, and cardiovascular effects of the NMDA antagonist, CNS 5161A, in isoflurane-anesthetized lambs.
BACKGROUND
N-methyl-d-aspartate (NMDA) receptor antagonists are neuroprotective in animal models of cerebral ischemia, but adverse cardiovascular and neurobehavioral effects have precluded their clinical use. The authors present 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, and ventilated and had thermodilution catheters placed in the pulmonary artery and 20-g catheters placed in the femoral artery. The minimum alveolar concentration (MAC) of isoflurane was determined using the "bracketing technique." 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 circulatory arrest (HCA) for 120 min. Eighteen received CNS 5161A, and seven received saline vehicle. One hour after CPB, brains were perfusion-fixed and removed for in situ hybridization and immunohistochemistry analysis in half of the animals. The other half survived 48 h before their brains were examined for neuronal degeneration.


RESULTS
Isoflurane at MAC significantly decreased blood pressure, heart rate, cardiac output, and systemic vascular resistance by 30-48% (n = 16; P < 0.05). CNS 5161A (n = 12) had no significant cardiovascular effects. All concentrations of CNS 5161A caused a significant reduction (21-29%) of the MAC of isoflurane (n = 12; P < 0.05). CNS 5161A, at serum concentrations greater than 25 ng/ml, completely inhibited c-fosmRNA and c-FOS protein expression in hippocampal neurons after 120 min of HCA, attenuated neuronal degeneration, and improved functional outcome by 47% (P < 0.05).


CONCLUSIONS
CNS 5161A at neuroprotective concentrations before CPB-HCA significantly reduces the MAC of isoflurane without cardiovascular effects.
Bokesch
P M
PM
Departments of Cardiothoracic Anesthesia, The Cleveland Clinic Foundation, OH 44195, USA. bokescp@ccf.org
Kapural
M
M
Drummond-Webb
J
J
Baird
K
K
Kapural
L
L
Mee
R B
RB
Trapp
B
B
Starr
N J
NJ
D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002315:Cardiopulmonary Bypass; D006324:Heart Arrest, Induced; D006439:Hemodynamics / Q000187:drug effects; D017403:In Situ Hybridization; D007530:Isoflurane / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000097:blood / Q000494:pharmacology*; D012756:Sheep
D018685:Anesthetics, Inhalation; D018696:Neuroprotective Agents; D016202:N-Methylaspartate; D007530:Isoflurane