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NEUROSURGICAL ANESTHESIA

The Role of Nitric Oxide Synthase Inhibition in the Adverse Effects of Etomidate in the Setting of Focal Cerebral Ischemia in Rats

John C. Drummond, MD^*, Lorne D. McKay, MD, Daniel J. Cole, MD, and Piyush M. Patel, MD^*

*Departments of Anesthesiology, University of California, San Diego, La Jolla; VA Medical Center, San Diego; Loma Linda University, Loma Linda, California; and Mayo Clinic College of Medicine, Rochester, Minnesota

Address correspondence and reprint requests to John C. Drummond, MD, VA Medical Center, Anesthesia Service-125, 3350 La Jolla Village Dr., San Diego, CA 92161. Address e-mail to jdrummond{at}ucsd.edu.

We evaluated the effect of N^G-nitro-l-arginine-methyl-ester (l-NAME, a nitric oxide synthase [NOS] inhibitor) and l-arginine (nitric oxide substrate) on cerebral mitochondrial dysfunction (hereafter referred to as "injury") after temporary middle cerebral artery occlusion (MCAo) during halothane or etomidate anesthesia in spontaneously hypertensive rats. Sixty minutes before MCAo, rats were randomized to 1 of 5 regimens (n = 8 per group): h/control, 1.2 minimum alveolar anesthetic concentration of halothane; h/l-NAME, 1.2 minimum alveolar anesthetic concentration of halothane and l-NAME (30 mg/kg); etomidate, an electroencephalographic (EEG) burst suppression dose of etomidate; e/l-NAME, an EEG burst suppression dose of etomidate and l-NAME (30 mg/kg); or e/l-NAME/arg, an EEG burst suppression dose of etomidate, l-NAME (30 mg/kg), and l-arginine (bolus of 300 mg/kg with an infusion at 35 mg · kg^–1 · min^–1). After 180 min of MCAo and 120 min of reperfusion, volume of injury was determined using 2,3,5-triphenytetrazolium stain. Injury volume (mm³, mean ± sd) was larger in the etomidate group (153 ± 17) than the halothane anesthetized h/control group (93 ± 16) (P < 0.05) but did not differ between the e/l-NAME (162 ± 17) and h/l-NAME groups (155 ± 26). Injury volume in the e/l-NAME/arg group (88 ± 15) was not different from the h/control group (93 ± 16) and was less than that in either the etomidate or the e/l-NAME groups (P < 0.05). The data reproduce our previous observation that, relative to a halothane-anesthetized control state, etomidate has an adverse effect on ischemic injury in the setting of temporary focal cerebral ischemia. Prior inhibition of NOS with l-NAME resulted in no difference in the volume of injury between groups receiving etomidate or halothane (162 ± 17 versus 155 ± 26). Administration of a large dose of l-arginine prevented the adverse effect of etomidate. The data were obtained after only 2 h of reperfusion and therefore cannot be construed as representative of final neurologic outcome. They nonetheless suggest that etomidate produces an adverse effect on mitochondrial function early in the course of focal cerebral ischemia, in part, by inhibition of NOS.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999