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ANESTHETIC PHARMACOLOGY

The Soluble Guanylyl Cyclase Inhibitor ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, Dose-Dependently Reduces the Threshold for Isoflurane Anesthesia in Rats

Department of Anesthesiology, University of Virginia Health System, Charlottesville

Address correspondence and reprint requests to Thomas Pajewski, PhD, MD, Department of Anesthesiology, University of Virginia, Health System, Box 800710, Charlottesville, VA 22908-0710. Address e-mail to tnp9s{at}virginia.edu

Nitric oxide (NO), a cell messenger for activating soluble guanylyl cyclase, is produced by activation of the enzyme NO synthase (NOS) in a wide variety of tissues, including the central nervous system. We have previously demonstrated that inhibition of NOS decreased the minimum alveolar anesthesia concentration (MAC) for isoflurane anesthesia. Moving more distally in the NOS-guanylyl cyclase signaling pathway, we investigated the effects of the specific soluble guanylyl cyclase inhibitor ODQ, 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one, on anesthetic requirements. The effect of ODQ on the MAC of isoflurane anesthesia was investigated in Sprague-Dawley rats while concurrently monitoring the their arterial blood pressure and heart rate. After determining control MAC, ODQ 20–500 mg/kg was administered intraperitoneally 30 min before re-determining MAC in the presence of the soluble guanylyl cyclase inhibitor. In one series, the effect of 250 mg/kg of ODQ on neuronal cyclase guanosine monophosphate production was determined by microdialysis. ODQ produced a statistically significant, dose-dependent decrease from isoflurane control MAC (maximal effect 52.4% ± 2.7%). No ceiling effect was observed over the dose-range studied. This reduction in isoflurane MAC was not accompanied by changes in either heart rate or blood pressure. Inhibition of the NOS-guanylyl cyclase signaling pathway decreased the MAC for isoflurane, which suggests that inhibition of this pathway may play a role in the anesthetic state. The MAC reduction by the soluble guanylyl cyclase inhibitor ODQ was devoid of any significant hemodynamic effects. The current findings, along with the previous observations that structurally distinct NOS inhibitors and the nonspecific soluble guanylyl cyclase inhibitor methylene blue decrease the MAC for volatile anesthetics, support that this is an effect specific to the NOS-guanylyl cyclase signaling pathway.

IMPLICATIONS: The nitric oxide-guanylyl cyclase signaling pathway has been proposed to be involved in sedation, analgesia, and anesthesia. Specific inhibitors of the enzyme nitric oxide synthase resulted in a reduction in the anesthetic requirements (MAC) for isoflurane. In the present study, we demonstrate that ODQ, a specific inhibitor of soluble guanylyl cyclase, was also capable of reducing the MAC for isoflurane anesthesia in the rat.

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