Intrathecally administered cGMP-dependent protein kinase Iα inhibitor significantly reduced the threshold for isoflurane anesthesia: Implication for a novel role of cGMP-dependent protein kinase Iα

Background: Inhalational anesthetics have been shown to inhibit the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Previous studies indicated that inhibition of the NO-cGMP pathway decreased the level of consciousness and augmented anesthesia, analgesia, or sedation. The current study investigated the possible involvement of cGMP-dependent protein kinases (PKGs) as major effectors for the NO-cGMP pathway in the anesthetic state. Methods: After initial baseline determination of the minimum alveolar concentration (MAC), a selective cGMP-dependent protein kinase Iα inhibitor, Rp-8-p-CPT-cGMPS, or an NO donor, (NOC-12), were injected intrathecally. Ten minutes later, MAC measurement was repeated. The rats also were evaluated for the presence of locomotor dysfunction by intrathecal administration of Rp-8- p-CPT-cGMPS and NOC-12 in conscious rats. Results: Rp-8-p-CPT-cGMPS at 25, 50, 100, and 200 μg/10 μl produced a significant decrease from isoflurane control MAC of -4 ± 3.1%, 16 +- 4.5%, 30 ± 5.0%, and 21 ± 2.2%, respectively, which was not accompanied by significant changes in either blood pressure or heart rate. In contrast, NOC-12 at 100 μg/10 μl caused an increase from isoflurane control MAC of 23 ± 5.8%, which was accompanied by significant decrease in blood pressure but not in heart rate. Rp-8-p-CPT- cGMPS (100μg/10μl) produced a significant reversal of isoflurane MAC increase induced by NOC-12 (100 μg/10 μl), which was accompanied by significant reversal of the reduction of blood pressure induced by NOC-12. Locomotor activity was not changed. Conclusions: The results indicate that cGMP-dependent protein kinase Iα inhibitor not only markedly reduces MAC for isoflurane, but also completely blocks the NO-induced increase in isoflurane MAC, which suggests that cGMP-dependent protein kinase Iα may mediate the action for the NO-cGMP pathway in anesthetic mechanisms at the spinal cord level.