Intrathecally administered cGMP-dependent protein kinase I alpha inhibitorsignificantly reduced the threshold for isoflurane anesthesia - Implication for a novel role of cGMP-dependent protein kinase I alpha

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 con sciousness and augmented anesthesia, analgesia, or sedation. The current st udy investigated the possible involvement of cGMP-dependent protein kinases (PKGs) as major effecters for the NO-cGMP pathway in the anesthetic state. Methods: After initial baseline determination of the minimum alveolar conce ntration (MAC), a selective cGMP-dependent protein kinase I alpha 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 evaluat ed 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 mu g/10 mu l produced a s ignificant 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, NO C-12 at 100 mu g/10 mu l caused an increase from isoflurane control MAC of 23 +/- 5.8%, which was accompanied by significant decrease in blood pressur e but not in heart rate. Rp-8-p-CPT-cGMPS (100 mu g/10 mu l) produced a sig nificant reversal of isoflurane MAC increase induced by NOC-12 (100 mu g/10 mu l), which was accompanied by significant reversal of the reduction of b lood pressure induced by NOC-12. Locomotor activity was not changed. Conclusions: The results indicate that cGMP-dependent protein kinase I alph a inhibitor not only markedly reduces MAC for isoflurane, but also complete ly blocks the NO-induced increase in isoflurane MAC, which suggests that cG MP-dependent protein kinase I alpha may mediate the action for the NO-cGMP pathway in anesthetic mechanisms at the spinal cord level.