Tao Y X, Hassan A, Johns R A
Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, USA.
Anesthesiology. 2000 Feb;92(2):493-9. doi: 10.1097/00000542-200002000-00032.
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.
After initial baseline determination of the minimum alveolar concentration (MAC), a selective cGMP-dependent protein kinase Ialpha 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.
Rp-8-p-CPT-cGMPS at 25, 50, 100, and 200 microg/10 microl 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 microg/10 microl 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 (100 microg/10 microl) produced a significant reversal of isoflurane MAC increase induced by NOC-12 (100 microg/10 microl), which was accompanied by significant reversal of the reduction of blood pressure induced by NOC-12. Locomotor activity was not changed.
The results indicate that cGMP-dependent protein kinase Ialpha 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 Ialpha may mediate the action for the NO-cGMP pathway in anesthetic mechanisms at the spinal cord level.
吸入性麻醉剂已被证明可抑制一氧化氮（NO）-环磷酸鸟苷（cGMP）途径。先前的研究表明，抑制NO-cGMP途径会降低意识水平并增强麻醉、镇痛或镇静作用。当前研究调查了cGMP依赖性蛋白激酶（PKG）作为NO-cGMP途径在麻醉状态下的主要效应器的可能参与情况。
在初步测定最低肺泡浓度（MAC）基线后，鞘内注射选择性cGMP依赖性蛋白激酶Iα抑制剂Rp-8-p-CPT-cGMPS或NO供体（NOC-12）。10分钟后，重复MAC测量。还通过在清醒大鼠鞘内注射Rp-8-p-CPT-cGMPS和NOC-12来评估大鼠是否存在运动功能障碍。
25、50、100和200微克/10微升的Rp-8-p-CPT-cGMPS分别使异氟烷对照MAC显著降低-4±3.1%、16±4.5%、30±5.0%和21±2.2%，且血压和心率均无显著变化。相比之下，100微克/10微升的NOC-12使异氟烷对照MAC升高23±5.8%，伴有血压显著降低但心率无变化。Rp-8-p-CPT-cGMPS（100微克/10微升）显著逆转了NOC-12（100微克/10微升）诱导的异氟烷MAC升高，并伴有NOC-12诱导的血压降低的显著逆转。运动活动未改变。
结果表明，cGMP依赖性蛋白激酶Iα抑制剂不仅显著降低异氟烷的MAC，还完全阻断NO诱导的异氟烷MAC升高，这表明cGMP依赖性蛋白激酶Iα可能在脊髓水平的麻醉机制中介导NO-cGMP途径的作用。
