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
Yx. Tao et al., 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, ANESTHESIOL, 92(2), 2000, pp. 493-499
Citations number
42
Categorie Soggetti
Aneshtesia & Intensive Care","Medical Research Diagnosis & Treatment
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.