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


RESULTS
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.


CONCLUSIONS
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.
Tao
Y X
YX
Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, USA.
Hassan
A
A
Johns
R A
RA
D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007278:Injections, Spinal; D007530:Isoflurane / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000008:administration & dosage / Q000494:pharmacology*
C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D018685:Anesthetics, Inhalation; D020030:Nitric Oxide Donors; D013873:Thionucleotides; D007530:Isoflurane; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP