Volatile anesthetics inhibit calcitonin gene-related peptide receptor-mediated responses in pithed rats and human neuroblastoma cells.
Calcitonin gene-related peptide (CGRP) has a potent vasodilatory effect that is mediated by specific receptors predominantly coupled to the activation of adenylate cyclase. The effects of volatile anesthetics on CGRP-induced vasodilation are unclear. We studied the effects of sevoflurane and isoflurane on CGRP-induced vasodilation in pithed rats and CGRP receptor-mediated responses in SK-N-MC cells, which are used as a model system to study the CGRP receptor and its downstream pathways. Male Wistar rats were pithed by inserting a stainless steel rod into the spinal cord. Mean arterial pressure (MAP) and cardiac output were maintained at approximately 100 mmHg and 50 ml.min(-1), respectively, with continuous infusion of noradrenaline. After 30 min of inhalation of anesthetics, CGRP (0.1, 0.3, 1.0, and 3.0 microg/kg) was administered intravenously. In SK-N-MC cells, CGRP-, forskolin-, or cholera toxin-induced cAMP production was measured with or without anesthetics using radioimmunoassays. CGRP receptor binding density and affinity for the agonist were determined with (2-[125I]iodohystidyl10) CGRP with or without the anesthetics. Sevoflurane (4%) and isoflurane (2%) significantly inhibited the decrease in MAP and systemic vascular resistance. Furthermore, both anesthetics significantly inhibited CGRP- but not forskolin-induced cAMP production. Sevoflurane (4%) and isoflurane (4%) significantly inhibited cholera toxin-induced cAMP production. Both anesthetics did not affect ligand binding. These data suggest that sevoflurane and isoflurane inhibit CGRP-induced vasodilation at the site between the CGRP receptor and adenylate cyclase activation. The inhibitory site of volatile anesthetics on the CGRP receptor-mediated response involves Gs protein.
Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi City 371-8511, Japan. mkuroda@med.gunma-u.ac.jp
Masataka
M
Kuroda
Daisuke
D
Yoshikawa
Koichi
K
Nishikawa
Shigeru
S
Saito
Fumio
F
Goto
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001932:Brain Neoplasms / Q000503:physiopathology*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D045744:Cell Line, Tumor; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003655:Decerebrate State / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000503:physiopathology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D018685:Anesthetics, Inhalation; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D005576:Colforsin; D002772:Cholera Toxin; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide