Abstract
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 mm Hg 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 μg/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.
Footnotes
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This work was supported by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (to D.Y., number 11671478) and a research fellowship from Kanae Memorial Foundation, Tokyo, Japan (to K.N.).
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doi:10.1124/jpet.104.071936.
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ABBREVIATIONS: NANC, nonadrenergic, noncholinergic; CGRP, calcitonin gene-related peptide; CO, cardiac output; GTPγS, guanosine 5′-O-(3-thio)triphosphate; GPCR, G protein-coupled receptor; IBMX, 3-isobutyl-1-methylxanthine; MAP, mean arterial pressure; MEM, minimal essential medium; SVR, systemic vascular resistance.
- Received May 25, 2004.
- Accepted August 5, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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