Halothane reduces myofilament Ca2+ sensitivity during muscarinic receptor stimulation of airway smooth muscle.
This study used a beta-escin-permeabilized canine tracheal smooth muscle preparation to test the hypothesis that the volatile anesthetic halothane decreases myofilament Ca2+ sensitivity by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity and not by inhibiting Ca(2+)-calmodulin activation of the contractile proteins. Acetylcholine (ACh) caused a GTP-dependent increase in force at constant submaximal cytosolic Ca2+ concentration. ACh, guanosine-5'-O-(3-thiotriphosphate), and the protein kinase C agonist 12,13-phorbol dibutyrate each significantly decreased the concentration of free Ca2+ producing a half-maximal response from 0.77 +/- 0.09 microM (Ca2+ alone) to 0.16 +/- 0.01, 0.19 +/- 0.02, and 0.37 +/- 0.03 microM, respectively, demonstrating an increase in myofilament Ca2+ sensitivity. Halothane (0.92 +/- 0.12 mM) had no effect on the free Ca2+ concentration-response curves generated by Ca2+ alone. However, in the presence of 3 microM ACh plus 10 microM GTP to maximally activate muscarinic receptors, halothane significantly increased the EC50 for free Ca2+ from 0.17 +/- 0.01 microM to 0.38 +/- 0.03 microM. These findings suggest that halothane decreases myofilament Ca2+ sensitivity in beta-escin-permeabilized canine tracheal smooth muscle by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity.
Akao
M
M
Department of Anesthesiology, Mayo Clinic Rochester, Minnesota 55905, USA.
Hirasaki
A
A
Jones
K A
KA
Wong
G Y
GY
Bremerich
D H
DH
Warner
D O
DO
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D004928:Escin; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology*
D011976:Receptors, Muscarinic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004928:Escin; D006160:Guanosine Triphosphate; D011493:Protein Kinase C; D000109:Acetylcholine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D006221:Halothane