Differential sensitivity of expressed L-type calcium channels and muscarinic M(1) receptors to volatile anesthetics in Xenopus oocytes.
Since volatile anesthetics inhibited high voltage-gated calcium channels and G-protein-coupled M(1) muscarinic signaling, their effects upon M(1) receptor-induced modulation of L-type (alpha1C) calcium channel was investigated. Voltage-clamped Ba(2+) currents (I(Ba)) were measured in Xenopus oocytes coexpressed with L-type channels and M(1) muscarinic receptors. M(1) receptor agonist, acetyl-beta-methylcholine (MCh) inhibited the peak and late components of I(Ba) in a dose-dependent manner. Analysis of I(Ba) after the treatment with MCh or volatile anesthetics revealed that the inactivating component, its time constant, and the noninactivating current were all decreased by these agents. MCh-induced inhibition followed a second messenger pathway that included G-proteins, phospholipase C, inositol-1,4,5-trisphosphate, and intracellular calcium [Ca(2+)](i). Although halothane or isoflurane inhibited I(Ba,) their effect was not mediated through these intracellular second messengers. By using volatile anesthetics and MCh sequentially, and in various combinations, the susceptibility of L-type currents and their modulation by M(1) receptors to volatile anesthetics were investigated. When MCh and volatile anesthetics were administered together simultaneously, a pronounced inhibition that was approximately equal to the sum of their individual effects was seen. Halothane or isoflurane further inhibited the I(Ba) when either volatile anesthetic was administered following the inhibition produced by prior administration of MCh. However, when MCh was administered following either volatile anesthetic, its effect was significantly reduced. Thus, whereas volatile anesthetics appear to directly inhibit L-type channels, they also interfere with channel modulation by G-protein-coupled receptors, which may have functional implications for both neuronal and cardiovascular tissues.
Kamatchi
G L
GL
Department of Anesthesiology, University of Virginia Health Science Systems, Charlottesville, Virginia, USA. gk3p@virginia.edu
Durieux
M E
ME
Lynch
C
C
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004056:Differential Threshold / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006221:Halothane / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D018685:Anesthetics, Inhalation; D020746:Calcium Channels, L-Type; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D007530:Isoflurane; D006221:Halothane