Abstract
Since volatile anesthetics inhibited high voltage-gated calcium channels and G-protein-coupled M1 muscarinic signaling, their effects upon M1 receptor-induced modulation of L-type (α1C) calcium channel was investigated. Voltage-clamped Ba2+ currents (IBa) were measured in Xenopus oocytes coexpressed with L-type channels and M1 muscarinic receptors. M1receptor agonist, acetyl-β-methylcholine (MCh) inhibited the peak and late components of IBa in a dose-dependent manner. Analysis of IBa 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 [Ca2+]i. Although halothane or isoflurane inhibited IBa, 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 M1 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 IBa 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.
Footnotes
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Send reprint requests to: Dr. Ganesan L. Kamatchi, 1877 Lane Rd. (Old Med. Sch.), Department of Anesthesiology, P.O. Box 800710, University of Virginia Health Science Systems, Charlottesville, VA 22908-0710. E-mail: gk3p{at}virginia.edu
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↵1 Present address: Department of Anesthesiology, University Hospital Maastricht, P. Debyelaan 25 Maastricht, The Netherlands.
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This work was supported by the National Institutes of Health Grants R29-GM52387 (to M.E.D.) and GM31144 (to C.L.).
- Abbreviations:
- HVGCC
- high voltage-gated calcium channel
- AT1A
- angiotensin receptor
- [Ca2+]i
- intracellular calcium
- IP3
- inositol-1,4,5-trisphosphate
- PLC
- phospholipase C
- PKC
- protein kinase C
- PMA
- phorbol 12-myristate 13-acetate
- IBa
- Ba2+ current
- I-V
- current-voltage
- MCh
- acetyl-β-methylcholine
- GDP-β-S
- guanosine-5′-O-(2-thiodiphosphate) trilithium
- BAPTA
- 1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid sodium
- GBa
- Ba2+ conductance
- GABAA
- γ-aminobutyric acid, type A
- Received October 27, 2000.
- Accepted January 26, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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