Vol. 297, Issue 3, 981-990, June 2001

Differential Sensitivity of Expressed L-Type Calcium Channels and Muscarinic M₁ Receptors to Volatile Anesthetics in Xenopus Oocytes

Ganesan L. Kamatchi, Marcel E. Durieux¹ and Carl Lynch, III

Department of Anesthesiology, University of Virginia Health Science Systems, Charlottesville, Virginia

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 (1C) calcium channel was investigated. Voltage-clamped Ba²⁺ currents (I_Ba) were measured in Xenopus oocytes coexpressed with L-type channels and M₁ muscarinic receptors. M₁ receptor agonist, acetyl--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 [Ca²⁺]_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 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 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.