The long-term goals of the proposed research are to understand the effects of volatile anesthetics on: 1) the regulation of [Ca2+]i; 2) the coupling between elevated [Ca2+]i and mechanical responses (excitation- contraction); and 3) the Ca2+ sensitivity of force generation in ASM cells. The proposed studies will use real-time confocal microscopy to examine the effects of halothane and sevoflurane on acetylcholine- induced [Ca2+]i oscillations in localized regions within freshly dissociated porcine ASM cells. Flash photolytic release of caged Ca2+ and ATP will be used to determine effects of volatile anesthetics on the intracellular process contributing to the delays during excitation- contraction coupling. There are four major specific aims in the proposed studies: 1) To determine the effect of volatile anesthetics on acetylcholine-induced [Ca2+]i oscillations, 2) To determine whether volatile anesthetics affect second messenger (IP3, and cADPR) production in response to acetylcholine, 3) To determine whether volatile anesthetics affect IP3 and cADPR-mediated SR Ca2+ release, and 4) To determine the effects of volatile anesthetic on the Ca2+ sensitivity of force generation and the dynamic coupling between elevated [Ca2+]i and ASM contraction. With regard to [Ca2+]i regulation, the authors hypothesize that volatile anesthetics 1) increase IP3 production but decrease cADPR production; 2) decrease SR Ca2+ content via an IP3- induced """"""""leak"""""""" and reduced SR Ca2+ reuptake, thereby decreasing the peak amplitude of [Ca2+]i oscillations; and 3) lower the sensitivity of Ca2+- induced Ca2+ release (CICR) via decreased cADPR production, thereby slowing [Ca2+]i oscillation frequency and propagation velocity. With regard to the coupling between elevated [Ca2+]i and ASM contraction, the investigators hypothesize that volatile anesthetics 1) decrease the steady-state Ca2+ sensitivity of force generation during muscarinic stimulation and 2) delay excitation-contraction coupling.
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