The goal of the proposed study is to determine the molecular mechanisms responsible for smooth muscle relaxation induced by halogenated volatile anesthetic agents. Contraction, intracellular calcium concentration, and contractile protein activation will be studied in small resistance arteries. Preliminary experiments have led to the hypothesis that anesthetics relax muscle by inhibiting myosin light chain phosphorylation independent of changes in intracellular calcium concentration. Experiments are proposed to validate the importance of this effect by determining the concentration dependence of anesthetic effects on calcium-activated contractions and myosin light chain phosphorylation in potassium-depolarized intact vascular smooth muscle. Differences between intact and membrane permeabilized smooth muscle suggest the hypothesis that the membrane permeabilized muscle lacks an important modulator essential for anesthetic-induced smooth muscle relaxation. To determine the nature of the missing modulator, experiments are proposed to characterize the systems which modulate contraction in both intact and permeabilized muscle. Finally, attempts will be made to reconstitute the relaxing effect of anesthetics in skinned muscle in order to identify the essential components of the modulator.
| Leone, Marc; Boyle, Walter A (2006) Decreased vasopressin responsiveness in vasodilatory septic shock-like conditions. Crit Care Med 34:1126-30 |
| Tsuneyoshi, Isao; Zhang, Dongya; Boyle 3rd, Walter A (2003) Ca2+- and myosin phosphorylation-independent relaxation by halothane in K+-depolarized rat mesenteric arteries. Anesthesiology 99:656-65 |
