The long-term goal of this research program is to continue to elucidate the underlying mechanism for impaired pulmonary gas exchange during general anesthesia. The specific goal of this project is to test the hypothesis that anesthetic agents a ' erect pulmonary resistance by a number of mechanisms. Pulmonary resistance is not only determined by the pressure loss along the airways (airway resistance), but also to a large extent by the pressure loss caused by the pressure-volume hysteresis of lung tissue (tissue resistance). We propose to test the hypothesis that anesthetics alter in humans both airway resistance and tissue resistance (specific aim 1). The tissue resistance could be altered by an effect of anesthetics on the function of the surfactant, the smooth muscles of the airways or alveolar ducts or a combination of these effects. If anesthetics had an effect on alveolar duct smooth muscles, pulmonary gas exchange may be affected, because the smooth muscles in the alveolar ducts may keep alveolar septa tense. If anesthetics were to relax these fibers, previously tense alveolar septa may slacken, thus decreasing the surface to volume ratio in the lung.
In specific aim 1 we will also determine whether N20 has an effect on airway resistance.
In specific aim 2 we will examine the hypothesis that volatile anesthetics inhibit airway smooth muscle constriction by reducing activity in nerves innervating the muscle, by direct effects on the smooth muscle cell, and by effects on airway epithelial function.
This aim addresses two previously unappreciated but important points. First, distinguishing between neurally-mediated and direct effects of anesthetics on the airways is important because in vivo airway smooth muscle may be constricted by both reflex and direct stimuli. For example, laryngeal irritation caused by an endotracheal tube may constrict the airways predominantly by a reflex mechanism. Conversely, humoral mediators released in response to an immunologic stimulus or during asthma may directly affect the airway smooth muscle cell. Secondly, if anesthetics affect epithelial function, then the response of patients with damaged airway epithelium (such as asthmatics) to volatile anesthetics may be altered. In the third specific aim we will test the hypothesis that injectable anesthetic agents attenuate hypocapnic bronchoconstriction in dogs. Attenuation of the hypocapnic bronchoconstriction may result in a loss of airway response to differences in regional P(CO2). This may cause increased VA/Q mismatch during anesthesia. We wish to test our hypothesis that injectable anesthetics may interfere less with hypocapnic bronchoconstriction than volatile anesthetics.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Mayo Clinic, Rochester
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Streiff, John H; Jones, Keith A (2008) Volatile anesthetic binding to proteins is influenced by solvent and aliphatic residues. J Chem Inf Model 48:2066-73
Nakayama, Tetsuzo; Penheiter, Alan R; Penheiter, Sumedha G et al. (2006) Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein. Anesthesiology 105:313-24
Hayashi, Masao; Penheiter, Sumedha G; Nakayama, Tetsuzo et al. (2006) Halothane does not inhibit the functional coupling between the beta2-adrenergic receptor and the Galphas heterotrimeric G protein. Anesthesiology 104:754-62
Streiff, John H; Allen, Thomas W; Atanasova, Elena et al. (2006) Prediction of volatile anesthetic binding sites in proteins. Biophys J 91:3405-14
Taniguchi, Miwa; Kwak, Young Lan; Jones, Keith A et al. (2006) Nitric oxide sensitivity in pulmonary artery and airway smooth muscle: a possible role for cGMP responsiveness. Am J Physiol Lung Cell Mol Physiol 290:L1018-27
Nakayama, Tetsuzo; Hayashi, Masao; Warner, David O et al. (2005) Anesthetics inhibit membrane receptor coupling to the Gq/11 heterotrimeric G protein in airway smooth muscle. Anesthesiology 103:296-305
Jin, Fang; Wang, Shuyan; Spencer, Joshua D et al. (2005) Effect of halothane on galphai-3 and its coupling to the M2 muscarinic receptor. Anesthesiology 103:1015-25
Streiff, John; Warner, David O; Klimtchuk, Elena et al. (2004) The effects of hexanol on Galpha(i) subunits of heterotrimeric G proteins. Anesth Analg 98:660-7, table of contents
Sakihara, Chie; Perkins, William J; Warner, David O et al. (2004) Anesthetics inhibit acetylcholine-promoted guanine nucleotide exchange of heterotrimeric G proteins of airway smooth muscle. Anesthesiology 101:120-6
Streiff, John H; Juranic, Nenad O; Macura, Slobodan I et al. (2004) Saturation transfer difference nuclear magnetic resonance spectroscopy as a method for screening proteins for anesthetic binding. Mol Pharmacol 66:929-35

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