M.S. (Master of Science)
Department of Biological Sciences
Dimethyl sulphoxide; Aliphatic compounds; Organic solvents; Analgesics--Effectiveness
Aliphatic solvents were tested for their ability to block action potentials (A.P.'s), and penetrate and fluidize membranes, to determine the mechanism of general anesthesia and the toxicity of solvents. Ten solvents were chosen exhibiting a range of molar volumes (dV/dM), polarizabilities (P) , and hydrogen bond acceptor basicities (/?) . DMSO was studied in more detail for its ability to block Na channels and thus produce analgesia. Solvents were applied in Ringer solution to A.P.'s recorded from desheathed frog sciatic nerves using the sucrose-gap technique to obtain dose-response curves. Solvent transport through lipid bilayers and estimates of membrane fluidity changes were obtained using a secretory granule lysis assay using rat pancreatic vesicles and a red cell crenation/lysis assay. Light microscopy (LM) studies were conducted to determine if polarizable solvents cause nerve structural changes. Na channel blockade in DMSO solutions was determined using the vaseline-gap voltage- clamp technique applied to single frog muscle fibers. Solvents decreased the A.P. height in a dose dependent way; the effective blocking dose (ED50) was hyperbolically related to the octanol/water partition coefficient of the solvent. The ED50 of all ten solvents was mathematically predicted as a hyperbolic function of dV/dM, P, and /3. Secretory lysis experiments showed that half of the solvents acted to increase bilayer fluidity. The toxicities of the solvents measured as the 50%-lethal dose (LD50) were found to correlate (r=0.89) with the measured ED50's. The results suggest that DMSO blocks A.P.'s by acting as an osmotic agent, a membrane fluidizer, and a denaturant to decrease Na currents without affecting their kinetics. Red cell, secretory lysis and LM experiments suggested that polarizable solvents act osmotically to produce structural changes in whole nerves that contribute to A.P. blockade and a slowed conduction velocity. The results show that small-sized solvents with low polarizability and small /? potently block A.P.'s. Solvents block A.P.'s without necessarily fluidizing the bilayer. Solvents induce A.P. block through a combination of effects: block of Na channels, changes in bilayer fluidity and bulk solution viscosity, and osmotically-induced structural changes in nerves.
Larsen, John J., "Predictions of anesthetic potency for aliphatic hydrocarbon solvents" (1993). Graduate Research Theses & Dissertations. 4475.
x, 143 pages
Northern Illinois University
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