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Development of new approaches for the study of mechanisms responsible for the generation and maintenance of resting membrane potentials in the heart

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Title	Development of new approaches for the study of mechanisms responsible for the generation and maintenance of resting membrane potentials in the heart
Author	Schilling, William P. (William Phillip)
Date	1981
Affiliation/College	College of Graduate Studies
Department	Pharmacology
Extent	viii, 172 leaves : ill.; 29 cm
Subject.MeSH	Membrane Potentials Academic Dissertations Academic Dissertations--South Carolina
Collection	MUSC Dissertations and Theses
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright is held by the author.
Language	English
Type	Text
Format	application/pdf
Media Type	Manuscripts
Resource Identifier	mtd1981_schilling_wp
Abstract	Two new approaches for the study of the mechanisms responsible for the generation and maintenance of resting membrane potentials in the heart have been developed and evaluated. In the first approach, mathematical expressions relating active Na[superscript +], K[superscript +] -pump activity, and passive flux to membrane potential changes were evaluated by computer simulated, hypothetical cell experiments. These experiments tested postulated mechanisms by which low external potassium and cardiac glycosides can produce a depolarization of the cell membrane, and by which elevation of the external potassium concentration can reverse cardiac glycoside-induced loss of membrane potential. The hypothetical cell simulations mimicked the loss of resting potential for both interventions. These studies suggested that the most likely mechanism for the loss of E[subscript m] was a decrease in permeability of the membrane to potassium and that elevation of external potassium can reverse cardiac glycoside toxicity via a potassium-induced increase in potassium permeability. The second approach, designed to complement the hypothetical cell studies, involved the characterization and evaluation of isolated cardiac sarcolemma preparations as a viable physiological model for the rigorous investigation of ion flux, membrane permeability, and resting membrane potential. It was found that the isolated cardiac sarcolemma preparation could, in some cases, develop and maintain a membrane potential that was defined by the Goldman-Hodgkin-Katz equation. The order of relative permeability coefficients for these preparations were P[subscript K] => P[subscript Li] > P [subscript Na] > P{subscript choline] as defined by P[subscript C] : P[subscript K] values of 0.9, 0.3 and 0.12 for lithium, sodium and choline, respectively. These data suggested that either P[subscript C] was elevated or that P[subscript K] was decreased in the isolated cardiac sarcolemma preparation compared to values observed for intact cardiac tissue. Other sarcolemma preparations could not develop a membrane potential with a potassium gradient, but these preparations retained selective permeability to lithium, sodium and choline. This strengthened the argument that the preparations have a low and variable P[subscript K]. In order to test this possibility, an analysis of potassium, sodium, chloride and sucrose fluxes under equilibrium and non-equilibrium conditions was carried out. Under equilibrium conditions, the unidirectional uptake of potassium and sodium were described by a bi-exponential process plus a small "instantaIleous" compartment. The permeability coefficients for the two major compartments, designated P[subscript slow] P[subscript fast], were found to be or to approach at certain salt activities, values of 1.77 x 10[superscript -9] and 1.1 x 10[superscript -8] cm/sec, respectively. At higher salt activities, the potassium flux for the slow component appeared to saturate whereas the sodium flux for the fast component increased. Thus, the permeability coefficients were not constant with increasing cation activity. Two nonequilibrium conditions were examined: 1) dilution of salt loaded vesicles into isosmotic sucrose; and 2) dilution of salt loaded vesicles into isosmotic salt. Under the first condition, the efflux of potassium and sodium was limited by the low permeability of the membrane to chloride. Under the second condition, the potassium, sodium and chloride flux data were analyzed via a non-linear, least squares iteration technique which was designed to predict the values of P[subscript K], P[subscript Na], P[subscript Cl] and E[subscript m]. The results of these studies were consistent with the hypothesis that the sarcolemma preparation possesses two populations of vesicles one of which has permeability characteristic similar to those observed for intact cardiac tissue (i.e., relatively high P[subscript K], low P[subscript Na] and a negative membrane potential in the presence of an outwardly directed potassium gradient). The second population of vesicles has a P[subscript Na] similar to the first population but with a low P[subscript K] and a positive potential in the presence of an outwardly directed potassium gradient. The ratio of these two populations in the sarcolemma preparation would define the extent to which a particular preparation would hyperpolarize in the presence of an outwardly directed potassium gradient. Small changes in the ratio of the two populations from preparation to preparation could account for substantial variations in P[subscript K] without significant variations in P[subscript Na] and for a variable ability of the preparations to hyperpolarize in the presence of a potassium gradient. By hypothesis, therefore, subfractionation of the sarcolemma preparation into the two populations should yield one population of vesicles with a P[subscript NA] : P[subscript K] similar to that of the cardiac cell. Studies with this population could hopefully then be combined with the hypothetical cell-simulation approach to yield new information about those mechanisms that are responsible for the generation and maintenance of resting membrane potentials in the heart.

Development of new approaches for the study of mechanisms responsible for the generation and maintenance of resting membrane potentials in the heart

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