Smooth muscle contraction is essential to normal function of many organ systems in the body. Therefore, an understanding of its normal contractile process is required before studying disease states (e.g. hypertension, atherosclerosis) in which smooth muscle function may be abnormal. Smooth muscle is characterized by its slow velocity of shortening and economical usage of ATP during force production. These contractile characteristics may reflect the mechanical properties of the basic force generating element, the crossbridge, as well as the kinetics of its cycle. Interpretation of studies in whole tissue, designed to characterize these crossbridge properties, are complicated by the heterogeneous response of a large population of cells that are embedded in a dense connective tissue matrix. To avoid the complexities of multicellular preparations, crossbridge properties will be studied directly, using state of the art techniques to measure mechanical responses from a single smooth muscle cell, isolated from the stomach of the toad, Bufo marinus. Crossbridges are arranged into contractile units within the cell. Contractile unit length will be determined by studying the length dependence of force production. Tension transients in response to small rapd length changes will be used to define the crossbridge elastic properties and rate constants for transitions between steps in the crossbridge cycle. The relationship between force and velocity will be obtained for the first time in single smooth muscle cells. The tension transient and force velocity data will then be used to construct a thermodynamic model of the crossbridge cycle in smooth muscle. The model will predict how the crossbridge cycle time and distribution of crossbridge states relate to smooth muscles slow, economical contraction. The proposed studies will be the first to correlate smooth muscles' contractile capabilities to crossbridge properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR034872-03
Application #
3156983
Study Section
Physiology Study Section (PHY)
Project Start
1984-12-01
Project End
1988-07-31
Budget Start
1986-12-01
Budget End
1988-07-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Harris, D E; Work, S S; Wright, R K et al. (1994) Smooth, cardiac and skeletal muscle myosin force and motion generation assessed by cross-bridge mechanical interactions in vitro. J Muscle Res Cell Motil 15:11-9
Harris, D E; Warshaw, D M (1993) Smooth and skeletal muscle actin are mechanically indistinguishable in the in vitro motility assay. Circ Res 72:219-24
Harris, D E; Warshaw, D M (1993) Smooth and skeletal muscle myosin both exhibit low duty cycles at zero load in vitro. J Biol Chem 268:14764-8
Work, S S; Warshaw, D M (1992) Computer-assisted tracking of actin filament motility. Anal Biochem 202:275-85
Harris, D E; Warshaw, D M; Periasamy, M (1992) Nucleotide sequences of the rabbit alpha-smooth-muscle and beta-non-muscle actin mRNAs. Gene 112:265-6
Harris, D E; Warshaw, D M (1991) Length vs. active force relationship in single isolated smooth muscle cells. Am J Physiol 260:C1104-12
Harris, D E; Warshaw, D M (1990) Slowing of velocity during isotonic shortening in single isolated smooth muscle cells. Evidence for an internal load. J Gen Physiol 96:581-601
Yamakawa, M; Harris, D E; Fay, F S et al. (1990) Mechanical transients of single toad stomach smooth muscle cells. Effects of lowering temperature and extracellular calcium. J Gen Physiol 95:697-715
Warshaw, D M; Yamakawa, M; Harris, D (1989) Evidence for an internal load in single smooth muscle cells. Prog Clin Biol Res 315:329-45
Warshaw, D M; Rees, D D; Fay, F S (1988) Characterization of cross-bridge elasticity and kinetics of cross-bridge cycling during force development in single smooth muscle cells. J Gen Physiol 91:761-79

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