title: Airway smooth muscle, tidal stretches, and dynamically determined contractile states.
abstract: In the classic theory of airway lumen narrowing in asthma, active force in airway smooth muscle is presumed to be in static mechanical equilibrium with the external load against which the muscle has shortened. This theory is useful because it identifies the static equilibrium length toward which activated airway smooth muscle would tend if given enough time. The corresponding state toward which myosin-actin interactions would tend is called the latch state. But are the concepts of a static mechanical equilibrium and the latch state applicable in the setting of tidal loading, as occurs during breathing? To address this question, we have studied isolated, maximally contracted bovine tracheal smooth muscle subjected to tidal stretches imposed at 0.33 Hz. We measured the active force (F) and stiffness (E), which reflect numbers of actin-myosin interactions, and hysteresivity (eta) which reflects the rate of turnover of those interactions. When the amplitude of imposed tidal stretch (epsilon) was very small, 0.25% of muscle optimal length, the steady-state value of F approximated the isometric force, E was large, and eta was small. When epsilon was increased beyond 1%, however, F and E promptly decreased and eta promptly increased. The muscle could be maintained in these steady, dynamically determined contractile states for as long as the tidal stretches were sustained; when epsilon subsequently decreased back to 0.25%, F, E, and eta returned slowly toward their previous values. The provocative stretch amplitude required to cause active force or muscle stiffness to fall by half, or hysteresivity to double, was slightly greater than 2%. These observations are consistent with a direct effect of stretch upon bridge dynamics in which, with increasing tidal stretch amplitude, the number of actin-myosin interactions decreases and their rate of turnover increases. We conclude that the interactions of myosin with actin are at every instant tending toward those that would prevail in the isometric steady state, but tidal changes of muscle length cause an excess in the rate of detachment. These stretch-induced detachment events can come so fast compared with the rate of attachment that static equilibrium conditions are never attained. If so, then airway lumenal narrowing and the underlying contractile state would be governed by a dynamic mechanical process rather than by a mechanical equilibrium of static forces.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Fredberg
authors.forename: D
authors.initials: D
authors.lastname: Inouye
authors.forename: B
authors.initials: B
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Nathan
authors.forename: S
authors.initials: S
authors.lastname: Jafari
authors.forename: S H
authors.initials: SH
authors.lastname: Raboudi
authors.forename: J P
authors.initials: JP
authors.lastname: Butler
authors.forename: S A
authors.initials: SA
authors.lastname: Shore
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002417:Cattle; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004548:Elasticity; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology*; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin / Q000494:pharmacology; D013990:Tidal Volume; D014132:Trachea / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D007213:Indomethacin