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The time course of length adaptation and tension recovery in airway smooth muscle Naghshin, Jahanbakhsh

Abstract

Airway smooth muscle (ASM) is known to adapt to large changes in length by restructuring its contractile apparatus. The temporary loss of the ability to generate maximal isometric force due to an acute length change usually recovers in 20-30 min when the muscle is stimulated periodically. ASM is capable of adapting to length changes even in the absence of repeated stimulation, although at a much slower rate. It has been previously shown that by setting the relaxed ASM at different lengths at 4 °C in physiological saline solution (PSS) for 24 hrs, the length-tension (L-T) relationship of the muscle could be plastically and reversibly altered [53]. In this study, I examined the time course of length adaptation at 4 °C to determine the minimum time needed for this process to happen. By measuring changes in the length associated with maximal force generation (L[sub max]), I found that under the same conditions used by Wang et al [53], the length adaptation became statistically significant after 6-12 hours of passive length change. I hypothesized that a similar length adaptation can also happen at 37°C when the ASM is maintained unstimulated at different lengths. The reversibility of active and passive length adaptations following prolonged length change was also examined. Rabbit tracheal muscle explants were passively maintained at shortened or in situ length for 3 and 7 days in culture media enriched with 5% fetal bovine serum. Using high K⁺ PSS to elicit contraction, the L-T relationship of control (CTL) and passively shortened (PS) preparations was examined and active tension recovery was measured on PS preparations. Formalin fixation, paraffin embedding, and morphometric analysis were used to measure the cross sectional area (CSA) of preparations, normalize the maximal active force (F[sub max]) and calculate the maximal stress (σ[sub max]. To examine the effect of muscle activation on passive tension recovery, using the same tissue preparation and culturing techniques, the recovery test was performed at Day 7 (or 8) PS preparations in the presence vs. absence of stimulations. Furthermore, the active recovery test was done on freshly isolated A SM preparations (Control Day 0; n = 5) and the active and passive force recovery rates were compared to those of the chronically length-adapted preparations (i.e. PS Day 7 or 8). Following 3 and 7 days of passive shortening (without stimulation), L[sub max] decreased by 10.6%±9.4 and 35.9%±15.9 (mean ±SD) respectively compared to the control preparations. There was also no significant change in σ[sub max] of PS smooth muscles compared to the control. After 7 days of passive shortening, it was either impossible to stretch the ASM preparations to their control lengths and/or they could not generate the same active force they did at their pre-stretched lengths. Following such a stretch, both active and passive force recoveries were incomplete. However, the passive tension recovery rate was not different in the presence vs. absence of muscle stimulations. It was observed that the active tension recovery could be initiated and progressed passively after stretching the PS preparations. Although the passive force recovery was greater than the active force recovery, these two processes were strongly correlated. Furthermore, the active force recovery was significantly slower in length adapted (Day 7 or 8) preparations compared to the CTL Day 0 group. However, the passive force recovery rate was not different between these two groups. I conclude that rabbit ASM is able to adapt to chronic shortening at body temperature even when it is not stimulated and the magnitude of the shift in L-T curve increases with time of length adaptation. By stretching a 7-day length adapted preparation to its original length, neither the active, nor the passive force could recover completely. Although muscle activation accelerates the active force recovery [14], it did not affect the passive force recovery. This result may have implications in asthma and COPD where chronic shortening of ASM could make the patients highly resistant to conventional bronchodilating therapies or to mechanical bronchodilating influences such as tidal breathing or deep inspiration.

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