INTRODUCTION

TOP ABSTRACT INTRODUCTION EFFECTS OF TIDAL STRETCH THE DYNAMICALLY DETERMINED FUNCTIONAL IMPLICATIONS REFERENCES

With the onset of a maximal contractile stimulus of isometric airway smooth muscle, myosin-actin cycling begins and the number of interactions (bridges) increases and approaches a plateau. During this process, rapidly cycling crossbridges convert progressively to slowly cycling latch bridges. This regulatory process eventually progresses to a steady state, and bridge dynamics are then said to have attained the latch state (1). In the latch state, the rate of bridge cycling has decreased to its smallest value attainable in maximally activated muscle (excepting the rigor state), the active force has increased to its maximum attainable value, and that value of the force defines one point on the static force-length characteristic of the muscle.

Like the unloaded shortening velocity after a quick release (Figure 1) and the rate of actomyosin ATP utilization, the hysteresivity of airway smooth muscle is also governed by the rate of bridge turnover. Because it can be measured continuously throughout the contractile event, whereas shortening velocity cannot, the hysteresivity provides a convenient window on the rate of bridge turnover and its changes in time. Using the muscle hysteresivity as a probe of bridge cycling rate, and muscle force and stiffness as probes of bridge numbers, we have extended the earlier work of Gunst and colleagues (4) and Sasaki and Hoppin (7). We studied isolated, maximally contracted tracheal smooth muscle and assessed the way in which the interactions of myosin with actin are altered as a result of imposed stretches that simulate the effects of tidal breathing.

View larger version (21K): [in this window] [in a new window]   Figure 1.   Velocity of shortening (in optimal lengths per second) on the left ordinate (open squares) and hysteresivity on the right ordinate (closed circles) measured as a function of time (t) after the onset of electrical field stimulation in canine trachealis. Maximal velocity (Vmax) was measured over the interval from 250 ms to 400 ms after the quick release to a small afterload, typically 1-2% of the maximum isometric force. Inset: regression line, Vmax = 1.91  + 0.0, r2 = 0.98, p = 0.0001, Fisher's z transform. (Reprinted with permission from Reference 3.)

	EFFECTS OF TIDAL STRETCH

TOP ABSTRACT INTRODUCTION EFFECTS OF TIDAL STRETCH THE DYNAMICALLY DETERMINED FUNCTIONAL IMPLICATIONS REFERENCES

We consider bovine tracheal smooth muscle mounted in a muscle bath (Krebs-Heinseleit solution, 37° C, aerated with 95% O₂-5% CO₂) and set to optimal length (Lo), where active force is maximal (Fo), and impose about Lo a sinusoidal length fluctuation of amplitude L (2L peak-to-peak) and frequency of 0.33 Hz, as might occur during tidal breathing. The amplitude of the imposed tidal stretch,  (L/Lo expressed as a percent), is maintained at a very small level, 0.25%, until the muscle is fully activated and the force versus length loop attains a steady-state configuration. Tidal stretch is then increased to either 0.5, 1, 2, 4, or 8%. From the resulting force versus length loops, we computed the mean force over the stretch cycle, F, the muscle stiffness, E, and the muscle hysteresivity, .

When  is maintained at 0.25%, addition of acetylcholine (ACh) to the bath (10⁴ M ACh at t = 100 s) causes E and F to increase monotonically and at similar rates (solid lines, Figure 2, top and center panels). Both attain plateau values within 300 s. Changes of , by contrast, are prominently dissociated from those of E and F (solid line, Figure 2, bottom panel). Addition of ACh causes  to follow a biphasic pattern in which it increases rapidly, peaks early in the contraction, and thereafter decreases slowly. Muscle hysteresivity also attains a plateau value within about 300 s. As with baseline values of passive muscle force and stiffness, the baseline value of muscle  is attributable to the passive mechanical properties of connective tissues. As such, these changes in  probably reflect rapidly cycling crossbridges early in the contractile event converting to slowly cycling latch bridges later in the contractile event.

View larger version (32K): [in this window] [in a new window]   Figure 2.   Time courses of total force averaged succeeding stretch periods (top panel ), stiffness (center panel ), and hysteresivity (bottom panel ) in a representative tracheal smooth muscle strip. Solid line in each panel corresponds to  maintained throughout at 0.25%. Broken lines correspond to runs in the same muscle subjected to graded increments of  from 0.25 to either 0.5, 1, 2, 4, or 8% over the time interval from 400 to 900 s. Control values are those measured at t = 400 s with  = 0.25%. (Reprinted with permission from Reference 10.)

Increasing tidal stretch amplitude causes F and E to decrease promptly and  to increase promptly, within two to three stretches (broken lines, Figure 2, where  was increased from 0.25% to a larger value at 400 s). The greater the increase in  , the greater are the resulting changes in F, E, and . Thereafter, the airway smooth muscle can be maintained in steady, dynamically determined contractile states that differ demonstrably from the state in isometric conditions. The plateau values of F, E, and  at t = 900 s are plotted versus  in Figure 3. F and E are expressed as a percent of their respective values measured at t = 400 s with  = 0.25%, which approximate isometric steady-state conditions. As  is increased from this level, F and E progressively decrease and  progressively increases (Figure 3).

View larger version (22K): [in this window] [in a new window]   Figure 3.   Plateau values (t = 900 s) of the stretch cycle (F) and the muscle stiffness (E) during tidal stretch expressed as a percent of control (values measured at t = 400 s with  = 0.25%); values of muscle hysteresivity () are absolute. The provocative stretch amplitude required to cause F or E to fall by half, or  to double, was slightly greater than 2%. (Reprinted with permission from Reference 10.)

	THE DYNAMICALLY DETERMINED MUSCLE STATE

TOP ABSTRACT INTRODUCTION EFFECTS OF TIDAL STRETCH THE DYNAMICALLY DETERMINED FUNCTIONAL IMPLICATIONS REFERENCES

These data show that maximally stimulated airway smooth muscle can be maintained in steady, dynamically determined contractile states for as long as the contractile stimulus and the tidal stretches are sustained. These states are characterized by graded stretch-effect relations in which the greater the tidal stretch amplitude, the greater are the departures of muscle force, muscle stiffness, and muscle hysteresivity from their values measured in conditions approximating the isometric steady state. The provocative stretch amplitude required to cause active force or muscle stiffness to fall by half, or hysteresivity to double, is slightly greater than 2%. Because muscle stiffness is a rough reflection of the numbers of actin-myosin interactions, and muscle hysteresivity is a rough reflection of the rate of turnover of those interactions (3), these results suggest that tidal stretch decreases the numbers of actin-myosin interactions and increases their turnover rate, although the effects of muscle plasticity may be important as well (8, 9). The dependencies of F, E, and  upon tidal stretch amplitude are uninfluenced by treatment of the tissues with tetrodotoxin and indomethacin, ruling out the importance of mechanisms based upon stretch-activated neural pathways or prostanoid release.

	FUNCTIONAL IMPLICATIONS

TOP ABSTRACT INTRODUCTION EFFECTS OF TIDAL STRETCH THE DYNAMICALLY DETERMINED FUNCTIONAL IMPLICATIONS REFERENCES

If muscle stretch scales isotropically as the cube root of lung volume change (10), then normal tidal lung inflations from functional residual capacity (FRC) would correspond roughly to  of 4%, a sigh from FRC would correspond roughly to  of 12%, and inflation from FRC to total lung capacity would correspond roughly to  to 25%. By contrast, the provocative stretch amplitude required to cause active force or muscle stiffness to fall by half, or hysteresivity to double, is slightly greater than 2% (Figure 3). Thus, small tidal stretches, even smaller than would be expected with normal tidal breathing, are seen to be a potent endogenous relaxing mechanism, and one that expresses its greatest sensitivity to muscle stretch remarkably close to the range that would be expected to occur during spontaneous breathing. Accordingly, it is conceivable if not likely that when airway smooth muscle of normal individuals is maximally stimulated, it operates on the part of the stretch- effect relationship (Figure 3) where force is profoundly inhibited (  4%). If so, then the isometric force-generating capacity of airway smooth muscle may not be applicable to the force generated in normal physiologic circumstances, even during maximal bronchial provocation.