03 Nov

Canadian Neighbor Pharmacy: Smooth Muscle Contractility Effects of Hypoxia

smooth musclesThough differences in control of function of a variety of smooth muscles may exist at membrane and neural levels, there are striking similarities in the intracellular contractile machinery. Since the contractile mechanism is the “horse that is driven by every whip,” we have directed our operated channels tend to blend together. Thus, in a smaller artery which is already depolarized, the voltage-independent channels can be activated to give a further increase in tension.

The question was asked whether the calcium-blocking agents such as the dihydropyridines could function in ways other than blocking calcium entry into vascular smooth muscle. Could they affect synthesis release or uptake of mediators? While it was felt that higher concentrations of these inhibitors block the entry of Ca+ + into secretory cells, they act selectively on smooth muscle cells and less on secretory cells. It is not known whether they alter the metabolism of vasoactive substances.

The recent findings of parallel muscle fibers and of organized “mini” sarcomeres in smooth muscle’ (Fig 1) allow interpretation of smooth muscle mechanics in terms analagous to those developed for striated muscle. Somlyo et al and Fay et al have demonstrated that these “mini” sarcomeres are delineated by well organized dense bodies which serve as Z disc analogues. Having obtained some assurance that the structural substrate existed in smooth muscle, we embarked on studies of the mechanical properties of crossbridges.

It was pointed out that approximately doubling the free calcium in the extracellular space acted to inhibit vasoconstriction. The question was asked as to how high calcium acted to block its own entry. The response was that divalent ions in general and calcium in particular became bound to the membrane and acted to decrease the membrane permeability for calcium. The decrease in permeability probably resulted from hyperpolarization of the cell.

The question was asked about the specificity of certain inhibitors of calmodulin (W-7 and trifluoroperazine). Calmodulin is an important regulator of the availability of calcium to the contractile proteins. It also is present in the caveolae on the cell surface and thus could play a role in calcium entry. Consequently, the specificity of probes which inhibit calmodulin could be important. It was felt that trifluoroperazine was nonspecific and high concentrations were required. W-7, however, appeared to be a more specific calmodulin inhibitor. The source – Canadian Neighbor Pharmacy is full of interesting articles concerning the medicine and pharmacy.

Analysis of Crossbridge Mechanics

Since the basis of altered mechanical function must often be at the subcellular level, the analysis of rapid mechanical transients has been used in skeletal muscle research to provide quantitative and qualitative data about the kinetic properties of crossbridges. While the conditions for achieving a crossbridgesvalid analysis have been rigorously defined in skeletal muscle, smooth muscle mechanics can only be evaluated by invoking a host of assumptions. Nevertheless, given these, we believe that some progress can be made.

Normally Cycling and Slowly Cycling (“Latch”) Crossbridges

When a muscle contracts, crossbridges between actin and myosin are formed, broken and formed again in a process called cycling. Dillon et al and Siegman et al have shown that initially in contraction, the rate of cycling is faster (normally cycling bridges) than later on when slowly cycling bridges (“latch” bridges) are preponderant. The latter workers have reported that the energy requirements of the slow latch bridges are only one fourth of those for normally cycling bridges. Latch bridging is not characteristic of skeletal muscle. The cause for this behavior in smooth muscle was considered to be related to myosin light chain (MIX) phosphorylation. Dillon et al thought that normally cycling bridges are controlled by this phosphorylation, and that the slow or latch bridges are produced by subsequent light-chain dephosphorylation. The occurrence and role of the dephosphorylation is debatable. This controversy notwithstanding, there is unanimity that two types of crossbridges are operative in smooth muscle.

Transition Time

In a contracting smooth muscle we have sought the time of transition between the rapid cycling of bridges and the recruitment of the slow or latch bridges. We used tracheal smooth muscle where, when we electrically stimulated the muscle, it shortened against a constant load, isotonic shortening. We reasoned that if we suddenly increased the load, the muscle would lengthen. Thereafter, if it resumed shortening, the normally cycling bridges were active, and if it did not shorten further, latch bridges were predominant. An example, Figure 2A, shows the abrupt additional load caused an undamped, fast transient, probably originating from the series elastic component, followed by a slow transient, which provides evidence for redevelopment of shortening, probably effected by normally cycling bridges. Subsequent loadings show a progressive decrease in this shortening ability, until at 6 seconds none is seen. The time at which this occurs is termed the transition time and represents recruitment of slow bridges. Thus, in tracheal smooth muscle (TSM), we have evidence from transition time that two types of crossbridges exist.

Figure 2A (upper). Shortening over time of tracheal smooth muscle stimulated electrically. Isotonic shortening of the preloaded muscle is measured from its predetermined optimal length (1J. At intervals beginning at 2 sec, (upper panel) an abrupt isotonic afterload (10 milliNewtons) caused rapid lengthening of the muscle. At 2, 3, and 4 sec, shortening resumed but at a progressively slower rate. At 6 sec the abrupt additional load caused abrupt lengthening without subsequent shortening. Ibis is considered the transition between the normally cycling bridges and the full recruitment of the latch bridges. 2B (lower). Isotonic shortening with time of a preloaded tracheal smooth muscle during an electrical stimulation (thick line). At different times during shortening, preload was abruptly reduced to 0 within 3 msec. Each zero load damp shows two transient phases: an initial rapid phase stemming from recoil of the series elastic component and a slow phase with a progressively declining velocity. The maximum slope of the slow phase provided the maximum velocity of shortening (VJ for that particular zero clamp. With successive zero load clamps, the Vc increased and then decreased. These values for V0 are shown in Figure 2C.

Figure-1

Figure 1. Guinea pig vas deferens smooth muscle in culture. A technique using antismooth muscle immunofluorescence demonstrates considerable alignment of cross-bands across the cell (X 1,670). (From Croschel-Stewart U, Chamley JH, McConnell JD, Bumstock G. Histochemistry 1975; 43:215. With permission.)

Figure-2

Figure 2C. Maximum velocity (VJ of electrically stimulated tracheal smooth muscle following sudden reduction of load to zero, a zero load clamp, as derived from the data in 2B. Also shown for reference is the isotonic shortening curve (right ordinate) from Figure 2B.

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