or a poet, is a maker of patterns.The mathematician's patterns, like the painter's or the poet's, must be beautiful; the ideas, like the colours or the words, must fit together in a harmonious way."In our opinion these sentiments also apply to all other areas of science.The work of Andrew F. Huxley (who passed away on May 30, 2012) is one of the finest examples not only because of its importance to applied mathematics, biomathematics, and physiology but also because of the beauty of the underlying conceptual framework.

Sir Andrew Huxley, grandson of T.H. Huxley and younger half-brother of Aldous and Julian Huxley, died May 30, 2012, at age 94.

those of us who pursue biological research do so mainly because of the intellectual satisfaction derived from making discoveries. But we are blessed with generous grants from our governments whose motivations are more practical and include improving the health of our populations, promoting new

Although acute hypertensive pulmonary edema is sometimes regarded as the most severe form of heart failure, at the peak of symptoms, hearts perform well above resting levels and cannot be said to be failing. Another characteristic of the condition, the rapidity of its onset and reversal when properly treated, suggests positive feedback as a causal mechanism. It is proposed that the syndrome results from a feedback loop with increased sympathetic tone as the efferent output, increased pulmonary vascular pressure as the stimulus to increased sympathetic tone, and positive feedback occurring because elevated sympathetic tone constricts systemic veins, thereby transferring blood from peripheral veins to the pulmonary vasculature. Evidence for the proposed mechanism derives from all the empirical treatments that have evolved. All remove blood from the pulmonary circuit, and all but the oldest, bloodletting, do so by transferring blood from the pulmonary circuit to the peripheral veins.

Postnatal decreases in vascular reactivity involve decreases in the thick filament component of myofilament calcium sensitivity, which is measured as the relationship between cytosolic calcium concentration and myosin light chain (MLC20) phosphorylation. The present study tests the hypothesis that downregulation of thick filament reactivity is due to downregulation of myosin light chain kinase (MLCK) activity in adult compared with fetal arteries. Total MLCK activity, calculated as %MLC20 phosphorylated per second in intact arteries during optimal inhibition of myosin light chain phosphatase activity, was significantly less in adult (6.56+/-0.29%) than in fetal preparations (7.39+/-0.53%). In situ MLC20 concentrations (microM) in adult (198+/-28) and fetal arteries (236+/-44) did not differ significantly. In situ MLCK concentrations (microM), however, were significantly greater in adult (8.21+/-0.59) than in fetal arteries (1.83+/-0.13). In situ MLCK activities (ng MLC20 phosphorylated.s(-1).ng MLCK(-1)) were significantly less in adult (0.26+/-0.01) than in fetal arteries (1.52+/-0.11). In contrast, MLCK activities in adult (15.8+/-1.5) and fetal artery homogenates (17.3+/-1.3) were not significantly different. When in situ fractional activation was calculated, adult values (1.72+/-0.17%) were significantly less than fetal values (9.08+/-0.83%). Together, these results indicate that decreased thick filament reactivity in adult compared with fetal ovine carotid arteries is due at least in part to greater MLCK activity in fetal arteries, which in turn cannot be explained by differences in MLCK, MLC20, or calmodulin concentrations. Instead, this difference appears to involve age-related differences in fractional activation of the MLCK enzyme.

It has been reported that sensitization of animals to allergens increases both early shortening velocity and myosin light-chain kinase of their airway smooth muscle without increasing force generated by these muscles. Since early shortening sets muscle length for the duration of a contraction, these responses might be expected to produce greater airway obstruction. Here, it is explained how the more rapid early shortening without increased force production is predicted by the 2-stage process of activation followed by contraction posited by the crossbridge theory of contraction when the rate, but not the extent, of activation is increased. The experimental results are reproduced by a simple model in which activation rate is increased 1.6-fold without any other changes in contractile parameters. These results reinforce suggestions that sensitized animals are a model for reactive airway disease.

The full functional length range of trachealis muscle was measured to identify a precise reference length and to assess the length changes that the myofilament lattice can accommodate. The initial reference length (L-10%) was that where rest tension equaled 10% of total force (passive tension plus active force). Total force at this length served as a force reference (F-ref = 219 +/- 12 kPa, N = 7). Muscles initially adapted at L-10% for 30-60 min had no rest tension when shortened to < 0.9 L-10%. Passive tension rose steeply and linearly with slope 11.2 F-ref/L-10% at lengths > 1.04 L-10%. Rest tension at 1.1 L-10% declined by < 10% over 1 h. The steep slope and stability of rest tension at long lengths suggest that a parameter of the slope could serve as a precise, reproducible reference length. Active force was nearly constant at lengths 0.33-1.0 L-10% and declined steeply at lengths between 0.1 and 0.2 L-10%, extrapolating to zero at 0.076 L-10%. Muscles visibly reextended during relaxation at lengths < 0.25 L-10%. At long lengths, force extrapolated to zero at 1.175 L-10%. The > 15-fold length range (0.076-1.175 L-10%) for force generation and nearly constant force over a greater than threefold length range is likely produced by several structural accommodations, including filament sliding, an increased number of sliding filaments in series, and increased length of passive structures in series with the sliding filaments. Visible reextension during relaxation suggests that the lattice does not undergo plastic adaptations at lengths < 25% L-10% and that lattice plasticity is limited to a three- to fourfold length range.

anyone contemplating dynamic roentgenograms of hollow viscera must be impressed that the length changes in the smooth muscles that comprise their walls are larger than the threefold range produced by skeletal muscle having a fixed filament array ([1][1]), and studies of muscles isolated from these

Reviewed by: A Life of Ernest Starling Lincoln E. Ford A Life of Ernest Starling. By John Henderson. Oxford: Oxford Univ. Press/American Physiological Society, 2005. Pp. xvi + 227. $59.50. This brief, well-written book will be very useful to anyone wanting to understand the origins of modern British physiology or to know the large personalities involved. It should be required reading for anyone teaching Starling's work on the heart. A place in scientific history is often marked by an accomplishment that can be summarized by a single phrase. In the case of Ernest Starling (1866–1927), it was his "Law of the Heart," the title of his 1918 Linacre Lecture, describing his 1914 work with Patterson and Piper. Most medical and physiology students will also have heard about the "Starling Principle" of fluid balance between capillaries and extracellular fluid, and know that this principle derives from his discovery that the osmotic pressure of blood proteins balances hydrostatic pressure in the capillaries. Only a few will know that he developed this principle as part of his research on lymph formation, which he showed to be a purely passive process, thus contradicting a secretory hypothesis put forward by Heidenhain a short time before. Some scholars will know that Starling and Bayliss coined the word hormone to name their discovery of the first hormone, secretin. However, without biographer John Henderson's research, very few would know that the discovery of secretin [End Page 633] made Starling a leading candidate for a Nobel Prize, until World War I suspended the awards. Starling's other accomplishments include: the discovery that omitting insulin from the perfusate of an isolated heart greatly reduces glucose uptake; the finding that glomerular filtration is a purely passive process, not the active secretory mechanism proposed by Heidenhain; the discovery with Bayliss that sympathetic stimulation increases heart rate while vagal stimulation lowers heart rate; the discovery, also with Bayliss, of peristaltic activity in the gut. Although intestinal contractions had been described earlier, Starling and Bayliss's finding of coordinated activity that moved semi-solid boluses along the gut brought substantial order to an area previously dominated by chaos and confusion. In addition to his scientific genius, Starling was a remarkably warm and loyal person. His professional life was closely interwoven with personal relationships. William Bayliss married his sister, Sydney Patterson married his favorite daughter, and Starling himself married a colleague's widow. A strong sense of loyalty to Guy's Hospital, where he qualified in Medicine in 1889, also kept him from accepting a prestigious position at Oxford in 1892, even though he was woefully underpaid and poorly treated by his colleagues at Guy's. After reviewing the available correspondence and the minutes of the Guy's Hospital Board, Henderson concludes that Starling was not well liked by his colleagues there, and that the cause of this dislike was almost certainly jealousy. After turning down the offer of a permanent job at Oxford, Starling was also forced to turn down a subsequent invitation from Burden Sanderson to give the student lectures in physiology at Oxford, when a colleague at Guy's refused to alter the lecture schedule. Henderson also points out that Frederick Gowland Hopkins, who was awarded the 1929 Nobel Prize for his discovery of vitamins, was in precisely the same position at Guy's and was rescued from it by an offer of a position in physiology at Cambridge, where he later became the first professor of biochemistry. In spite of the hardships at Guy's, and perhaps because of the lack of distractions that might have been afforded by adequate salaries, both Starling and Hopkins were very productive there. In addition to their research, they have been credited by other authors with helping to design and build new laboratories for the Guy's Medical School, although Henderson admits that he was unable to document their precise contributions in the minutes of the Medical School Committee. Starling was elected a fellow of the Royal Society early in 1899, about the time of his 33rd birthday, and later in the same year he applied for the Jodrell Chair of Physiology in University College. The competition was stiff and...

Muscle birefringence, caused mainly by parallel thick filaments, increases in smooth muscle during stimulation, signalling thick filament formation upon activation. The reverse occurs in skeletal muscle, where a decrease in birefringence has been correlated with crossbridge movement away from the thick filaments. When force generation by trachealis muscle was inhibited with wortmannin, which inhibits myosin light‐chain phosphorylation and thick‐filament formation, but not the calcium increase caused by stimulation, the birefringence response inverted, suggesting crossbridge movement similar to that of skeletal muscle. Resistance to quick stretches was much greater in stimulated muscle than in unstimulated muscle before wortmannin treatment and no different in stimulated and unstimulated muscle after force inhibition by wortmannin. Before wortmannin treatment, stimulation reduced thick‐filament cross‐sectional areas in electron micrographs by 44%. After force inhibition by wortmannin, filament areas were not significantly different in stimulated and unstimulated muscle and not significantly different from those of relaxed muscle without wortmannin treatment. These results suggest that myofibrillar‐space calcium causes crossbridges to move away from the thick filaments without firmly attaching to thin filaments.

Reviewed by: Collapse: How Societies Choose to Fail or Succeed Lincoln E. Ford Collapse: How Societies Choose to Fail or Succeed. By Jared Diamond. New York: Viking, 2004. Pp. 592. $29.95. Jared Diamond has done it again. In 1997, he burst into the reading public's consciousness with a Pulitzer Prize–winning book, Guns, Germs, and Steel, a work of awe-inspiring scholarship and sweeping breadth that explained how Europeans and their culture came to dominate the world. Diamond explained the large disparity between wealth and technology in different parts of the world as an accident of geography. The temperate latitudes of Eurasia facilitated the East-West dispersion of species over an extensive area, allowing a diversity of plants and animals to be domesticated, and this domestication led to increasing civilization as nomadic hunter-gatherers put down roots and progressed in their communities from families to tribes to villages, cities, nations, and empires. By contrast, the Americas with their North-South axis had little opportunity for the diffusion of species and thus were much slower to develop. China lagged behind Europe for different geographical reasons. The mountains, rivers, and irregular coastline of Europe ensured its division into competitive nation-states, which fostered technological development and the rise of a merchant class. With its regular coastline, absence of mountain ranges dividing its mid-section, and two navigable rivers connecting much of the country, [End Page 464] China was easily ruled for millennia by a central government that did not encourage development. Although many of the technical inventions, such as gunpowder and large ships, were made about the same time as in Europe, these discoveries were not put to the same effective use. And this, in a nutshell, is why the modern world is dominated by Europeans and their wares. Guns, Germs, and Steel has been criticized by some as being too "deterministic." To me, this is not a criticism but one of the book's virtues. The author marshals his facts with such logical order that the outcomes seem inevitable. In Collapse, Diamond provides further insight into where we could be going, through case examples of societies that have either perished or survived. He extends his insights into the interactions between geography and societies to explore how man's interaction with his environment affects societies. From analysis of these case studies, he has identified five factors that determined whether a society succeeded or failed: environmental damage; climate change; hostile neighbors; lack of friendly trading partners; and, most important, the society's response to the first four factors. In general, none of these factors by itself has brought down a society, but collectively they bring doom. Diamond analyzes both large and small communities, some that have lasted for millennia. On the survival side, he examines Tikopia, an isolated island of 1.8 square miles that has been settled and inhabited continuously for 3,000 years, currently by about 1,200 people or 700 people per square mile. A larger example of success is the New Guinea Highlands, an isolated civilization that was not discovered by modern man until air travel revealed its existence. At 7,000 years, it is one of the world's longest-running experiments in sustainable food production. These successes are contrasted with Easter Island and the Pitcairn Islands, which were once extensively populated by relatively sophisticated Polynesians but were nearly completely depopulated by the time they were discovered by Europeans. Diamond compares the Norse settlements that survived in Greenland for nearly 500 years and collapsed entirely in the early 1400s when the climate became colder with the successful Norse colony of Iceland and the Inuit civilization, both of which continue to thrive in the same inhospitable climate. He also compares Haiti and the Dominican Republic, two countries that occupy the island of Hispaniola. Both have recently emerged from prolonged periods of dictatorship, with Haiti as the Western Hemisphere's basket case and the Dominican Republic as one of the most popular tourist destinations in the Caribbean. How did this happen? It turns out that Trujillo and Belaguer were more far-sighted dictators than the Duvaliers. In presenting these cases, Diamond describes some modern societies that may or...

EDITORIAL FOCUSThe importance of maturational studies in airway smooth muscleLincoln E. Ford, and Susan H. GilbertLincoln E. Ford, and Susan H. GilbertPublished Online:01 Dec 2005https://doi.org/10.1152/ajplung.00328.2005MoreFiguresReferencesRelatedInformationPDF (53 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat asthma affects 17.7 million Americans, 5 million of them children (41). Its incidence has more than doubled in the general population since 1980, with a disproportionate increase in children under the age of 4 (41). Measures of the yearly burden of this disease, 5,500 deaths (31), nearly $6 billion in direct treatment costs, and a total of >$25 billion in all costs, including lost productivity, costs of concomitant conditions, as well as treatment costs, place asthma among the five most burdensome diseases in the United States (6). But even these numbers fail to capture the costs of impaired development and the emotional toll taken by this chronic illness in children. These facts are marshaled to call attention to the importance of the study of the basic mechanisms of asthma, particularly in two papers bearing upon these mechanisms (Refs. 43 and 44, see pp. L902 and L909, respectively, in this issue).Although asthma and reactive airway disease are commonly believed to result from immune responses in the lungs, manifest by eosinophils and mast cells in the bronchi, there is ample evidence that airway smooth muscle hyperresponsiveness is equally important. Perhaps the most direct evidence is that hyperreactive airways are defined by their augmented response to methacholine, which stimulates the muscle directly and not through immune or inflammatory pathways. Other evidence for nonimmune causes of wheezing include the not infrequent absence of immune-reactive cells in the bronchi (45) and the observation that nonspecific airway inflammation, such as a new viral infection, can initiate prolonged periods of wheezing (26). Evidence reviewed at the end of this editorial suggests that there is at least one “asthma phenotype” resident within the muscle that is expressed in response to immune stimuli and that remains dormant until the muscle is activated by nonimmune stimuli.Asthma frequently begins at a young age and lasts for life. But reactive airway disease of children may have three distinct clinical courses (25): one begins in infancy and disappears during early childhood; a second begins in infancy and continues for the life of the affected person; and a third begins in later childhood and continues into adulthood. These observations raise intriguing questions regarding maturational changes in the airway that occur during childhood. Understanding the nature of these changes could identify targets for therapies both to curtail the continuation of infantile wheezing into adulthood and to prevent the development of asthma in childhood and later life. Wang et al. (43, 44) describe maturational changes in the contractile mechanics of airway smooth muscle, which is likely to become a fertile area of investigation.Most muscle scientists would likely agree that striated muscle is better understood than smooth muscle. This better understanding comes largely from the correlations between muscle function and the structures that produce the striations. Because these structures are common to all striated muscle, information gained in one muscle is often transferable to another, so that for many purposes, there is a single large community of striated muscle investigators. The situation is different in smooth muscle, which is richer in the diversity of its characteristics and mechanisms. Examples include: 1) the type of contractions produced [tonic in vascular muscle, phasic in visceral muscle (39)], 2) the different responses to agonists and antagonists, and 3) the functional length range [long in muscles of the urinary bladder (42) and airway muscle (30), short in arterial muscle (29)]. These large tissue differences have understandably fragmented the study of smooth muscle into distinct tissue groups with much less cross fertilization of ideas. There is a robust community of scientists studying airway muscle, but given their relatively small number, only scant attention has been paid to maturational changes in this muscle. This deficiency is now being rectified by the Pediatric Research Unit at Duke University, which contributed the two articles in focus here.In discussing these two articles, we call on our prior experience in striated muscle to draw parallels with the newer work in smooth muscle. Finally, we suggest how a theory of skeletal muscle contraction can explain one model of an asthma phenotype.Maturational changes in airway smooth muscle velocity.The first of the two papers (43) extends a prior study by the same group (2) showing that isolated airway smooth muscle from juvenile (3-wk-old) guinea pigs shortened faster than muscles from both newborn (1-wk-old) and adult (3-mo-old) animals. Maximum velocities were assessed from complete force-velocity curves, which is a more reliable way of assessing shortening capability than single measurements of unloaded shortening (7). Analysis of the curves suggested that the higher velocity in juvenile muscle was associated with a lower resistance to shortening. In this first paper, the authors applied oscillations to stimulated and unstimulated muscles from animals in the three age groups and found that the only age-related difference was reduced stiffness and viscosity in the unstimulated juvenile muscles. This leads to the logical hypothesis that the reduced passive stiffness and viscosity in the juvenile group impose less load on contractile elements of the muscles in this age group.But a different interpretation is suggested by similar maturational changes in cardiac muscle discovered decades ago (reviewed in Ref. 47). There are two cardiac myosin heavy chain isoforms, α (fast) and β (slow), that are expressed in different proportions to alter the speed of muscle contraction as animals mature. Could it be that there are similar maturational changes in myosin isoforms in airway smooth muscle? There are known to be different myosin isoforms in airway smooth muscle (38), and the isoforms produce different shortening velocities in motility assays (32). These considerations raise the question of the relative preponderance of different isoforms in muscles from different age groups. If substantial differences are found, intact muscles from animals of different ages could be used to explore the physiology of the different isoforms in whole muscle, as they were in cardiac muscle.The suggestion that the higher shortening velocity in the juvenile muscle could result from a faster myosin isoform raises the question of how the finding of a lower stiffness and viscosity in the unstimulated juvenile muscle fits into the overall scheme. One possible explanation is that the oscillations induce more resting tone in unstimulated newborn and adult muscle. Suggestively, in the second paper in focus here (44), Wang et al. found that oscillations of newborn muscles increased force in subsequent tetani, although there is not yet data to indicate whether oscillations partially activate unstimulated muscle. Because activation is controlled by myosin light chain phosphorylation, this hypothesis could be tested by measuring phosphorylation levels in oscillated muscles from different age groups, a necessary control before stiffness measurements in unstimulated muscle can be accepted as truly passive.Maturational changes in airway muscle response to oscillations.In the second article in focus (44), the same authors showed that length oscillations applied to the relaxed muscle reduced force by 15–20% in tetanic contractions immediately following the oscillations. In juvenile and adult muscles, tetanic force recovered toward its preoscillation level over several tetani, but in muscles from newborn animals, it increased over 2 tetani to a level ∼10% above the control level and remained at that augmented level for at least 6 additional tetani. To explore possible explanations of this curious result, the authors assessed the effect of cytochalasin D, which blocks the addition of actin monomers to actin filaments. They first established conditions (10−7 M, 20-min exposure) that did not alter force during electrically stimulated tetani in nonoscillated muscle and then showed that this concentration: 1) nearly doubled the initial force deficit caused by the oscillation in all three age groups, 2) eliminated differences between muscles from different age groups, and 3) caused the level toward which force recovered in all three groups of muscles to be reduced to 80–85% of the preoscillation level. They then showed that indomethacin, known to inhibit the intracellular cyclooxygenase pathway, eliminated the oscillation-induced force potentiation in newborn muscle and reduced the initial force reduction caused by oscillation in both newborn and adult muscle.The effects of cytochalasin D in the first set of observations suggest that the initial force reduction caused by oscillation is due, at least in part, to a disruption of the filament lattice. Some smooth muscles, including airway smooth muscle, differ from skeletal muscle in that they rapidly adapt their filament structures to maintain nearly constant force over a much wider length range than could be accommodated by the fixed array of filaments in striated muscle (30). We have proposed (9, 30) that this lattice plasticity is enabled by thick-filament evanescence, with thick filaments dissociating partially during relaxation and reforming upon activation. Our initial proposal was founded on early electron microscope studies of smooth muscle (22, 34, 35), and thick-filament evanescence has since been confirmed both by electron microscopy (11, 14, 15, 46) and by optical birefringence (11, 12, 37). Experiments similar to the present ones have been done in adult pig muscles, and the transient decline in developed force following oscillations has been correlated with a decline in thick-filament mass (24). Thus it is expected that the decline in force immediately following oscillations in the guinea pig is associated with a decline in thick-filament mass. The observation that cytochalasin D increased the force deficit following oscillations and decreased the level toward which force recovered suggests that actin filaments may also be depolymerized by the oscillations.Our colleague at Indiana University, Dr. Susan Gunst, has proposed a theory of filament lattice plasticity based on actin filament evanescence (13, 27). It seems likely that we are all looking at different aspects of the same phenomenon, and the effects of cytochalasin D in the present experiments strengthen this likelihood. Support for Dr. Gunst's theory of thin-filament plasticity is based on the finding that inhibitors of thin-filament formation reduce force production. The finding that cytochalasin D inhibits the recovery of force attributed to thick-filament reformation suggests that thick- and thin-filament formation are linked.The force potentiation following oscillations in the newborn muscle and its abolition by indomethacin are likely caused by increases in activation rather than by changes in the filament lattice, and it reveals interactions between intracellular signaling pathways not present in striated muscle. The authors have previously shown that (2, 3): 1) adult muscle stimulated electrically for long periods relaxes spontaneously in spite of continued stimulation, 2) newborn muscle maintains tension during continued stimulation of the same duration, 3) several prostanoids are more abundant in newborn muscle, and 4) indomethacin causes the newborn muscle to relax spontaneously in the presence of continued electrical stimulation, in a manner similar to adult muscle. Others have shown that indomethacin inhibits stretch activation in adult guinea pig tracheal muscle (10). Together, these findings suggest that elevated intracellular prostanoids contribute to hyperreactivity of newborn guinea pig muscle and that this signaling pathway can modulate the activation produced by direct stimulation of the muscle. Although the precise mechanisms have yet to be defined and the signaling pathways may differ in humans (36), these results open new avenues of investigation and suggest possible targets for treating wheezing in infants.An asthma phenotype.As discussed above, several lines of evidence suggest that airway hyperresponsiveness is partly due to changes in the contractile apparatus that lead to an asthma phenotype. Thus a scientific and clinical issue is to discover the number and nature of these phenotypes. Evidence for one possible phenotype comes from the group in Winnipeg who first developed an animal model in which one-half of a litter of mongrel dogs were injected with ragweed pollen (sensitized) while the other half served as “littermate controls” (23). When muscles from both sensitized and control animals were stimulated electrically, force rose to its plateau level in ∼10 s. The rate of rise and the final level of force were similar in both types of muscle (1); however, muscles from the sensitized animals had significantly higher shortening velocities for the first 2 s of stimulation and achieved substantially shorter lengths when allowed to shorten under light load early in the tetanus (40). This potential for more extensive early shortening would facilitate greater bronchoconstriction when the smooth muscle is first stimulated and could therefore be an asthma phenotype. Chemical assays revealed that myosin light chain kinase was significantly increased in the sensitized animals (21).We focus on this work because it is not intuitively obvious that an increase in activating enzyme would increase only the velocity and extent of shortening at light loads early in a contraction without affecting later force or shortening and without substantially altering the rise of isometric force. But these results are easily explained by the original, two-state, cross-bridge theory proposed by A. F. Huxley in 1957 (18) to demonstrate how a sliding filament mechanism produces the force, shortening, and heat rates measured in skeletal muscle (16).In this model, force and shortening were assumed to be generated by sidepieces extending from the myosin filaments that cyclically attached to and detached from actin filaments, so that the two states were attached and detached. By endowing each bridge with an internal spring that supported force between the filaments when the bridge was attached and by judicious choice of functions to describe the attachment and detachment rates for crossbridges, Huxley (18) quantitatively reproduced the mechanical behavior of skeletal muscle. By allowing one ATP molecule to be hydrolyzed per cross-bridge attachment-detachment cycle, he reproduced the heat data.The model has since been expanded to include additional states (19) to account for more recently discovered mechanical “transients” that occur when attached cross bridges undergo movement that alters spring tension (20) and for chemical reactions that must occur as ATP is consumed. But this recent emphasis on more complex models does not detract from the utility of the original theory in explaining steady-state behavior when attachment and subsequent force generation are lumped into a single transition, and chemical reactions are assumed not to affect these mechanical transitions.The model is already familiar in the airway smooth muscle community, having been used by a group at the Harvard School of Public Health to model aspects of tracheal muscle behavior (28). Only one aspect of the model is needed for the current discussion. This relates to events during the rise of force in a tetanic contraction.In his classic description of “active state,” A. V. Hill (17) proposed that muscle was activated almost instantly and that the observed slow force development was due to internal shortening of the contractile elements as they stretched the series elastic elements. Huxley (18) offered a different explanation, that the slow force development is not necessarily due to internal shortening but to slow attachment of bridges in the fully activated isometric muscle. This explanation has been confirmed by the finding that force rises relatively slowly when the sarcomeres are held rigidly isometric, so that there is no internal shortening, and that stiffness, taken as a measure of attached cross bridges, rises only slightly faster than force (8). In contrast to the slow rise of isometric force, the model predicts, and experiment confirms, that shortening velocity under a constant load achieves its steady value very rapidly, within the time taken to shorten ∼0.1–0.15% of muscle length (5), equivalent to ∼1 cross-bridge stroke length. Rapid attainment of steady shortening occurs because bridges detached by the shortening begin new cycles according to the new steady conditions. The disparity between the slow rise of isometric force and the rapid approach to steady shortening velocity under light loads early in a tetanus is precisely the mechanism to explain the results from Winnipeg. More rapid activation, caused by more abundant light chain kinase, will not substantially increase the rate of force development because this is determined largely by the rate of cross-bridge attachment under isometric conditions. It will also not increase the final level of force achieved because the force developed during a tetanus is near the maximum that the muscle can achieve, but it will significantly increase the ability of the muscle to shorten under light loads early in the contraction.The importance of the Winnipeg experiments is that they explain how immune reactions can lead to expression of an altered smooth muscle phenotype that will produce bronchospasm when the muscle is first activated. Their relevance to the articles in focus is that they show how events in early development can alter the expression of the muscle phenotype to make it hyperresponsive.The two articles in focus open a window on important changes that occur in airway smooth muscle as an animal matures. These studies emphasize both the relevance of mechanical measurements of muscle activity in the study of reactive airway disease and the importance of maturational changes in the development and maintenance of asthma. The work completed thus far already suggests likely areas to search for therapeutic targets for treating airway hyperreactivity in infants and young children and for preventing the development of hyperresponsive airways in susceptible children.AUTHOR NOTESAddress for reprint requests and other correspondence: L. E. Ford, Krannert Institute of Cardiology, Indiana Univ. School of Medicine, 1800 No. Capitol Ave., Indianapolis, IN 46202 (e-mail: lieford@iupui.edu) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationREFERENCES1 Antonissen LA, Mitchell RW, Kroeger EA, Kepron W, Tse KS, and Stephens NL. Mechanical alterations of airway smooth muscle in a canine asthmatic model. J Appl Physiol 46: 681–687, 1979.Link | ISI | Google Scholar2 Chitano P, Wang J, Cox CM, Stephens NL, and Murphy TM. Different ontogeny of rate of force generation and shortening velocity in guinea pig trachealis. 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Pabelick15 October 2012 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 303, No. 8Regulation of Lower Airway FunctionDisruption of NO-cGMP signaling by neonatal hyperoxia impairs relaxation of lung parenchymaRamadan B. Sopi, Musa A. Haxhiu, Richard J. Martin, Ismail A. Dreshaj, Suneel Kamath, and Syed I. A. Zaidi1 October 2007 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 293, No. 4 More from this issue > Volume 289Issue 6December 2005Pages L898-L901 Copyright & PermissionsCopyright © 2005 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00328.2005PubMed16280458History Published online 1 December 2005 Published in print 1 December 2005 Metrics Downloaded 141 times 4 CITATIONS 4 Total citations 0 Recent citations 0.58 Field Citation Ratio 0.08 Relative Citation Ratio publications3supporting0mentioning2contrasting0Smart Citations3020Citing PublicationsSupportingMentioningContrastingView CitationsSee how this article has been cited at scite.aiscite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

W hen a muscle is stimulated electrically, its ability to contract rises and then falls. It is conceptually easy to imagine, therefore, that something called the "active state" might rise and fall with a well-defined time course. Although the concept is simple, the attempts to measure this time course have produced such conflicting results that the whole concept has fallen into disrepute.1 These conflicting results generally are attributed to the fact that the perturbations used to make the measurements frequently altered the active state. Another good reason is that many different parameters were being measured as a reflection of the active state, and some of them may have been inappropriate. As a result, the terms "active state" and "activation" became imprecise and vague, even though they have remained in general use and embody a potentially useful concept. As the concept of active state became more imprecise, interest among muscle physiologists shifted away from this area to studies of the individual mechanisms responsible for activation. These newer studies were made possible by the development of chemical techniques that permitted the exploration of molecular mechanisms. Many of these mechanisms now have been elucidated, and the first purpose of this review is to describe them. This description leads to a definition of what is meant, and what is not meant, by the term "activation." The second, and major, purpose of this review is to examine the changes in contractile properties of muscle that accompany changes in activation. In the course of this examination, an effort will be made to define mechanical parameters that signal changes in activation. As with the first section, emphasis will be given to showing that some parameters do not accurately signal changes in activation. A third and final purpose of the article is to review the history of the

Birefringence and force produced by pig tracheal smooth muscles were recorded every 100 ms during electrically stimulated tetani at muscle lengths that varied 1.5‐fold and at the peak of acetylcholine contractures at the same lengths. Isometric force was nearly the same at all lengths. Resting birefringence at the longest length was 30% greater than that at the shortest length. During tetani, birefringence increased with approximately the same time course as force, rising by 20% at the shortest length and 9% at the longest length, and continued to increase by an additional 0.5–1.5% of the resting value for 2–8 s after stimulation ended and force began to fall. This late increase was greatest and more sustained at longer lengths. During contractures, birefringence increased by 25 and 18% at the shortest and longest lengths, respectively. Comparison of these results with our published thick‐filament densities suggests that thick‐filament density increased by about 80, 72 and 50% during contractures at the short, intermediate and long lengths, and that ∼35% of birefringence in the resting muscle at the longest length was not due to thick filaments. These findings support the hypotheses that tracheal smooth muscle adapts to longer lengths by increasing thick‐filament mass and that myosin thick filaments are evanescent, dissociating partially during relaxation and reforming upon activation. The results further suggest that thick‐filament formation is sufficiently rapid to account for the velocity slowing and some of the force increase observed during the rise of activation of tracheal smooth muscle.