Force-velocity properties of two avian hindlimb muscles

Recent work has provided measurements of power output in avian skeletal muscles during running and flying, but little is known about the contractile properties of avian skeletal muscle. We used an in situ preparation to characterize the force-velocity properties of two hind limb muscles, the lateral gastrocnemius (LG) and peroneus longus (PL), in Wild Turkeys (Meleagris gallopavo). A servomotor measured shortening velocity for at least six different loads over the plateau region of the length-tension curve. The Hill equation was fit to the data to determine maximum shortening velocity and peak instantaneous power. Maximum unloaded shortening velocity was 13.0+/-1.6 L s(-1) for the LG muscle and 14.8+/-1.0 L s(-1) for the PL muscle (mean+/-S.E.M.). These velocities are within the range of values published for reptilian and mammalian muscles. Values recorded for maximum isometric force per cross-sectional area, 271+/-28 kPa for the LG and 257+/-30.5 kPa for the PL, and peak instantaneous power output, 341.7+/-36.4 W kg(-1) for the LG and 319.4+/-42.5 W kg(-1) for the PL, were also within the range of published values for vertebrate muscle. The force-velocity properties of turkey LG and PL muscle do not reveal any extreme differences in the mechanical potential between avian and other vertebrate muscle.     

Changes in cardiac output during sustained maximal ventilation in humans

To determine the increment in cardiac output and in O2 consumption (Vo2) from quiet breathing to maximal sustained ventilation, Vo2 and cardiac output were measured using an acetylene rebreathing technique in five subjects. Cardiac output and Vo2 were measured multiple times in each subject at rest and during sustained maximal ventilation. During maximal ventilation subjects breathed 5% CO2 to prevent hypocapnia. The increase in cardiac output from rest to maximal breathing was taken as an estimate of respiratory muscle blood flow and was used to calculate the arteriovenous O2 content difference across the respiratory muscles from the Fick equation. Cardiac output increased by 4.3 +/- 1.0 l/min (mean +/- SD), from 5.6 +/- 0.7 l/min at rest to 9.9 +/- 1.1 l/min, during maximal ventilations ranging from 127 to 193 l/min. Vo2 increased from 312 +/- 29 to 723 +/- 69 ml/min during maximal ventilation. O2 extraction across the respiratory muscles during maximal breathing was 9.6 +/- 1.0 vol% (range 8.5 to 10.7 vol%). These values suggest an upper limit of respiratory muscle blood flow of 3-5 l/min during unloaded maximal sustained ventilation.     

Theophylline does not increase maximal tetanic force or diaphragm endurance in vitro

These experiments tested the capacity of theophylline to improve diaphragm strength (maximal force development) and endurance (maintenance of force output during repeated contractions). Rodent diaphragm strips were mounted at optimal length in oxygenated Krebs-Ringer solution (37 degrees C, pH 7.37). Direct stimuli used supramaximal current density, 0.2-ms pulses, and 250-ms tetanic trains. Theophylline (500 mg/ml) increased force development at low stimulation frequencies but did not increase maximal force [25.7 +/- 0.5 for theophylline vs. 26.0 +/- 0.4 (SE) N/cm2 for control (n = 34)]. During repeated submaximal (25-36 Hz) tetanic contractions, theophylline did not affect endurance. During repeated maximal (160 Hz) tetanic contractions theophylline reduced endurance, accelerating the fall of developed force. Theophylline also inhibited recovery of force after endurance trials ended. We conclude that theophylline does not increase maximal tetanic force and can reduce diaphragm endurance in vitro.     

模拟失重降低大鼠心肌细胞对异丙肾上腺素的反应性

本文旨在研究模拟失重对大鼠单个心肌细胞无负荷收缩功能的影响以及对异丙肾上腺素(isoproterenol,ISO)反应性的变化.采用人鼠尾部悬吊法在地面模拟失重状态,4周后以胶原酶I消化分离心肌细胞,分别对左、右两心室心肌细胞进行收缩功能测量.结果显示,悬吊4周大鼠(悬吊组)左,右心室心肌细胞的长度和宽度与正常大鼠(对照组)相比均无显著差异.随刺激频率增加,对照组与悬吊组大鼠心肌细胞缩短幅值均逐步增加.在1.0、2.0与4.0 Hz刺激下,对照组大鼠左心室心肌细胞缩短幅值分别为(8.50±1.26)%、(9.00±1.38)%与(9.23±1.83)%,右心室心肌细胞缩短幅值分别为(9.80±2.48)%、(10.03±2.48)%与(10.28±2.27)%;与对照组大鼠相比,在1.0与2.0Hz刺激下,悬吊组大鼠左心室心肌细胞无负荷缩短幅值分别降低12.2%、10.9%(P《0.05),右心室则分别降低16.5%、16.3%(P《0.05);但是在4.0 Hz刺激下却无显著性改变.与同一频率刺激下的对照组大鼠相比,悬吊组大鼠左、右心室心肌细胞达到缩短峰值的时程(time to peak shortening,TPS)明显缩短(P《0.05);而从缩短峰值至75%舒张的时程(TR75)则明显延长(P《0.05).在各刺激频率下,悬吊组大鼠左、右心室心肌细胞缩短(+dL/dtmax)与舒张(-dL/dtmax)速度均未发生明显改变.用1、5、10 nmol/L ISO灌流达稳态水平后,对照组大鼠心肌细胞缩短幅值分别增加了(10.63±0.83)%、(35.06±5.22)%和(71.64±6.83)%;而悬吊组大鼠心肌细胞缩短幅值仅增加(5.75±0.76)%、(23.97±4.50)%和(26.38±8.13)%,均有显著性差异(P《0.05,P《0.01).用10、50、100 nmol/L forskolin 灌流达稳定水平后,对照组大鼠心肌细胞缩短幅值分别增加了(3.04±0.27)%、(9.81±2.66)%、(20.20±3.47)%;而悬吊组大鼠心肌细胞缩短幅值仅增加了(1.42±0.53)%、(3.83±1.71)%、(5.49±4.08)%,均有显著性差异(P《0.05).以上结果表明,模拟失重4周降低人鼠心肌细胞无负荷缩短幅值以及对ISO的反应性.     

Calculation of muscle maximal shortening velocity by extrapolation of the force-velocity relationship: afterloaded versus isotonic release contractions

The maximal shortening velocity of a muscle (V(max)) provides a link between its macroscopic properties and the underlying biochemical reactions and is altered in some diseases. Two methods that are widely used for determining V(max) are afterloaded and isotonic release contractions. To determine whether these two methods give equivalent results, we calculated V(max) in 9 intact single fibres from the lumbrical muscles of the frog Xenopus laevis (9.5-15.5 °C, stimulation frequency 35-70 Hz). The data were modelled using a 3-state cross-bridge model in which the states were inactive, detached, and attached. Afterloaded contractions gave lower predictions of Vmax than did isotonic release contractions in all 9 fibres (3.20 ± 0.84 versus 4.11 ± 1.08 lengths per second, respectively; means ± SD, p = 0.001) and underestimated unloaded shortening velocity measured with the slack test by an average of 29% (p = 0.001, n = 6). Excellent model predictions could be obtained by assuming that activation is inhibited by shortening. We conclude that under the experimental conditions used in this study, afterloaded and isotonic release contractions do not give equivalent results. When a change in the V(max) measured with afterloaded contractions is observed in diseased muscle, it is important to consider that this may reflect differences in either activation kinetics or cross-bridge cycling rates.     

The dependence of isometric tension, isometric ATPase activity, and shortening velocity of limulus muscle on the MgATP concentration.

The dependence of the isometric tension, the velocity of unloaded shortening, and the steady-state rate of MgATP hydrolysis on the MgATP concentration (range 0.01-5 mM MgATP) was studied in Ca-activated skinned Limulus muscle fibers. With increasing MgATP concentration the isometric tension increased to a peak at approximately 0.1 mM, and slightly decreased in the range up to 5 mM MgATP. The velocity of unloaded shortening depended on the MgATP concentration roughly according to the Michaelis-Menten law of saturation kinetics with a Michaelis-Menten constant Kv = 95 microM and a maximum shortening velocity of 0.07 muscle lengths s-1; the detachment rate of the cross-bridges during unloaded shortening was 24 s-1. The rate of MgATP splitting also depended hyperbolically on the MgATP concentration with a Michaelis-Menten constant Ka = 129 microM and a maximum turnover frequency of 0.5-1 s-1. The results are discussed in terms of a cross-bridge model based on a biochemical scheme of ATP hydrolysis by actin and myosin in solution.     

Respiratory effects of the scalene and sternomastoid muscles in humans.

Previous studies have shown that in normal humans the change in airway opening pressure (DeltaPao) produced by all the parasternal and external intercostal muscles during a maximal contraction is approximately -18 cmH(2)O. This value is substantially less negative than DeltaPao values recorded during maximal static inspiratory efforts in subjects with complete diaphragmatic paralysis. In the present study, therefore, the respiratory effects of the two prominent inspiratory muscles of the neck, the sternomastoids and the scalenes, were evaluated by application of the Maxwell reciprocity theorem. Seven healthy subjects were placed in a computed tomographic scanner to determine the fractional changes in muscle length during inflation from functional residual capacity to total lung capacity and the masses of the muscles. Inflation induced greater shortening of the scalenes than the sternomastoids in every subject. The inspiratory mechanical advantage of the scalenes thus averaged (mean +/- SE) 3.4 +/- 0.4%/l, whereas that of the sternomastoids was 2.0 +/- 0.3%/l (P < 0.001). However, sternomastoid muscle mass was much larger than scalene muscle mass. As a result, DeltaPao generated by a maximal contraction of either muscle would be 3-4 cmH(2)O, which is about the same as DeltaPao generated by the parasternal intercostals in all interspaces.     

Passive and active mechanical properties of the superficial and deep digital flexor muscles in the forelimbs of anesthetized Thoroughbred horses

The superficial (SDF) and deep digital flexor (DDF) muscles are critical for equine forelimb locomotion. Knowledge of their mechanical properties will enhance our understanding of limb biomechanics. Muscle contractile properties derived from architectural-based algorithms may overestimate real forces and underestimate shortening capacity because of simplistic assumptions regarding muscle architecture. Therefore, passive and active (=total - passive) force-length properties of the SDF and DDF muscles were measured directly in vivo. Muscles from the right forelimbs of four Thoroughbred horses were evaluated during general anesthesia. Limbs were fixed to an external frame with the muscle attached to a linear actuator and load cell. Each muscle was stretched from an unloaded state to a range of prefixed lengths, then stimulated while held at that length. The total force did not exceed 4000 N, the limit for the clamping device. The SDF and DDF muscles produced 716+/-192 and 1577+/-203 N maximum active isometric force (F(max)), had ascending force-length ranges (R(asc)) of 5.1+/-0.2 and 9.1+/-0.4 cm, and had passive stiffnesses of 1186+/-104 and 1132+/-51 N/cm, respectively. The values measured for F(max) were much smaller than predicted based on conservative estimates of muscle specific tension and muscle physiological cross-sectional area. R(asc) were much larger than predicted based on muscle fiber length estimates. These data suggest that accurate prediction of the active mechanical behavior of architecturally complex muscles such as the equine DDF and SDF requires more sophisticated algorithms.     

Different ontogeny of rate of force generation and shortening velocity in guinea pig trachealis.

Juveniles of many species, including humans, display greater airway responsiveness than do adults. This may involve changes in airway smooth muscle function. In the present work we studied force production and shortening velocity in trachealis from 1-wk-old (1 wk), 3-wk-old (3 wk), and 3-mo-old (adult) guinea pigs. Strips were electrically stimulated (60 Hz, 18 V) at their optimal length (l(o)) to obtain maximum active stress (P(o)) and rate of stress generation. Then, force-velocity curves were elicited at 2.5 s from the onset of the stimulus. By applying a recently developed modification of Hill's equation for airway smooth muscle, the maximum shortening velocity at zero load (V(o)) and the value alpha. gamma/beta, an index of internal resistance to shortening (Rsi), were calculated (alpha, beta, and gamma are the constants of the equation). P(o) increased little with maturation, whereas the rate of stress generation increased significantly (0.40 +/- 0.03, 0.45 +/- 0.03, 0. 51 +/- 0.03 P(o)/s for 1 wk, 3 wk, and adult animals). V(o) slightly increased early with maturation to decrease significantly later (1. 79 +/- 0.67, 2.45 +/- 0.92, and 0.55 +/- 0.09 l(o)/s for 1 wk, 3 wk, and adult animals), whereas the Rsi showed an opposite trend (14.98 +/- 5.19, 8.99 +/- 3.01, and 32.07 +/- 5.54 mN. mm(-2). l(o)(-1). s for 1 wk, 3 wk, and adult animals). This early increase of force generation in combination with late increase of Rsi may explain the changes of V(o) with age. An elevated V(o) may contribute to the incidence of airway hyperresponsiveness in healthy juveniles.     

Phosphorylation of two sites on smooth muscle myosin. Effects on contraction of glycerinated vascular smooth muscle

Contraction of glycerinated porcine carotid artery smooth muscle in response to calcium (20 microM), calmodulin (10 microM), and MgATP was associated with phosphorylation of the 20,000-dalton myosin light chain (LC20) to an average stoichiometry of 1.47 mol of PO4/mol of LC20. Tryptic and chymotryptic phosphopeptide maps of the mono- and diphosphorylated forms of LC20 purified from skinned muscles demonstrated the presence of a single phosphopeptide in all cases. Phosphoamino acid analysis indicated that the monophosphorylated form contained primarily phosphoserine, whereas the diphosphorylated form contained both phosphoserine and phosphothreonine. Thiophosphorylation of LC20 by adenosine 5'-O-(thiotriphosphate) resulted in the incorporation of 1 mol of thiophosphate into phosphoserine. Thiophosphorylated LC20 could be subsequently phosphorylated at a threonine residue to a stoichiometry of 1.7 mol of PO4/mol of LC20 by incubation in the presence of MgATP, calcium, and calmodulin. The extent of multiple site phosphorylation of LC20 was dependent upon both the ionic strength and the free Mg2+ concentration in the muscle bath; increasing either ionic strength (0.07-0.15 M) or [Mg2+] (1-20 mM) resulted in lower stoichiometries of LC20 phosphorylation. The effect of multiple site phosphorylation on contraction was examined in muscles which were seqentially phosphorylated at serine followed by threonine. Full activation (21 degrees C) of both isometric force (1.4 newtons/cm2) and unloaded shortening velocity (0.016 L0/s) was achieved following thiophosphorylation to 1.1 mol of PO4/mol of LC20. No further activation of either isometric force (1.5 newtons/cm2) or unloaded shortening velocity (0.015 L0/s) occurred following phosphorylation to 1.7 mol of PO4/mol of LC20.     

Effects of phosphate and ADP on shortening velocity during maximal and submaximal calcium activation of the thin filament in skeletal muscle fibers.

The effects of added phosphate and MgADP on unloaded shortening velocity during maximal and submaximal Ca2+ activation of the thin filament were examined in skinned single skeletal fibers from rabbit psoas muscle. During maximal Ca2+ activation, added phosphate (10-30 mM) had no effect on unloaded shortening velocity as determined by the slack-test technique. In fibers activated at submaximal concentrations of Ca2+ in the absence of added phosphate, plots of slack length versus duration of unloaded shortening were biphasic, consisting of an initial high velocity phase of shortening and a subsequent low velocity phase of shortening. Interestingly, in the presence of added phosphate, biphasic slack-test plots were no longer apparent. This result was obtained in control fibers over a range of submaximal Ca2+ concentrations and in maximally Ca2+ activated fibers, which were first treated to partially extract troponin C. Thus, under conditions that favor the appearance of biphasic shortening (i.e., low [Ca2+], troponin C extraction), added phosphate eliminated the low velocity component. In contrast, in fibers activated in the presence of 5 mM added MgADP, biphasic slack-test plots were apparent even during maximal Ca2+ activation. The basis of biphasic shortening is not known but it may be due to the formation of axially compressed cross-bridges that become strained to bear a tension that opposes the relative sliding of the myofilaments. The present findings could be explained if added phosphate and MgADP bind to cross-bridges in a strain-dependent manner. In this case, the results suggest that phosphate inhibits the formation of cross-bridges that bear a compressive strain. Added MgADP, on the other hand, may be expected to detain cross-bridges in strong binding states, thus promoting an increase in the population of cross-bridges bearing a compressive strain. Alterations in the population of strained cross-bridges by added phosphate and MgADP would alter the internal load within the fiber and thus affect the speed of fiber shortening.     

Effects of passive tension on unloaded shortening speed of frog single muscle fibers.

Experiments were performed to determine the influence of sarcomere length and passive tension on the velocity of unloaded shortening (Vu) as measured by the slack test technique. Slack test results were obtained from intact twitch fibers isolated from the frog (Rana temporaria). Measurements were made both in the absence and presence of passive tension using two different protocols. In one, all releases were initiated from the same sarcomere length and passive tension level; in the other, all releases ended at the same sarcomere length. In the absence of passive tension, no difference was observed between the results from the two slack test protocols. When passive tension was present, performing all releases from the same initial sarcomere length and passive tension level resulted in linear step size-slack time relationships in which the slopes (Vu) were independent of length over a sarcomere length range extending to 3.1 microns, and the intercepts increased with increasing sarcomere length. Performing all releases to the same final sarcomere length in the presence of passive tension produced nonlinear step size-slack time relationships. The results presented here show that, in the presence of significant levels of passive tension, the traditional interpretation of the slope of the slack test plot as the constant unloaded shortening velocity is only correct when all length steps are initiated from the same initial sarcomere length and level of passive tension.     

Alpha 1-adrenergic stimulation increases the Vmax of isolated myocardial papillary muscles.

alpha-Adrenergic agonists have been shown to increase the tension developed by myocardial muscle. However, their effects on the maximum velocity of unloaded muscle shortening (Vmax) have not been rigorously examined. In this study, the contractile effects of the alpha-adrenergic agonist phenylephrine were examined in the presence of propranolol in papillary muscles of two species, the dog and the rabbit. In rabbit papillary muscles studied at physiological calcium concentrations (1.25 mM), phenylephrine increased all indices of contractility (Vmax, tension, and maximum rate of tension developed (dT/dt)) starting at 10(-8) M. The percent increase in Vmax (121 +/- 8%) was less than that of tension (188 +/- 20%, p less than 0.05) and dT/dt (262 +/- 35%, p less than 0.01). These findings occurred at both 29 and 35 degrees C and were inhibited by adding 10(-5) M prazosin. Increasing extracellular calcium concentration from 1.25 to 15 mM caused changes in twitch configuration that were significantly different from those of phenylephrine. Calcium increased all indices of contractility more than did phenylephrine. This was particularly true for dT/dt (502 +/- 82 vs. 262 +/- 35% for phenylephrine, p less than 0.01). Nonetheless, the ratio of increase in tension to increase in Vmax under both experimental conditions was similar (the increase in Vmax was 64% of that of tension with phenylephrine and 69% with increased calcium). At 1.25 mM calcium, the increase in contractility caused by phenylephrine was much smaller in dog myocardium as compared with rabbit myocardium. Rather, the effects of phenylephrine on dog myocardium studied at 1.25 mM calcium resembled that of rabbit myocardium studied at 15 mM calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aminophylline increases submaximum power but not intrinsic velocity of shortening of frog muscle.

We hypothesized that methylxanthines, such as aminophylline, increase the power developed by submaximally activated frog skeletal muscles by increasing the force developed at any given velocity of shortening. Frog semitendinosus muscles were excised and tested at 20 degrees C in oxygenated control and aminophylline Ringer solutions. Force-velocity relationships were determined and power was calculated from muscles stimulated at frequencies of 80 and 300 Hz. The 300-Hz frequency of stimulation produced a maximum rate of force development. In 50 and 500 microM aminophylline, twitch force increased by 25 +/- 12 and 75 +/- 13%, respectively. Aminophylline did not affect maximum isometric force generation or the shortening velocity at any relative load. At 80-Hz stimulation and in the presence of 500 microM aminophylline, power increased by an average of 11% at 10 of 14 relative loads. At maximum frequencies of stimulation, aminophylline had no effect on any measured parameter. We conclude that aminophylline increases the power developed by submaximally activated frog muscles through an increase in the force generated particularly at the lower velocities of shortening.     

Mechanical properties of denervated amphibian muscle

Denervated amphibian muscle does not show the prolongation of action potential found in mammalian denervated muscle. It was, therefore, predicted that denervated amphibian muscle would not show prolongation of the mechanical twitch. The sartorius muscles in one leg of toads--Xenopus borealis--were denervated for 140-268 days. Isometric twitch time to peak, time to half relaxation and twitch/tetanus ratio were not changed following denervation, confirming our prediction. Twitch tension decreased to 68% and tetanic tension decreased to 75% of control values. The maximum velocity of unloaded shortening (muscle length/s) was also unchanged.     

Free radicals may contribute to oxidative skeletal muscle fatigue

We used mouse soleus in vitro (n = 30) and canine gastrocnemius-plantaris preparations (n = 20) pump-perfused at the animal's blood pressure to establish if free radicals contribute to fatigue in oxidative skeletal muscle. The soleus from each leg contracted for 200 ms (70 Hz) once every minute for 60 min in Hepes buffer gassed with 100% oxygen at 27 degrees C. When contracting in Hepes alone, both muscles fatigued at 0.9 mN/mm2.min over the 60 min. The addition of purines to the bath increased the rate to 1.4 mN/mm2.min and the addition of xanthine oxidase to generate free radicals increased the rate again to 1.9 mN/mm2.min. Thus free radicals appeared to attenuate oxidative skeletal muscle function. Each canine muscle contracted isometrically at 4 Hz for 30 min and then rested for 45 min before contracting for a second 30 min at 4 Hz. In each experiment, we infused saline at 0.76 mL/min into resting muscle and at 1.91 mL/min during the first contraction period. During the remainder of the experiment, we infused, at the same rates, saline (n = 4), 10 microM dimethyl sulfoxide (DMSO) (n = 4) to identify the effect of scavenging hydroxyl radicals, 1 mM allopurinol to establish the effect of blocking xanthine oxidase (n = 4), or 200 microM desferoxamine to determine the effect of chelating iron (n = 4). With saline, the fatigue rate over the 30 min of contractions increased from 5.0 +/- 0.2 to 6.3 +/- 0.5 N/kg.min from the first to the second stimulation period. The fatigue rate was slower in the second period with each of the three experimental substances (DMSO, 5.9 +/- 0.8 to 3.2 +/- 0.3; allopurinol, 7.3 +/- 1.1 to 4.6 +/- 0.6; desferoxamine, 6.8 +/- 0.8 to 4.4 +/- 0.8 N/kg.min). The fatigue rate was the same as control when DMSO was infused only during the second contraction period. Therefore, free radicals appeared to contribute to fatigue in oxidative skeletal muscle.     

Effect of abdominal compression on diaphragmatic tendon organ activity.

Previous studies suggest that afferents in the diaphragm participate in the reflex reduction in phrenic nerve efferent activation when the length of the diaphragm is increased by abdominal compression. The present study determined the response of tendon organ afferents in the diaphragm to increases in abdominal pressure. Five cats were anesthetized with thiopental sodium (60 mg/kg ip to induce, supplemented intravenously). Extracellular recordings from nine individual tendon organ afferents were made from right cervical dorsal root ganglia 5 and 6. Right crural electromyographic activity was recorded. The right extrathoracic phrenic nerve was isolated and stimulated to identify tendon organs on the basis of conduction velocity and response to twitch. The response to ramp-and-hold stretch of the diaphragm was used as an additional test to differentiate tendon organs from muscle spindles. The mean level of activity of the tendon organs during the 1st s of the inspiratory phase was 47 +/- 10 (SD) Hz. Abdominal compression was associated with a significant increase in the activity of these afferents to 61 +/- 11 Hz. Results indicate that increases in the activity of diaphragmatic tendon organs are associated with moderate increases in abdominal pressure and are likely the result of elevations in the active tension developed by the diaphragm. Combined with results from previous studies, it is possible that diaphragmatic tendon organs may play a role in the attenuation of respiratory muscle activation when abdominal pressure is increased.     

Treatment of nocturnal asthma: the role of sustained-release theophylline and oral beta-2-mimetics

In two double-blind, multiple-dose cross-over studies the therapeutic effects of SR theophylline preparations given once each night (mean 11.2 mg/kg per day) versus twice daily in equal doses (mean 10.3 mg/kg per day) (study I) and SR-terbutaline in equal doses (mean 0.25 mg/kg per day) versus SR theophylline in unequally divided daily doses (mean 5.3 mg/kg morning dose, 10.6 mg/kg evening dose) study II) were compared in 19 patients with nocturnal asthma. At the end of each treatment period drug serum concentrations and PEFR were measured every 2 hr over a 24-hr period. With the twice-daily, equally divided regimen, serum theophylline concentrations were lower at night than during the day (mean 9.4 +/- 0.9 versus 11.3 +/- 1.0 mg/l). With the single evening administration, serum theophylline concentrations were considerably higher at night (Cmax 16.3 +/- 1.4 mg/l) and the circadian variation of PEFR was significantly reduced. PEFR was higher during night and early morning (283 +/- 14 versus 217 +/- 11 l/min, P less than 0.005). During daytime in study II, PEFR values were slightly higher with theophylline than terbutaline. There was no significant difference in peak flow between either treatment during the night and early morning. However, additional use of inhaled beta-2-mimetics because of asthmatic attacks occurred more often during terbutaline (79 times in 8/10 patients) than theophylline treatment (29 times in 5/10 patients). Symptom scores, number of attacks and side-effects clearly favor the theophylline regimen. We conclude that for patients with nocturnal asthma a once-nightly dose of SR theophylline can be sufficient for stabilization of the airways.     

Correlated reduction of velocity of shortening and the rate of energy utilization in mouse fast-twitch muscle during a continuous tetanus

Isometric tetani of slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles of the mouse were studied at 20 degrees C. The total energy cost for 3- and 9-s isometric tetani was measured as a function of length above L0 and partitioned into a filament overlap-dependent fraction and a smaller filament overlap-independent fraction. In both muscles, the rate of filament overlap-independent energy cost did not change with tetanic duration. In the EDL, but not in the soleus, the rate of filament overlap-dependent energy utilization was greater in a 3-s tetanus than in a 9-s tetanus. The force-velocity relationships were studied after 3 and 9 s of isometric tetanus. In the soleus, Vmax was 2 fiber lengths/s and was not dependent on the duration of isometric tetanus. In contrast, in the EDL, Vmas decreased from 5.9 fiber lengths/s at 3 s to 3.9 fiber lengths/s at 9 s. The velocity of unloaded shortening (Vus) was examined by the slack test method as a function of the duration of isometric tetanus duration over the range of 1-15 s. In the soleus, Vus did not change, whereas in the EDL, Vus declined progressively from 6.4 to 3.2 fiber lengths/s after an isometric tetanus of increasing duration from 1 to 15 s. These results cannot exclude the hypothesis that in a maintained tetanus there is a decrease in the intrinsic cross- bridge turnover rate in the fast-twitch EDL, but not in the slow-twitch soleus muscle.     

Caffeine and theophylline counteract diazepam effects in man

A total of 237 healthy subjects were studied in four placebo-controlled double-blind trials with parallel treatment groups. The subjects ingested a capsule (diazepam or placebo) and decaffeinated coffee with or without added caffeine or theophylline. Diazepam (10 and 20 mg) impaired dose dependently cognitive skills as measured by digit symbol substitution and letter cancellation, the balance of extraocular muscles, flicker fusion, and tapping speed. With diazepam 10 mg statistically significant effects were seen on digit symbols and exophoria only. Theophylline (10 mg/kg) increased tapping speed and heart rate, whereas other objective measurements were negative for the effects of theophylline or caffeine (250 and 500 mg) alone. Subjectively they reduced calmness, and caffeine also increased alertness. Caffeine 250 mg counteracted diazepam induced (10 mg) impairment of cognitive skills and relaxation of extraocular muscles whereas caffeine 500 mg counteracted the same effects of diazepam 20 mg, respectively. Theophylline antagonized diazepam-induced impairment in digit symbol substitution and tapping speed tests. Subjectively, caffeine and theophylline counteracted diazepam induced drowsiness and mental slowness. The results suggest, therefore, that the ample use of methylxanthines compensates various side-effects of benzodiazepines in man. It may also increase the need of sedation and thus the consumption of benzodiazepines.