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The force-velocity relation agreeable to the experimental results of muscle contraction research, is obtained. The relation has been obtained on the basis of force generation model founded on the existence of mechanical vibration in muscle fibrils.
The morphological changes in the sarcomeres of frog sartorii heavily loaded with 600 times muscle weight and fixed in the inactive and in the actively contracting states were studied in longitudinal electron micrographs. The sarcomere in actively contracting muscles, but not in the inactive ones, assumed a distinctive barrel shape which was referrable to the interaction of thick myofilaments distal ends, normally beyond interaction range because of their tapered structure, with thin myofilaments in an attempt to generate maximal force.
1. The effects of phosphate and protons on the mechanics and energetics of muscle contraction have been investigated using glycerinated rabbit psoas muscle. 2. Fibres were fully activated by addition of Ca2+ (pCa 4-5) at 10 degrees C. The velocities of contraction were measured in isotonic load clamps, and the velocities of unloaded fibres were measured by applying a series of step changes in fibre length. Fibre ATPase activity was monitored using an enzyme system to couple ADP production to reduced nicotinamide-adenine dinucleotide (NADH) and measuring the depletion of NADH by optical density. 3. At pH 7.0 and 3 mM-phosphate, isometric tension (P0) was 13.2 +/- 0.9 N/cm (mean +/- S.E.M., n = 10 observations), the maximum contraction velocity (Vmax) was 1.63 +/- 0.05 lengths/s (n = 5) and the ATPase activity was 1.27 +/- 0.12 s-1 myosin head-1 (n = 35). Increasing phosphate from 3 to 20 mM at pH 7.0 does not affect Vmax, causes a small decrease in the ATPase activity (15-20%) and decreases P0 by approximately 20%. Changing pH from 7 to 6 at 3 mM-phosphate decreases P0 by 45% and both Vmax and ATPase activity by 25-30%. The effects of changing both pH and phosphate were approximately additive for all parameters measured. The inhibition of these parameters by low pH and high concentration of phosphate was reversible. 4. The force-velocity relation was fitted by the Hill equation using a non-linear least-squares method. The value of the parameter which describes the curvature, a/P0, was 0.20. The curvature of the force-velocity relation was not changed by addition of phosphate or by changes in pH. 5. These data provide information on both the kinetics of the actomyosin interaction and on the process of muscle fatigue. The data are consistent with models of cross-bridge kinetics in which phosphate is released within the powerstroke in a step involving a rapid equilibrium between states. The inhibition by protons is more complex, and may involve less specific effects on protein structure. 6. During moderate fatigue of living skeletal muscle, MgATP concentration is known to remain approximately constant at 4 mM, phosphate to increase from 3 to 20 mM, and protons from 0.1 to 1 microM. The data suggest that much of the inhibition of P0 observed during moderate fatigue can be explained by the increased levels of phosphate and protons, and that much of the inhibition of fibre Vmax and ATPase activity can be explained by the increase in protons.
We tested the hypothesis that static contraction causes greater reflex cardiovascular responses than dynamic contraction at equivalent workloads [i.e., same tension-time index (TTI), holding either contraction time or peak tension constant] in chloralose-anesthetized cats. When time was held constant and tension was allowed to vary, dynamic contraction of the hindlimb muscles evoked greater increases (means +/- SE) in mean arterial pressure (MAP; 50 +/- 7 vs. 30 +/- 5 mmHg), popliteal blood velocity (15 +/- 3 vs. 5 +/- 1 cm/s), popliteal venous PCO(2) (15 +/- 3 vs. 3 +/- 1 mmHg), and a greater decrease in popliteal venous pH (0.07 +/- 0.01 vs. 0.03 +/- 0.01), suggesting greater metabolic stimulation during dynamic contraction. Similarly, when peak tension was held constant and time was allowed to vary, dynamic contraction evoked a greater increase in blood velocity (13 +/- 1 vs. -1 +/- 1 cm/s) without causing any differences in other variables. To investigate the reflex contribution of mechanoreceptors, we stretched the hindlimb dynamically and statically at the same TTI. A larger reflex increase in MAP during dynamic stretch (32 +/- 8 vs. 24 +/- 6 mmHg) was observed when time was held constant, indicating greater mechanoreceptor stimulation. However, when peak tension was held constant, there were no differences in the reflex cardiovascular response to static and dynamic stretch. In conclusion, at comparable TTI, when peak tension is variable, dynamic muscle contraction causes larger cardiovascular responses than static contraction because of greater chemical and mechanical stimulation. However, when peak tensions are equivalent, static and dynamic contraction or stretch produce similar cardiovascular responses.
In a wide variety of cellular settings, from organelle transport to muscle contraction, Ca2+ binding to members of the EF hand family of proteins controls the interaction between actin and different myosins that are responsible for generating movement. In vertebrate skeletal and cardiac muscle the Ca(2+)-binding protein troponin C (TnC) is one subunit of the ternary troponin complex which, through its association with actin and tropomyosin on the thin filament, inhibits the actomyosin interaction at submicromolar Ca2+ concentrations and stimulates the interaction at micromolar Ca2+ concentrations. Because TnC does not interact directly with actin or tropomyosin, the Ca(2+)-binding signal must be transmitted to the thin filament via the other two troponin subunits: troponin I (TnI), the inhibitory subunit, and troponin T (TnT), the tropomyosin-binding subunit. Thus, the troponin complex is a Ca(2+)-sensitive molecular switch and the structures of and interactions between its components have been of great interest for many years. Although the crystal structure of TnC has been known for almost a decade, the molecular structures of TnI and TnT are not known and therefore convincing models of the organization of the troponin complex and the Ca(2+)-induced changes in its structure have not been forthcoming. Recent advances on a wide variety of fronts including 1) the bacterial expression and characterization of mutants of TnC, TnI, and TnT; 2) cross-linking and fluorescence studies; and 3) the determination of the crystal and nuclear magnetic resonance structures of synthetic and recombinant troponin fragments and complexes between EF hand proteins and their target peptides have provided new insights into the nature of the interactions between troponin subunits. This review discusses these recent advances with the aim of critically assessing molecular models of the nature of the Ca(2+)-induced structural transition in troponin.
1. The effects of haloperidol on smooth muscle contraction induced by carbachol, histamine, high K or caffeine in the presence or absence of extracellular Ca were investigated. 2. In the presence of extracellular Ca, the maximal contraction induced by carbachol was reduced by haloperidol, while that by histamine or high K was much less affected. 3. In Ca-free solution, contraction induced by histamine was extremely reduced by haloperidol, while that by carbachol was not affected. 4. These results suggest that haloperidol selectively inhibited signal transduction processes from activation of muscarinic acetylcholine receptors to influx of extracellular Ca and from activation of histamine H1-receptors to release of intracellularly stored Ca. 5. Caffeine-induced contraction in Ca-free solution was markedly potentiated by haloperidol, although haloperidol did not elicit contraction in Ca-free solution by itself. 6. These results suggest that haloperidol increased the sensitivity of Ca-induced Ca release channels to caffeine.
We have examined K(+) channels and their function in human esophageal smooth muscle using perforated patch recording, RT-PCR to identify channel mRNA, and muscle contraction to study the effects of channel blockers. Depolarization revealed at least two types of currents: a 4-aminopyridine (4-AP)-sensitive transient delayed rectifier K(+) (K(V)) and a Ca(2+)-dependent K(+) (K(Ca)) current. K(Ca) current was active at positive potentials and was blocked by tetraethylammonium (TEA), iberiotoxin, and charybdotoxin but was insensitive to 4-AP. The mRNA encoding the gene products of Kv1.2 and Kv1.5 was identified in muscle and dissociated cells, consistent with these channel types contributing to K(V) current. 4-AP increased resting tension of muscle strips, suggesting a role for K(V) in setting the membrane potential. TEA, but not 4-AP, augmented the amplitude and duration of electrically evoked contraction, effects that were abolished by nifedipine. Here we provide the first description of macroscopic K(+) currents in human esophagus. K(V) channels participate in regulation of resting tension, whereas the K(Ca) channel limits depolarization and contraction during excitation.
The duration of the late exteroceptive suppression period (ES2) of temporal muscle EMG activity has been reported to be reduced in patients suffering from chronic tension-type headache. Methods of recording and analysing ES2 have varied between centers and reproducibility of results within subjects, although insufficiently studied, has generally been poor. ES2 was investigated in 30 healthy subjects, using a computerized technique of recording, rectifying and averaging the EMG signals. Hour to hour and week to week variations of ES2 durations were calculated, and the influence of pain during a cold pressor test and of sustained muscle contraction on ES2 durations was investigated. The intra-individual variation of ES2 durations was 16.0% from hour to hour and 20.7% from week to week. The inter-individual variation was 36.7%. The present method for analysis of ES2 periods proved to be reliable, as the intra-observer variation was 4.2% and the inter-observer variation 4.6%. ES2 periods were significantly shorter on the first compared to the second day of examination (p = 0.006) and during experimental pain (p = 0.0005). We recommend the use of the computerized average technique in future studies and caution against the dependence of results upon factors such as conditioning and pain.
OBJECTIVES: To compare the effect of electric stimulation (ES)-induced twitch with tetanic leg muscle contractions on blood flow responses and to assess blood flow responses in the contralateral inactive leg. DESIGN: Intervention with within-subject comparisons. SETTING: University research laboratory. PARTICIPANTS: A volunteer sample of 12 healthy men (mean age, 25.1+/-3.0y). INTERVENTION: ES was applied at 1 and 3Hz to induce twitch contractions and at 35Hz to induce tetanic contractions of the lower- and upper-leg muscles. Exercise periods consisted of ES/rest cycles (6s/20s) for 5 minutes. MAIN OUTCOME MEASURES: Blood flow velocity changes measured by echo Doppler ultrasonography at rest and during the first 2 subsequent ES cycles. RESULTS: Blood flow significantly increased from resting values for the tetanic 2-leg, tetanic 1-leg, and 3-Hz conditions, but not for the 1-Hz twitch condition or in the inactive leg. CONCLUSIONS: Both tetanic and 3-Hz twitch contractions, but not 1-Hz twitch contractions, increased leg blood flow in humans. Because blood flow elevations induced by the 3-Hz contractions did not differ statistically from those induced by the tetanic contractions but were realized with less discomfort, this mode is preferable for therapeutic interventions. Because stimulation of the ipsilateral leg muscles did not change blood flow in the contralateral inactive leg, the muscles in the area of desired effect must be stimulated.
Signalling by cGMP-dependent protein kinase type I (cGKI) relaxes various smooth muscles modulating thereby vascular tone and gastrointestinal motility. cGKI-dependent relaxation is possibly mediated by phosphorylation of the inositol 1,4,5-trisphosphate receptor I (IP(3)RI)-associated protein (IRAG), which decreases hormone-induced IP(3)-dependent Ca(2+) release. We show now that the targeted deletion of exon 12 of IRAG coding for the N-terminus of the coiled-coil domain disrupted in vivo the IRAG-IP(3)RI interaction and resulted in hypomorphic IRAG(Delta12/Delta12) mice. These mice had a dilated gastrointestinal tract and a disturbed gastrointestinal motility. Carbachol- and phenylephrine-contracted smooth muscle strips from colon and aorta, respectively, of IRAG(Delta12/Delta12) mice were not relaxed by cGMP, while cAMP-mediated relaxation was unperturbed. Norepinephrine-induced increases in [Ca(2+)](i) were not decreased by cGMP in aortic smooth muscle cells from IRAG(Delta12/Delta12) mice. In contrast, cGMP-induced relaxation of potassium-induced smooth muscle contraction was not abolished in IRAG(Delta12/Delta12) mice. We conclude that cGMP-dependent relaxation of hormone receptor-triggered smooth muscle contraction essentially depends on the interaction of cGKI-IRAG with IP(3)RI.
An overview is presented of the physiology and so-called pathophysiology of static muscle contractions in the intact living organism. Static muscle activity produces no external mechanophysical work, but is used for fixation. Contingent upon the levels of the generated forces, and the duration of the isometric contractions, static activities give rise to fatigue and pains. The discomforts are viewed as somatic responses that are normally within physiological limits. That is, upon cessation of isometric contractions there is usually rapid recovery from the discomforts, and they do not normally induce chronic lesions.
The morphological changes in the sarcomeres of frog sartorii lightly loaded with 25 times muscle weight and fixed in the inactive and in the actively contracting states were studied in longitudinal electron micrographs. The sarcomere in actively contracting muscles, but not in the inactive ones, assumed a distinctive double-concave shape which was due to the bowing-out of the thick myofilaments distal ends at the contraction bands. The drop in tension in extremely shortened muscles was explained on the basis of this behavior.
OBJECTIVE: To study the effects of a high-calcium diet upon blood pressure, vascular smooth muscle contractions and intracellular free calcium in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. DESIGN: Eight-week old animals were placed on a normal-calcium diet (1.1% calcium; SHR and WKY rat groups) or a high-calcium diet (2.1% calcium; Ca-SHR and Ca-WKY rat groups) and observed for 12 weeks. METHODS: Blood pressure was measured indirectly by the tail-cuff method and in vitro smooth muscle responses were studied using a standard organ bath chamber. Platelets were used as a cell model for analysis of intracellular free calcium concentration, measured by the fluorescent indicator Quin-2. RESULTS: The blood pressure of Ca-WKY and WKY rats did not differ, but increased systolic blood pressure was attenuated in Ca-SHR compared with SHR. The concentration-response curves of mesenteric arterial rings for potassium chloride and noradrenaline were not affected by the high-calcium diet in either SHR or WKY rats. The time required for total relaxation after washout of contractile agents (washout time) was shortest in WKY and Ca-WKY rats after both agonists, and shorter in Ca-SHR than in SHR after noradrenaline. Smooth muscle responses were also studied by contracting the preparations with noradrenaline and potassium chloride in a calcium-free solution, after which, calcium was added to the organ bath in increasing concentrations. Calcium contraction responses were similar in WKY and Ca-WKY rats; SHR displayed an attenuated response to calcium addition in mesenteric rings stimulated by both agonists. After potassium chloride as agonist, the responses of SHR and Ca-SHR did not deviate but, after noradrenaline, a significant shift in the calcium contraction curve towards the normotensive curve was observed in Ca-SHR. Intracellular free calcium was clearly lower in WKY rats than in SHR, and was significantly reduced by calcium supplementation in the hypertensive but not the normotensive animals. CONCLUSIONS: A reduction in intracellular free calcium concentration and an effect upon receptor-mediated vascular smooth muscle contraction and excitation-contraction coupling may participate in the blood pressure lowering effect of a high-calcium diet.
Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction occur in aortas from New England Deaconess Hospital (NEDH) rats harboring pheochromocytoma (PHEO) and following chronic exposure to the alpha-adrenergic agonist phenylephrine in vitro. Endothelium is known to release an endothelial cell-derived relaxing factor that promotes smooth muscle relaxation. We wondered if the endothelium might contribute to the desensitization of contraction. The role of the endothelium in desensitization was studied using aortic rings with endothelium [E(+)] and with endothelium removed [E(-)]. Maximal phenylephrine (PE)-induced contraction (Emax) for E(+) was 1.7 +/- 0.3 g in controls and 0.4 +/- 0.1 g in PHEO (p less than 0.001), demonstrating desensitization; however, for E(-), Emax was 2.4 +/- 0.2 g in PHEO vs. 2.5 +/- 0.2 g in controls, demonstrating restoration of maximal contraction when the endothelium was removed. However, sensitivity [-log EC50(M)] to PE in E(-) remained significantly lower in PHEO compared to controls (6.94 +/- 0.12 vs. 7.51 +/- 0.14, respectively, p less than 0.001). Similarly, in aortic ring segments desensitized in vitro with phenylephrine, the maximal contraction in phenylephrine-exposed aortas was 60% of that seen in controls. Removal of the endothelium from the vessels pretreated with phenylephrine fully restored the maximal response and sensitivity of these vessels. Treatment of desensitized vessels with hemoglobin (5 x 10(-5) M) restored the maximal contraction and sensitivity to phenylephrine. When the endothelium was removed prior to chronic exposure to phenylephrine, the sensitivity to phenylephrine decreased while the Emax remained similar to controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Urinary trypsin inhibitor (UTI) and its precursor form inter-alpha trypsin inhibitor (ITI) are present in plasma. To determine the action of UTI on blood vessels, we performed isometric vascular muscle contraction tests, microcirculation studies and measurement of cytosolic free Ca2+ in vascular smooth muscle cells. An isometric vascular muscle contraction test showed that the contractions stimulated by endothelin-1 or norepinephrine were suppressed in the presence of UTI, and that the contractions were not inhibited in the presence of ITI. The microcirculation study showed that the contraction of mesenteric arterioles of WKY rats induced by norepinephrine were inhibited by treatment of UTI, and that they did not alter by treatment of ITI. Pre-incubation of UTI, but not ITI, with vascular smooth muscle cells inhibited the increase of cytosolic free Ca2+ induced by endothelin-1 or norepinephrine. Cell-binding study by biotinylated UTI showed that vascular smooth muscle cells have specific binding site for UTI, but not for ITI. We propose that circulating UTI converted from ITI has a regulatory effect on local vascular tone by regulation of Ca2+ influx into smooth muscle cells.
The effects of single and repetitive injections of neostigmine on neuromuscular physiology were examined in rat extensor digitorum longus muscles. The characteristic facilitation of neuromuscular transmission associated with acute anticholinesterase treatment was accompanied by significant pre- and postsynaptic alterations in neuromuscular transmission. Three days of neostigmine treatment caused a decrease in indirectly and directly elicited muscle contraction. Miniature end-plate potential amplitude and frequency, end-plate potential amplitude, junctional acetylcholine sensitivity and quantal content of nerve-evoked end-plate potentials were also decreased by this treatment. By 22 to 25 days of continued treatment, the decreased rate of transmitter release had returned almost to normal, whereas the alterations of the postsynaptic membrane persisted for as long as 106 days. Alterations were also found in the muscle action potential and in certain passive electrical properties of the extrajunctional muscle membrane. In addition, many of the physiological changes were correlated directly with the morphological changes observed in rats treated similarly. We conclude that neostigmine treatment in rats in therapeutic doses has deleterious effects on neuromuscular physiology and neuromuscular ultrastructure. Although the pattern of these changes is not identical with that seen in rabbit and human myasthenia gravis, the neostigmine treatment used in patients with myasthenia gravis may contribute in part to the neuromuscular alterations observed in this disease.
Over the past decade, reactive oxygen species (ROS) and nitric oxide (NO) derivatives have been established as physiological modulators of skeletal muscle function. This mini-review addresses the roles of these molecules as endogenous regulators of muscle contraction. The article is organized in two parts. First, established concepts are briefly outlined. This section provides an overview of ROS production by muscle, antioxidant buffers that oppose ROS effects, enzymatic synthesis of NO in muscle, the effects of endogenous ROS on contractile function, and NO as a contractile modulator. Second, a selected group of unresolved topics are highlighted. These more controversial issues include putative source(s) of regulatory ROS, the relative importance of the two NO synthase isoforms constitutively coexpressed by muscle fibers, molecular mechanisms of ROS and NO action, and the physiological relevance of redox regulation. By discussing current questions, as well as the established paradigm, this article is intended to further debate and stimulate research in this area.
The accessory radula closer (ARC) buccal muscle motor neuron B16 is buccalin-immunoreactive and it synthesizes a peptide with chromatographic properties identical to those of buccalin. Terminal varicosities in the ARC muscle are buccalin-immunoreactive, and buccalin reduces muscle contractions evoked by stimulation of neuron B16, probably by a presynaptic action.