Intensity Of Active State Research Articles

Effect of calcitonin gene-related peptide on skeletal muscle via specific binding site and G protein

In curarized rat skeletal muscle, rat calcitonin gene-related peptide (CGRP), a peptide coexisted with acetylcholine in the motor nerve terminal, increased the isometric twitch force, accompanied by an increase in the active state intensity of shortening, prolonged duration of the active state and additive effect of a phosphodiesterase inhibitor; the results reflect a potentiation in the sarcoplasmic calcium transport system. This CGRP effect was enhanced by cholera toxin, suggesting the activation of guanine nucleotide binding regulatory protein (G protein) that stimulates adenylate cyclase (Gs). The pertussis toxin (IAP), a factor to prevent the cyclic AMP decrease by inactivating the G protein that inhibits adenylate cyclase (Gi), provided no effect on the action of CGRP. The existence of CGRP binding site in the sarcolemmal membrane was confirmed by Scatchard analysis of binding data; affinity of the binding site for CGRP was decreased in the presence of guanosine-5′-[γ-thio]triphosphate (GTP γS). The Gs protein is thus implicated in the CGRP binding site and intracellular processes of signal transduction. CGRP did not modify the neuromuscular transmission and cable properties of the muscle membrane.

Regulation of contractility of the fish ( Carassius carassius L.) heart ventricle

1. Basic electrophysiological and contractile properties of the fish ( Carassius carassius L.) heart ventricle were examined in vitro. Resting potential and characteristics of the action potential were typical for a vertebrate heart. The duration of action potential was long (APD 50 = 556 ±56 ms at 20°C) and correlated with the duration of isometric contraction (TPT = 496 ± 26 ms at 20°C). 2. The force of isometric contraction declined with increasing stimulation rate. This effect was due to the shortened duration of active state at low frequencies (0.2-0.6 Hz) but at higher rates (0.8 and 1.0 Hz) it was also due to the decline of intensity of active state. 3. Decrease in bath temperature increased force of contraction, which was caused by the lengthening of the duration of the active state. 4. Isoprenaline and adrenaline improved contractility but phenylephrine, in the presence of β -blocker propranolol, had no effect. This shows the presence of functional β-receptors but absence of β-receptors in the fish ventricle. 5. Catecholamines were not detected in the ventricular myocardium by fluorescence spectrophotometry, and tyramine failed to improve the contractility of ventricular strips, suggesting that adrenergic innervation of the crucian carp ventricle is sparse or nonexistent. 6. The positive inotropic effect of isoprenaline in fish ventricle is qualitatively different from that found in mammalian hearts in that the specific relaxing influence of β -receptor activation is totally lacking. 7. Caffeine (5 mmol/l) improved contractility without effect on relaxation. 8. These results suggest that the contraction of crucian carp ventricle is primarily regulated by sarcolemmal mechanisms and its contractility is modulated by circulating catecholamines through β -adrenergic receptors.

Active state properties ofdenervated and immobilized muscle

Possible roles of neurotrophic mechanisms and muscle activity in the contractile abnormalities of muscular dystrophy were studied by comparing human dystrophic muscle to denervated and immobilized muscle. As evident in denervated muscle from the decreased acceleration of twitch development (decreased active state intensity of shortening), and isoproterenol-induced decrease of twitch with shortened decay of the active state, part of the abnormality in the subcellular calcium transport system in dystrophic muscle seems to be influenced by disordered neural regulation. Other active state abnormalities relating to activation processes and contractile proteins in dystrophic muscle were also demonstrated in both denervated and immobilized muscle, with some being more marked in immobilized muscle. The findings indicate that a neurogenic hypothesis cannot entirely explain the pathogenesis of progressive muscular dystrophy.

Simulation of inotropy in myocardial mechanics: Comparison to pharmacologic interventions

An improved mathematical model for muscle contraction recently developed by Y. C. Fung, based on the classical Hill Equation, was evaluated by simulation of isometric contractions on the digital computer, using CSMP. Comparison with experimental twitch tension curves developed from the isolated, supported cat papillary muscle in response to the drugs isoproterenol, digoxin, propranolol and sodium pentobarbital indicate that the amplitude factor, λ representing intensity of active state was appropriately affected by these positive or negative inotropic agents. Further, the model allowed the insight into the mechanism of action of commonly used drugs; e.g. isoproterenol increased peak tension and shortened time to peak tension whereas digoxin only increased peak tension without changing time to peak tension. From these studies, it was also possible to formulate a simplified version of the parent equation. This investigation demonstrates the utility of the Fung model in accurately representing the properties of cardiac muscle mechanics during interventions which rapidly alter contractile state.

The force-velocity relation in phasic contractions of venous smooth muscle.

The force-velocity relation of the rat portal vein has been studied during regular spontaneous contractions induced by elevated levels of [K-+]O AND [Ca-2+]o. No satisfactory description of the force-velocity relation was obtained by measuring shortening velocity in afterloaded isotonic contractions. Therefore the method of isotonic quick release was used, as this permits mechanical studies at specified instants of the contraction-relaxation cycle. The temporal development of the force-velocity relation in the phasic response was investigated. During a time interval in the rising phase of the contraction, at about the time for maximal dP/dt, the force-velicity curves were practically identical, suggesting a plateau in the intensity of active state. At later stages of the twitch the curves were progressively displaced towards the origin, the intercepts on both the force and the velocity axis becoming smaller. At the time of the isometric peak the maximal shortening velocity had declined relatively more than the isometric force. This is presumably caused by inhomogeneous activation of the muscle at the beginning of relaxation, The maximal force-velocity relation in the rising phase of the contraction can be described by Hill's (1938) equation with the following parameters (at 37 degrees tc): a/Po = 0.73 plus or minus 0.04, b = 0.54 plus or minus 0.04 lengths/s, Vmax = 0.74 plus or minus 0.02 lengths/s (n = 7, mean plus or minus S.E,). The force-velocity relation of the portal vein in comparison with other kinds of muscle is discussed.

A note on the influence of asynchronous activation on myocardial contraction.

AbstractPairs of rabbit papillary muscles were mounted in series to make it possible to study the effects of asynchronous activation on myocardial contraction. The two muscles were connected together via platinum loops hooked to a lever (displacement transducer), the other end of each muscle being fixed to a force transducer. The force of each muscle was measured at various contraction frequencies with the lever fixed (isometric contractions) or freely movable (auxotonic contractions). With auxotonic contractions, asynchronous activation (25 or 50 ms interval between stimulation of the two muscles) increased the movements of the muscles, decreased their force, and prolonged the duration of the contraction at 37°C. These effects were greater, the higher the contraction frequency within the range 30–150 beats/min. On the basis of these results, it is suggested that the physiological asynchrony of the myocardial contraction in vivo tends to offset frequency‐induced changes at the cellular lever (enhanced intensity of active state, shortening of active state duration).

Contractile properties of human skeletal muscle. Normal and thyroid disease.

Active state duration and active state intensities of shortening and load-bearing were determined in the adductor pollicis muscle of 20 normal subjects, and seven hyperthyroid and four hypothyroid patients. Normal subjects showed a marked posttetanic and staircase twitch potentiation related primarily to an increase in active state intensity of shortening. In hyperthyroidism, active state duration in the unconditioned twitch was shortened while in hypothyroidism it was prolonged. Active state intensity of load-bearing was normal in hyperthyroidism (five of seven patients) and decreased in hypothyroidism (three of four patients). After repetitive stimulation (tetanus and staircase), both groups showed either a less than normal twitch potentiation (less than normal increase of active state intensity of shortening) or twitch depression below the control level (decreased active state duration without normal increase of active state intensity of shortening).

Relationships between force and velocity of shortening in rabbit papillary muscle.

AbstractThe instantaneous relationship between isotonic load and velocity of shortening was studied in rabbit papillary muscles using a quick‐release technique which involved critical damping of the lever. The force‐velocity curve was determined from the experimental data by means of the least squares method using a computer program. The curve exhibited a true hyperbolic shape and virtually the same values of the constants a and b in Hill's equation were obtained when the analysis was carried out during the rising or falling phase of an isometric contraction. The experimental basis of the discrepant results reported in previous studies has been scrutinized. Variability in active state intensity and contractile element length between individual force‐velocity determinations may account for the non‐hyperbolic shape of the force‐velocity curve obtained in an analysis of after loaded contractions. Quick releases performed without critical damping of the lever movements were found to have a depressant effect upon the myocardial activity resulting in a distortion of the force‐velocity curve at intermediate and small loads. The distortion of the curve was more pronounced when the analysis was carried out during relaxation than during the rising phase of the contraction. The deactivating effect is most likely attributable to the rapid fluctuations in speed of shortening of the contractile unit caused by inertial oscillations of the lever system after an underdamped quick‐release.

Effects of abrupt load alterations on force-velocity-length and time relations during isotonic contractions of heart muscle: load clamping.

1. Abrupt alterations in load (load-clamping) have been imposed on cat papillary muscles during the course of isotonic shortening, between the onset of shortening and peak shortening.2. For any given total load, whether imposed during the course of shortening or before stimulation, the velocity of shortening is determined solely by the instantaneous length, and not by the sequence of length and tension changes through which it arrived at that length.3. This unique force-velocity-length relation is independent of time from just after the onset of shortening until just prior to peak shortening.4. These results suggest that a steady state exists for the maximum intensity of active state in heart muscle over a major portion of the time during which isometric force is rising, and that heart muscle always senses total load while shortening.

The effects of temperature upon contraction and ionic exchange in rabbit ventricular myocardium. Relation to control of active state.

The mechanical responses (active and resting tension, dP/dt, TPT) and ionic exchange characteristics (Ca(++), K(+), Na(+)) which follow upon a variation in temperature, rate, and [K(+)](0) were studied in the rabbit papillary muscle and arterially perfused rabbit interventricular setpum. Abrupt changes in temperature provided a means of separating the contributions of rate of development (intensity) of active state and duration of active state to total active tension development (approximated by isometric tension). Threefold changes in duration of active state with proportional changes in active tension can be induced without evidence for alteration of Ca(++), K(+), or Na(+) exchange. Abrupt cooling produced a moderate ( approximately 15%) increase of dP/dt which suggests an augmentation of active state intensity. Evidence is presented to suggest that this increase of dP/dt is based upon an increase in membrane Ca(++) concentration which occurs secondary to inhibition of active Na(+) transport. The alterations in ionic exchange and active state produced by variation of temperature are discussed in terms of a five-component control system.

The Effects of Temperature upon Contraction and Ionic Exchange in Rabbit Ventricular Myocardium

The mechanical responses (active and resting tension, dP/dt, TPT) and ionic exchange characteristics (Ca(++), K(+), Na(+)) which follow upon a variation in temperature, rate, and [K(+)](o) were studied in the rabbit papillary muscle and arterially perfused rabbit interventricular setpum. Abrupt changes in temperature provided a means of separating the contributions of rate of development (intensity) of active state and duration of active state to total active tension development (approximated by isometric tension). Threefold changes in duration of active state with proportional changes in active tension can be induced without evidence for alteration of Ca(++), K(+), or Na(+) exchange. Abrupt cooling produced a moderate ( approximately 15%) increase of dP/dt which suggests an augmentation of active state intensity. Evidence is presented to suggest that this increase of dP/dt is based upon an increase in membrane Ca(++) concentration which occurs secondary to inhibition of active Na(+) transport. The alterations in ionic exchange and active state produced by variation of temperature are discussed in terms of a five-component control system.

Effects of halothane on isometric contractions of isolated heart muscle.

In isometric contractions of an isolated heart muscle preparation exposed to halothane (0.10, 0.40, 0.85, 1.05 and 2.35 volumes per cent), peak developed tension and maximum rate of tension development were reduced as much as 53 per cent and 57 per cent, respectively, in direct proportion to the concentration of the anesthetic. Time to peak tension and total twitch duration were not decreased more than 6.3 per cent by any concentration of halothane. Resting tension was affected only by the highest concentration, 2.35 volumes per cent, which lowered it 6.8 per cent Relaxation time and muscle length were not altered. Recovery from the effect of halothane was essentially complete in each instance. The results are consistent with the concept that halothane exerts its cardiac effects primarily by a direct reduction in active state intensity of heart muscle.

Regulation of cardiac muscle contractility.

The heart's physiological performance, unlike that of skeletal muscle, is regulated primarily by variations in the contractile force developed by the individual myocardial fibers. In an attempt to identify the basis for the characteristic properties of myocardial contraction, the individual cardiac contractile proteins and their behavior in contractile models in vitro have been examined. The low shortening velocity of heart muscle appears to reflect the weak ATPase activity of cardiac myosin, but this enzymatic activity probably does not determine active state intensity. Quantification of the effects of Ca(++) upon cardiac actomyosin supports the view that myocardial contractility can be modified by changes in the amount of calcium released during excitation-contraction coupling. Exchange of intracellular K(+) with Na(+) derived from the extracellular space also could enhance myocardial contractility directly, as highly purified cardiac actomyosin is stimulated when K(+) is replaced by an equimolar amount of Na(+). On the other hand, cardiac glycosides and catecholamines, agents which greatly increase the contractility of the intact heart, were found to be without significant actions upon highly purified reconstituted cardiac actomyosin.

Active state in heart muscle. Its delayed onset and modification by inotropic agents.

The course of active state in heart muscle has been analyzed using a modified quick release method. The onset of maximum active state was found to be delayed, requiring 110-500 msec from time of stimulation, while the time to peak isometric tension required 250-650 msec. Further, the time from stimulation to peak tension was linearly related to the time required to establish maximum intensity of active state as well as to the duration of maximum active state. The duration of maximum active state was prolonged (90-220 msec), occupying most of the latter half of the rising phase of the isometric contraction. Norepinephrine (10(-5) M) shortened the latency from electrical stimulus to mechanical response, accelerated the onset of maximum active state, increased its intensity, decreased its duration, and accelerated its rate of decline. These changes were accompanied by an increase in the rate of tension development and the tension developed while the time from stimulation to peak isometric tension was abbreviated. Similar findings were shown for strophanthidin (1 microgram/ml) although lesser decrements in the duration of maximum active state and time to peak tension were found than with norepinephrine for similar increments in the maximum intensity of active state.

The effect of deuterium oxide on the mechanical properties of muscle.

The effect of deuterium oxide on the isometric contraction of frog's muscle was investigated. In 99.8 per cent deuterium oxide the twitch force was reduced to 2–70 per cent of the force in aqueous Ringer, the rate of force development to 12–30 per cent, the tetanic force to 61–96 per cent while the latency of force development was approximately doubled. The total duration of the twitch was unchanged. The duration of the plateau of maximum intensity of active state remained unaltered by deuterium while its decline was enhanced. The conduction time of the action potential was not affected by deuterium but the reduction in frequency at which a complete tetanus could be maintained indicated an effect on the excitatory processes. It remained undecided whether the reduction in force is due to an effect of deuterium on the contractile elements or on the excitation‐contraction coupling.