Effects of inotropic agents on contraction and relaxation of papillary muscle.

The effects of epinephrine and caffeine on isometric rabbit papillary muscle preparations were observed after maximum peak tension was produced by adjustment of initial length and Ca⁺⁺ concentration. Without change in peak tension, epinephrine caused increased positive dP/dt (p < .005), increased negative dP/dt (p < .001) and decreased time to peak tension (TP) (p < .001), while caffeine resulted in decreased positive dP/dt (p < .02), decreased negative dP/dt (p < .005) and prolonged TP (p < .001). Caffeine added to muscles being perfused with epinephrine reversed the epinephrine effects. The data suggest that epinephrine increases the influx of Ca⁺⁺ into the cell and the uptake of Ca⁺⁺ by the sarcoplasmic reticulum, and that caffeine exerts opposite effects on Ca⁺⁺ exchange. However, an additional mechanism not dependent on changes in Ca⁺⁺ flux is suggested. Epinephrine and caffeine may directly effect the rates of actin-myosin interaction, the former agent increasing, the latter decreasing the rates of attachment and detachment of actin-myosin bridges.     

Treatment and prevention of delayed onset muscle soreness

Eccentric exercise continues to receive attention as a productive means of exercise. Coupled with this has been the heightened study of the damage that occurs in early stages of exposure to eccentric exercise. This is commonly referred to as delayed onset muscle soreness (DOMS). To date, a sound and consistent treatment for DOMS has not been established. Although multiple practices exist for the treatment of DOMS, few have scientific support. Suggested treatments for DOMS are numerous and include pharmaceuticals, herbal remedies, stretching, massage, nutritional supplements, and many more. DOMS is particularly prevalent in resistance training; hence, this article may be of particular interest to the coach, trainer, or physical therapist to aid in selection of efficient treatments. First, we briefly review eccentric exercise and its characteristics and then proceed to a scientific and systematic overview and evaluation of treatments for DOMS. We have classified treatments into 3 sections, namely, pharmacological, conventional rehabilitation approaches, and a third section that collectively evaluates multiple additional practiced treatments. Literature that addresses most directly the question regarding the effectiveness of a particular treatment has been selected. The reader will note that selected treatments such as anti-inflammatory drugs and antioxidants appear to have a potential in the treatment of DOMS. Other conventional approaches, such as massage, ultrasound, and stretching appear less promising.     

The activation of pyruvate dehydrogenase in the perfused rat heart by adrenaline and other inotropic agents.

Adrenaline resulted in a reversible 4-fold increase in the amount of pyruvate dehydrogenase in its active non-phosphorylated form in the perfused rat heart within 1 min. The increase was less in extent in hearts from starved or diabetic rats or in hearts from control rats oxidizing acetate, unless pyruvate was added to the perfusion medium. Increases could also be induced by other inotropic agents, supporting the hypothesis that increases in cytoplasmic Ca2+ can be relayed into mitochondria and influence oxidative metabolism.     

Active state of muscle in iodoacetate rigor

Frog sartorius muscles, equilibrated to 2 x 10(-4)M iodoacetic acid-Ringer's solution and activated by a series of twitches or a long tetanus, perform a rigor response consisting in general of a contractile change which plateaus and is then automatically reversed. Isotonic rigor shortening obeys a force-velocity relation which, with certain differences in value of the constants, accords with Hill's equation for this relation. Changes in rigidity during either isotonic or isometric rigor response show that the capacity of the rigor muscle to bear a load increases more abruptly than the corresponding onset of the ordinarily recorded response, briefly plateaus, and then decays. A quick release of about 1 mm. applied at any instant of isometric rigor output causes the tension to drop instantaneously to zero and then redevelop, the rate of redevelopment varying as does the intensity of the load-bearing capacity. These results demonstrate that rigor mechanical responses result from interaction of a passive, undamped series elastic component, and a contractile component with active state properties like those of normal contraction. Adenosinetriphosphate is known to break down in association with development of the rigor active state. This is discussed in relation to the apparent absence of ATP splitting in normal activation of the contractile component.     

Ruthenium Red inhibits the activation of pyruvate dehydrogenase caused by positive inotropic agents in the perfused rat heart.

The increases in the amount of active, non-phosphorylated, pyruvate dehydrogenase caused by positive inotropic agents (from a control value of about 10%, to 40% of total enzyme) in the perfused rat heart could be completely blocked by prior perfusion with 2.5 micrograms of Ruthenium Red/ml. A similar increase caused by 5 mM-pyruvate was not blocked. This concentration of Ruthenium Red caused a 25% decrease in contractile force of hearts perfused in the absence of positive inotropic agents; however, in their presence the contractile force reached the same value in the absence or presence of Ruthenium Red. Neither control nor stimulated phosphorylase a content was affected by Ruthenium Red. Verapamil (0.1 microM) also decreased control contraction (by 40%), but did not block the activation of pyruvate dehydrogenase caused by a rise in extracellular [Ca2+]. The results support the hypothesis that positive inotropic agents activate pyruvate dehydrogenase in rat heart by increasing intramitochondrial [Ca2+].     

Developmental changes in inotropic actions of neurotoxins observed in ventricular muscle of rat heart.

Developmental changes in functions of myocardial sodium channels were examined from inotropic effects of several neurotoxins in ventricular muscle preparations obtained from prenatal (20-22 day gestation) or adult (3-4 months old) rat hearts. Tetrodotoxin caused a negative inotropic effect in low concentrations and a loss of muscle responsiveness to electrical stimulation in high concentrations in preparations obtained from either prenatal or adult rat heart. The tetrodotoxin concentration that caused a 50% decrease in developed tension was higher in prenatal rats. Anemonia sulcata toxin, Androctonus australis toxin, veratridine, and Centruroides sculpturatus toxin all produced positive inotropic effects in adult rat heart. The effects were largest with A. sulcata and A. australis toxins, intermediate with veratridine, and smallest with C. sculpturatus toxin. Prenatal heart required higher concentrations of either veratridine, or A. sulcata or A. australis toxins to produce comparable positive inotropic effects. With C. sculpturatus toxin, no significant positive inotropic effect was observed in prenatal heart muscle preparations. These results indicate that cardiac sodium channels undergo significant functional changes during development and that negative and positive inotropic effects of neurotoxins resulting from inhibition and enhancement of fast Na+ channels reflect developmental changes in the cardiac sodium channels.     

The consequences of eccentric contractions and their relationship to delayed onset muscle pain

Exercise can cause muscle pain for a number of reasons. Usually the pain is experienced during the exercise and recovers rapidly afterwards. There is one type of muscle pain that has a very different and characteristic time course. In this situation the exercise itself, and the immediate post-exercise period are painfree. The pain is not felt for about eight hours and is maximal 1 or 2 days later. Delayed onset muscle pain occurs after unaccustomed, high force contractions and is particularly associated with eccentric contractions. The concensus of opinion is that the pain is caused by some form of damage, but the mechanism for the pain is not known. This review summarises the literature on the consequences of eccentric contractions and relates them to delayed onset muscle pain. There is clear evidence of damage to the muscle fibres themselves, their membranes and, at a later stage, mononuclear cell infiltration, but all these have very different time courses and none are the same as the pain. Intramuscular pressures are raised in some, but not all, painful compartments and even when raised follow a different time course to the pain. Anti-inflammatory agents do not affect the pain, but due to the incomplete understanding of the action of these drugs, the role of inflammation in delayed onset muscle pain is uncertain. Despite the considerable evidence of damage after eccentric contractions, the cause of delayed onset muscle pain is still unknown.     

Piroxicam fails to reduce myocellular enzyme leakage and delayed onset muscle soreness induced by isokinetic eccentric exercise

To test the hypothesis that delayed onset muscular soreness (DOMS) following intense eccentric muscle contraction could be due to increased production of prostaglandin E(2) (PGE(2)), ten healthy male subjects were studied. Using a double-blind randomized crossover design, each subject performed two isokinetic tests separated by a period of at least 6 weeks: once with placebo, and once with piroxicam (Feldene((R))). They were given one capsule containing either placebo or piroxicam (20 mg) per day for 6 days with initial doses given starting 3 days prior to isokinetic testing. Exercise consisted of eight stages of five maximal contractions of the knee extensor and flexor muscle groups of both legs separated by 1 min rest phases, on a Kin Trex device at 60( degrees )/s angular velocity. The subjective presence and intensity of DOMS were evaluated using a visual analogue scale immediately after, and 24 and 48 h after each test. The mean plasma concentration of PGE(2) measured at rest and after exercise was significantly lower in the group treated with piroxicam (p < 0.05). However, statistical analysis (two-way ANOVA test) revealed that exercise did not cause any significant change of mean plasma PGE(2) over time in either of the two groups. Eccentric work was followed by severe muscle pain in extensor and flexor muscle groups. Maximal soreness was noted 48 h postexercise. Serum creatine kinase activity and the serum concentration of myoglobin increased significantly, and reached peak values 48 h after exercise in both experimental conditions (p < 0.001). By paired t-test, it appeared that there were no significant differences in the serum levels of these two markers of muscle damage between the two groups at any time point. We conclude that: (1) oral administration of piroxicam fails to reduce muscle damage and DOMS caused by strenuous eccentric exercise; and (2) the hypothetical role of increased PGE(2) production in eccentric exercise-induced muscle damage, DOMS, and reduced isokinetic performance is not substantiated by the present results.     

Desmin and actin alterations in human muscles affected by delayed onset muscle soreness: a high resolution immunocytochemical study

Lack of staining for desmin in muscles in animal models of eccentric exercise has been suggested to reflect disruption of the desmin intermediate filament network and proposed to cause disruption of the myofibrillar apparatus and deterioration of muscle fibers. In a recent study, we examined muscle biopsies from persons who had performed different eccentric exercise protocols, which induced delayed onset muscle soreness (DOMS). We were unable to verify that loss of staining for desmin was a feature of sore muscles. Nevertheless, we observed changes in the desmin cytoskeleton, but the meaning of the observations was not conclusive. In the present study, a high resolution immunocytochemical method was used to investigate the changes of desmin and actin in human muscles following a bout of eccentric exercise that lead to DOMS 2-3 days post-exercise. Biopsies were taken before exercise and 1 h and 2-3 and 7-8 days after exercise. Phalloidin, a ligand that labels filamentous actin, and anti-desmin antibodies were used to stain semithin (approximately 0.5 micro m) cryosections. At 1 h post-exercise, the staining of actin and desmin did not differ from the controls, whereas in biopsies taken 2-3 and 7-8 days after exercise, 12.5% (SD 5.8%) and 6.1% (SD 2.3%) fibers showed areas of increased staining for actin. Corresponding values for fibers with increased staining for both actin and desmin were 8.7% (SD 3.9%) and 11.4% (SD 4.6%), respectively. We suggest that the increased staining of actin and desmin reflects an increased synthesis of these proteins as part of an adaptation process following the unaccustomed eccentric exercise.     

Insulin-dependent glycogen synthesis is delayed in onset in the skeletal muscle of food-deprived aged rats

Insulin resistance with aging may be responsible for impaired glycogen synthesis in the skeletal muscle of aged rats and contribute to the well-known decreased ability to respond to stress with aging. For this reason, to assess the ability of the skeletal muscle to utilize glucose for glycogen synthesis during aging, the time course of glycogen synthesis was continuously monitored by 13C nuclear magnetic resonance for 2 h in isolated [13C] glucose-perfused gastrocnemius-plantaris muscles of 5-day food-deprived adult (6-8 months; n=10) or 5-day food-deprived aged (22 months; n=8) rats. [13C] glucose (10 mmol/L) perfusion was carried out in the presence or absence of an excess of insulin (1 micromol/L). Food deprivation only decreased glycogen level in adult rats (8.9+/-2.4 micromol/g in adults vs. 35.6+/-2.4 micromol/g in aged rats; P<.05). In the presence of an excess of insulin, muscle glycogen synthesis was stimulated in both adult and aged muscles, but the onset was delayed with aging (40 min later). In conclusion, this study highlights the important role of glycogen depletion in stimulating glycogen synthesis in muscles. Consequently, the absence of glycogen depletion in response to starvation in aged rats may be the origin of the delay in insulin-stimulated glycogen synthesis in the skeletal muscle. Glycogen synthesis clearly was not impaired with aging.     

Gender effects on trapezius surface EMG during delayed onset muscle soreness due to eccentric shoulder exercise.

The purpose of this study was to investigate gender-specific motor control strategies during eccentric exercise and delayed onset muscle soreness (DOMS) in the shoulder region. Twelve healthy males and females participated in the study. Eccentric shoulder exercises were conducted on the dominant shoulder while the other side served as control. The exerted force, range of shoulder elevation, rating of perceived exertion, pain intensity, and surface electromyography (EMG) from the trapezius muscles were recorded and analyzed. A significant decrease in exerted force during exercise was only found in males despite similar rating of perceived exertion among genders. During eccentric exercise: males showed increasing root mean square (RMS) of the EMG while a decrease occurred for females, no difference between genders in mean power frequency of the EMG were seen. During static and dynamic contractions: no differences between genders in pain intensity or RMS were observed; RMS of the exercised side were lower than that of the control side (P<0.05) at 24 h after exercise. The results indicated a more prominent muscle fatigue resistance in females compared with males and mobilization of different muscle activation strategies during eccentric exercise. A protective adaptation to DOMS, i.e. decrease in RMS values was found with no gender differences.     

Effect of inotropic stimulation on mitochondrial calcium in cardiac muscle.

Ca(2+)-dependent activation of citric acid cycle enzymes has been demonstrated in isolated cardiac mitochondria. These observations led to the hypothesis that Ca2+ is the signal coupling myofibrillar energy use to mitochondrial energy production in vivo. To test this hypothesis we have measured mitochondrial Ca2+ content during increased energy demand, using electron probe microanalysis. Mitochondrial Ca2+ was measured in hamster papillary muscles rapidly frozen at the peak rate of tension rise under control conditions and after stimulation with the beta-adrenergic agonist isoproterenol (10(-6) M). A third group of muscles was frozen after incubation in low (46.5 mM) Na+ solution to Ca2+ load the cells. Pyruvate dehydrogenase activity was measured in each of the muscles. Isoproterenol caused a 39% increase in force and a 43% increase in pyruvate dehydrogenase activity but no change in mitochondrial Ca2+ (0.46 +/- 0.19 (S.E.) mmol of Ca2+/kg, dry weight) compared with control (0.54 +/- 0.12). In contrast, low Na+ increased pyruvate dehydrogenase activity by 56% and also elevated mitochondrial Ca2+ to 1.28 +/- 0.31 (p less than 0.02). These results demonstrate that mitochondrial Ca2+ is not elevated after inotropic stimulation of cardiac muscle by beta-adrenergic agonists although pyruvate dehydrogenase activity is increased. We conclude that Ca2+ uptake by mitochondria is not a requirement for activation of mitochondrial respiration after increased energy demand.