Recovery Half-time Research Articles

Effects of oral supplementation of coenzyme Q 10 on 31P-NMR detected skeletal muscle energy metabolism in middle-aged post-polio subjects and normal volunteers

The effects of oral supplementation of 100 mg coenzyme Q 10 (CoQ 10) for 6 months on muscle energy metabolism during exercise and recovery were evaluated in middle-aged post-polio ( n = 3) and healthy subjects ( n = 4) by the use of phosphorus-31 nuclear magnetic resonance spectroscopy. The metabolic response to isometric plantar flexion at 60% of maximal voluntary contraction force (MVC) for 1.5 min was determined in gastrocnemius muscles before, after 3- (3MO) and 6-month (6MO) of CoQ 10 supplementation. The MVC of plantar flexion was unchanged following CoQ 10 supplementation. The resting P i PCr ratio in gastrocnemius muscles of all subjects decreased after 3MO- and 6MO-CoQ 10 ( P < 0.05). The post-polio individuals showed a progressive decrease in this ratio, while less pronounced changes were observed in the control subjects. Similarly, the post-polio individuals showed a lower P i PCr ratio at the end of 60% MVC in both 3MO- and 6MO-CoQ 10, whereas no change in the ratio was observed in the control subjects. A less pronounced decrease in muscle pH was observed at the end of 60% MVC in both 3MO- and 6MO-CoQ 10 in the post-polio individuals, but not in the control subjects. No systematic difference in end-exercise ATP was observed between the three phases in both groups. The half-time of recovery for PCr decreased in all subjects after 6MO-CoQ 10 supplementation ( P < 0.05). The results suggest that CoQ 10 supplementation affects muscle energy metabolism in post-polio individuals to a greater extent than in control subjects. The mechanism for this effects is not clear, but may involve an effect of CoQ 10 on peripheral circulation in the calf muscles, its action in mitochondrial oxidative phosphorylation and/or its antioxidant potential.

Changes in Energy Metabolism of Calf Muscle in Patients with Intermittent Claudication Assessed by 31P Magnetic Resonance Spectroscopy: A Phase II Open Study

Energy status and metabolism in skeletal muscle of nine patients with peripheral arterial disease and suffering from intermittent claudication were evaluated using 31phosphorus magnetic resonance spectroscopy (MRS) before and after treatment for 3 months with propionyl-L-carnitine (PLC; 2 g/day p.o.). Maximum walking distance (MWD) was assessed on a standard treadmill (4 km/h, zero incline). For the group as a whole 31P MRS results did not change significantly with PLC. Although MWD increased by a mean of 36%, this change did not reach significance. However, when these variables were assessed with respect to the change in MWD, there were significant differences between those who increased MWD by > 30% (responders, R; n = 5) and those who did not (nonresponders, NR; n = 4). Compared with pretreatment values, during exercise the decrease in muscle pH in R relative to the decrease in phosphocreatine was less after PLC (p = 0.04). After exercise there was a significant inverse correlation between the changes in recovery half-time (t1/2) for phosphocreatine and in MWD (r = -0.91, p = 0.01). With PLC, Vmax increased in R (p = 0.04), but not in NR. For the patient group as a whole, the changes in Vmax and MWD correlated positively (r = 0.90, p = 0.01). This study helps to identify the changes in muscle metabolism that correlate with changes in exercise performance, and may accompany treatment with PLC.

Kinetics of homomeric GluR6 glutamate receptor channels

We studied the kinetics of the unedited version of rat GluR6 glutamate (glu) receptor channels, GluR6Q, in outside-out patches using a system for submillisecond solution exchange. Half-maximum activation of the channels was reached with approximately 0.5 microM glu. The maximum slope of the double-logarithmic plot of the peak current versus glu was approximately 1.3, indicating that at least two binding steps are necessary to open the channels. Currents in response to a pulse of 10 microM glu had a short rise time (10-90% of peak current) of approximately 220 microseconds at approximately 20 degrees C. The rise time increased with falling glu concentration, reaching approximately 6.0 ms with 10 microM glu. In the continued presence of glu, the channels desensitized, and this desensitization can be described with a single time constant of approximately 7.0 ms for a pulse of 10 microM glu. The steady-state current in response to a long pulse of 10 microM glu was below 1/280th of the peak current. The time constant of desensitization was found to be independent of concentration between 30.0 and 0.3 microM glu, but to be increased for lower concentrations. After a short pulse of 1 ms duration and 10 or 0.3 microM glu, currents decayed with a time constant of approximately 2.5 ms. Recovery from desensitization after a pulse took approximately 5 s, and the half-time of recovery was approximately 2.2 s. Continuous application of low concentrations of glutamate reduced the peak currents in response to a pulse of 10 microM glu markedly. Fifty percent response reduction was observed in the continuous presence of approximately 0.3 microM glu. Our results for homomeric GluR6 agree with a cyclical reaction scheme developed for completely desensitizing, glu-activated channels on crayfish muscles.

Better autonomic conditioning and faster electrodermal half-recovery time at age 15 years as possible protective factors against crime at age 29 years.

This prospective study tests the hypothesis that antisocial adolescents who desist from adult crime show better classical conditioning and faster skin conductance half-recovery times at age 15 compared with antisocial adolescents who go on to become adult criminals at age 29. Measures were assessed in 101 unselected 15-year-old male school children. Of these, 17 antisocial adolescents who desisted from adult crime (desistors) were matched with 17 antisocial adolescents who became criminal by age 29 (criminals) and 17 nonantisocial noncriminals (controls). Desistors had significantly better conditioning and faster recovery times than both criminals and controls. These initial findings suggest that better conditioning and enhanced information processing to emotion-relevant events may constitute biological protective factors against crime development.

Kinetics of oxygen consumption during and after exercise in patients with dilated cardiomyopathy New markers of exercise intolerance with clinical implications

Objectives. This study analyzed the kinetics of oxygen consumption during and after a maximal cardiopulmonary exercise test in patients with dilated cardiomyopathy. The prognostic information derived from indexes of recovery was also studied.Background. Previous studies have examined the kinetics of oxygen consumption during a short recovery period in a limited number of patients. To our knowledge, no study has examined the prognostic information derived from indexes of recovery.Methods. We studied 153 patients and 55 control subjects. We calculated the ratio between total oxygen consumption during exercise and recovery, the half-recovery time of peak oxygen consumption, the time constant of recovery, the recovery time and the ratio between duration of exercise and recovery time.Results. Recovery of oxygen consumption was significantly delayed in patients, and this delay was related to the degree of exercise intolerance. After a median follow-up period of 439 days, for the total study group, percent of predicted peak oxygen consumption (p = 0.003) and ejection fraction (p = 0.03) were independent predictors of survival. In a subgroup of patients with moderate exercise intolerance (percent peak oxygen consumption >40%), the ratio between total oxygen consumption during exercise and recovery (p = 0.013) and the ejection fraction (p = 0.013) were independent predictors of survival.Conclusions. The kinetics of oxygen consumption during recovery was delayed in patients with dilated cardiomyopathy. Although indexes of recovery were not prognostic markers in the total study group, the ratio between total oxygen consumption during exercise and recovery was an independent prognostic marker in patients with moderate exercise intolerance.

Impairment of muscle mitochondrial oxidative metabolism in McArdles's disease.

Impairment of muscle glycogenolysis in McArdle's disease (myophosphorylase deficiency) leads to exercise intolerance and exercise-induced myalgia. The pathophysiology of these symptoms is not entirely clear. We used phosphorus magnetic resonance spectroscopy to measure muscle phosphate metabolite concentrations and intracellular pH during brief ischemic exercise and in the period of aerobic metabolic recovery after exercise, with special attention to cytoplasmic adenosine 5'-diphosphate (ADP). In 5 patients with McArdle's disease, calculated muscle intracellular ADP concentrations at the beginning of recovery were higher than in normal control subjects (70-425 mmol/L, control mean: 73 +/- 40 mmol/L, P < 0.05). The half-time for intracellular ADP recovery after exercise, an index of maximal mitochondrial oxidative phosphorylation, was 0.16 +/- 0.07 in normal controls and was independent of metabolic state or intracellular pH. ADP recoveries were abnormally slow in all patients with McArdle's disease (range: 0.32-0.83 min, mean = 0.2 min, P < 0.0001). These results are indicative of a limitation in the rate of oxidative phosphorylation in muscle of patients with McArdle's disease, most likely due to impaired substrate delivery to mitochondria. This impairment of mitochondrial function may contribute to the exercise-related symptoms in McArdle's disease.

The Hemodynamic Abnormalities in Short-Term Insulin Deficiency: The Role of Prostaglandin Inhibition

It has been suggested that the hemodynamic derangements present in diabetic ketoacidosis are the results not only of profound volume depletion but also of the effects of increased production of vasodilating prostaglandins (PGs), principally PGI2, released by adipose tissue. In animal and in vitro models, prostaglandin synthesis is increased during insulin deficiency. We assessed the effects of short-term ketosis on the metabolic and hemodynamic variables of 10 IDDM patients free from long-term complications and of 9 normal control subjects after a 7-day randomized double-blind indomethacin (INDO) (50 mg q.i.d.) or placebo treatment period. Calf blood flow (CBF), postocclusive reactive hyperemia (PORH), and recovery half-time (an index of overall perfusion) after PORH were measured by plethysmography. Left ventricular and myocardial functions were also studied in each different condition during placebo and INDO treatment in IDDM patients. During placebo treatment, the increase in CBF during ketosis was higher (1.75 +/- 0.29 ml / min / 100 ml muscle) than during INDO (0.85 +/- 0.17 ml / min) / 100 ml muscle; P = 0.007). PORH was similar in baseline conditions, during ketosis, and in recovery in both the placebo and INDO arms. Recovery half-time significantly increased during placebo (10 +/- 2; 200%; P < 0.01) but not during INDO (1 +/- 1; 106%; NS) treatment. In normal control subjects, insulin deficiency did not induce any significant effect on hemodynamic variables. In IDDM patients, during placebo treatment, ketosis increased both the cardiac index (from 3.4 +/- 0.7 to 4.1 +/- 0.81 / min / m; P < 0.01) and the stroke index (from 42 +/- 8 to 49 +/- 7 ml/m2; P < 0.01) without changes in left ventricular ejection fraction but with a significant increase in both left and right ventricular end-diastolic volumes. Metabolic recovery induced a normalization of these parameters. INDO treatment significantly blunted these alterations. In summary, we showed that during acute insulin deficiency, INDO-sensitive mechanisms mediate vascular disturbances. Moreover, INDO treatment was capable of completely preventing the cardiac venous return and the left ventricular alterations. INDO does not interfere with the overall ketogenetic process or with insulin-induced metabolic recovery.

MPR 14]-rADM(14–50), A novel analog of adrenomedullin, possesses potent vasodilator activity in the hindlimb vascular bed of the cat

Responses to [Mpr 14]-rADM (14–50), a novel analog of adrenomedullin, were investigated in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intraarterial injections of [Mpr 14]-rADM(14–50) in doses of 0.003-1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, [Mpr 14]-rADM(14–50) was more potent than human synthetic adrenomedullin (hADM) in doses of 0.003-0.1 nmol. The recovery half-times ( T 1 2 ) for the vasodilator response to [Mpr 14]-rADM(14–50) were significantly greater than the recovery half-times for hADM in all doses studied. Decreases in hindlimb perfusion pressure in response to [Mpr 14]-rADM(14–50) were not altered by the calcitonin generelated peptide receptor antagonist rCGRP(8–37) at the same time vasodilator responses to calcitonin gene-related peptide were significantly reduced. The present data demonstrate that [Mpr 14]-(14–50) has potent and long-lasting vasodilator activity when compared to hADM, and that vasodilator responses to [Mpr 14]-rADM(14–50) are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat.

Nicotinamide as a Repair Inhibitor In Vivo: Studies Using Single and Fractionated X-Ray Doses in Mouse Skin and Kidneys

Inhibitors of adenosine diphosphoribosyl transferase, like nicotinamide, 3-aminobenzamide and other analogues, can inhibit repair of radiation-induced sublethal and/or potentially lethal damage in some in vitro systems. Therefore, we have tested the effect of nicotinamide on repair parameters in vivo in two rodent normal tissues. In skin, the sensitivity to dose fractionation (1, 2, 5 or 10 X-ray fractions in 5 days) was monitored by defining the alpha/beta ratio in the presence or absence of nicotinamide (0.5 mg g-1) in air or carbogen. Pre- and postirradiation sensitization were investigated using an X-ray schedule of 5 fractions/5 days in carbogen alone or combined with nicotinamide given 1 h before, immediately after or 8 h after irradiation. Also, changes in the steepness of the underlying X-ray survival curve for the target skin clonogens, reflected by a change in the alpha/beta ratio, were investigated using the neutron top-up design. Underlying survival curves for oxygen +/- nicotinamide were obtained over the X-ray dose range 2.5 to 25 Gy, by administering single X-ray doses and following these with single top-up doses of d(4)-Be neutrons. Finally, in mouse kidney, recovery half-times (t1/2) were obtained by determining the time-dependent disappearance of X-ray damage using a split-dose design of two 6-Gy fractions separated by an interval which varied from 0 to 48 h and followed by two top-up doses from a neutron beam. No increase in alpha/beta for epidermal damage was seen with nicotinamide alone and, although sensitization was observed when the drug was given 1 h before irradiation, no postirradiation sensitization was detected. In kidney, there was no significant difference in the proportion of total repairable damage or in the half-life of recovery between treatments given with or without nicotinamide. Therefore, no decrease in normal tissue tolerance should be observed with the use of nicotinamide in clinical radiotherapy resulting either from reduced sparing with dose fractionation or from an increase in residual damage when shortening the interfraction interval. Finally, unless repair of radiation damage in normal tissues in vivo differs markedly from that of tumors, it is unlikely that the large sensitization seen in rodent tumors at 1.5 to 2 Gy per fraction, with carbogen and nicotinamide, can be attributed to nicotinamide acting as a repair inhibitor.

Computer simulation of factors involved in the down-regulation of hormonal effects

Down-regulation of hormonal effects is in the presented simulation related to the number of functional receptors and quantity of available hormonal stimulation. The former is in the model substituted with the quantity of stimulation able to produce a full down-regulation ( Hs 100) of target cells. The halftime ( t 1/2) of the hormonal effect recovery means the interval before the second hormonal stimulation can elicit half of the initial hormonal effect. Recovered hormonal effects are calculated after periods of two, three, four and five t 1/2. The interval among hormonal stimulations varied from 1/2 to 5/2 of t 1/2. Shorter than t 1/2 intervals showed profound down-regulation even at weak hormonal stimulations (> 20% of Hs 100). Stable levels of hormonal effects after frequent hormonal stimulations are found only in cases of very weak stimulations (< 10% of Hs 100). Intervals equalling t 1/2 among weak stimulations (< 20% Hs 100) produced stable hormonal effects. Further prolongation among repeated stimulations improved stability of hormonal effects and even strong stimulations (> 60% of Hs 100) were followed with only temporary profound down-regulation. Hormone-binding receptors unable to activate target cells are in the model described as defective. Probability for the target cell to be stimulated is in the model defined as P. Relative quantity of hormonal stimulation per target cell needed to achieve certain P is calculated for cells bearing different proportions of defective receptors. Activation following weak hormone stimulations is highly probable (> 90%) for cells bearing less than 30% of defective receptors. With the proportion of defective receptors over 60%, the activation probability after weak hormone stimulations is reduced (< 66%). Down-regulation can be considered as a modulator of hormonal effects. In prediabetic patients, intense stimulation of pancreatic insulin secretion by frequent or increased ingestion of carbohydrates might lead to sustained hyperinsulinemia. A substantial portion of the target tissue would become down-regulated with increased number of defective insulin receptors. Poor glucose utilization in the down-regulated tissue with resultant hyperglycemia would further stimulate insulin secretion until failure. Reduced tissue transportability of large hormone molecules, such as hGH, or proinsulin, can make their effects more pronounced in the perivascular space. Circulating hormone binding proteins or the basal membrane thickening in small vessels can further decrease the hormonal effects on more remote cells. Physical activity in IDDM patients increases insulin effect. Possible explanation is that increased muscle perfursion is making more insulin available to the less down-regulated skeletal muscle cells.

Better autonomic conditioning and faster electrodermal half-recovery time at age 15 years as possible protective factors against crime at age 29 years.

Better autonomic conditioning and faster electrodermal half-recovery time at age 15 years as possible protective factors against crime at age 29 years.

Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study

Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48-72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P < 0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P < or = 0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P < or = 0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.

Rat skeletal muscle metabolism in experimental heart failure: effects of physical training.

Skeletal muscle metabolic abnormalities exist in chronic heart failure. The influence of physical training on muscle metabolism after myocardial infarction was studied in a rat model. 31P magnetic resonance spectroscopy and enzyme assays were performed in Wistar rats 12 weeks after coronary artery ligation. Infarcted rats were allocated randomly to either 6 weeks of training or non-training. Spectra were collected from the calf muscles during sciatic nerve stimulation at 2 Hz. Fibre typing and enzymatic assays were performed on the muscles of the contralateral non stimulated leg. Post-mortem rats were also divided into severe and moderate heart failure according to the lung weight per body weight. At 200 g twitch tension, phosphocreatine and pH were found to be significantly lower in the non-trained severe heart failure group compared with the other groups. Phosphocreatine recovery half-time was significantly longer in the non-trained group with severe heart failure and correlated with the citrate synthase activity in the muscle. The training did not induce a change in the enzyme activities in the infarcted animals with moderate heart failure but did correct the lower citrate synthase activity in the non-trained severe heart failure animals. This normalization of muscle metabolism was achieved by training without any change in calf muscle mass, making atrophy unlikely to be the sole cause of the metabolic changes in heart failure. Training in rats with severe heart failure can reverse the abnormalities of skeletal muscle metabolism, implicating decreased physical activity in the aetiology of these changes.

Prolonged kinetics of recovery of oxygen consumption after maximal graded exercise in patients with chronic heart failure. Analysis with gas exchange measurements and NMR spectroscopy.

Patients with chronic heart failure (CHF) often complain of prolonged dyspnea after exercise. The determinants of oxygen consumption after exercise in these patients are unknown. We hypothesized that the kinetics of oxygen consumption recovery after graded exercise was prolonged in parallel with the recovery of muscle energy stores, was not affected by the exercise level, and could be used to assess the circulatory response to exercise. Seventy-two patients with CHF in Weber's class A (n = 28), B (n = 21), and C/D (n = 23) and 13 healthy subjects performed maximal upright bicycle exercise with breath-by-breath respiratory gas analysis. Kinetics of recovery of ventilation (VE), oxygen consumption (VO2), and CO2 production (VCO2) after exercise were characterized by T1/2, the time to reach 50% of the peak value. T1/2 VO2 (seconds) increased with the severity of CHF (97 +/- 17 for CHF A [P < .05 versus CHF B, P < .05 versus CHF C/D], 119 +/- 22 for CHF B [P < .05 versus control subjects, P < .05 versus CHF A, and P < .05 versus CHF C/D], 155 +/- 55 for CHF C/D [P < .05 versus control subjects, P < .05 versus CHF A, and P < .05 versus CHF B] compared with 77 +/- 17 for control subjects). T1/2 VCO2 and T1/2 VE also increased similarly with the worsening of CHF. T1/2 VO2 was correlated negatively with peak VO2 (r = .65) and was reproducible (r = .96). To study the relation between T1/2 VO2 and the duration of exercise, 10 healthy subjects and 22 patients underwent a second graded test at 75% and/or 50% of peak workload. T1/2 VO2 was minimally shortened, at only 50% of peak workload (P = .02). Finally, 19 patients underwent 31P nuclear magnetic resonance spectroscopy of the anterior compartment of the leg during exercise; the half-time of recovery of the ratio of inorganic phosphate to creatine phosphate (T1/2 Pi/PCr), reflecting the level of involvement of oxidative metabolism in the restoration of energetic metabolites after exercise, was linearly correlated with the half-time of VO2 recovery (r = .70, P < .01). Postexercise T1/2 VO2 increases when CHF worsens, perhaps in part a result of slower kinetics of recovery of muscle energy stores. The time course of oxygen consumption recovery may represent a simple new criterion for measuring the impairment of the circulatory response to exercise in CHF, even submaximal exercise.

Tubulin dynamics in neuronal axons of living zebrafish embryos

The mechanism of cytoskeletal protein transport, especially the question of what kind of form the cytoskeletal proteins assume during transport in neurons in situ, has been an important, as yet unsettled issue. To clear up this matter, we adopted the embryonic zebrafish as a living animal model and applied the fluorescence recovery after photobleaching (FRAP) method. The zebrafish embryo is appropriate for this kind of study because of its transparency during the early developmental stage, allowing the observation of neurons that incorporate the microinjected fluorescent tubulin directly under fluorescence microscopy. FRAP revealed no movement of the bleached zone proximodistally, where fluorescence recovered gradually (recovery half-time, 44.2 +/- 11.2 min; n = 36), suggesting that the polymers are stationary but dynamic and that the true moving form could be small oligomers or heterodimers.

Intracellular pH of bovine sperm increases during capacitation

The effect of heparin-induced capacitation on the intracellular pH (pHi) of individual bovine sperm was determined with image analysis. Sperm were loaded with the acetoxymethyl ester of the pH sensitive fluorescent indicator, 2',7'-bis(carboxyethyl)-5(6)-carboxy-fluorescein (BCECF). The pHi of 5303 sperm was evaluated from a total of five bulls at .5, 2, 3, 4, and 5 h of incubation. The pHi did not differ between the sperm head and mid-piece (P > 0.05). An increase in sperm head pHi was seen in heparin-treated sperm at 3, 4, and 5 h of incubation relative to sperm incubated without heparin (control, P < 0.05). At 5 h of incubation, the pHi in heparin-treated sperm was 6.92 +/- 0.07, while control-treated sperm pHi was 6.70 +/- 0.03. Initially a normal frequency distribution was seen for sperm pHi in both heparin- and control-treated sperm. As the incubation progressed, the frequency distribution began to skew towards higher pHi in both samples but was more dispersed for the heparin-treated sperm. Following an NH4Cl-induced alkaline load, the pHi of both control- and heparin-treated sperm recovered toward the resting pHi with a half-time of recovery of 1.5-1.7 min. The recovery of sperm pHi was not due to leakage of NH4+ into sperm because recovery also occurred with trimethylamine. The instantaneous velocity of the pHi recovery (v(i)) was dependent on pHi and decreased as pHi decreased. Capacitation by heparin was associated with an 81% decrease in v(i) at a pHi of 7.00, but there was no effect of capacitation on the proton buffering power of the sperm, which was 87 +/- 8 mM/pH unit. Results demonstrate that both the regulation of pHi and resting pHi were altered during capacitation of bovine sperm by heparin.

981-49 Post Exercise Expired Gas Analysis in Patients with Dilated Cardiomyopathy

In normal subjects, after a maximal exercise, oxygen consumption (VO 2 ) declines exponentially towards baseline value. Few studies have examined the kinetics of VO 2 after exercise in patients with dilated csrdiomyopathy (DCM). We studied the kinetics of post exercise VO 2 in 167 cardiopulmonary exercise tests performed in 153 ambulatory patients with DCM and in 45 controls. Patients and controls performed the same exercise (bicycle:l0 watts/min, Medical Graphic analyzer). Mean left ventricular ejection fraction was 29.8 ± 12% (mean ± SD). The VO2-time relationship was fitted to a monoexponential curve for the determination of the time constant of recovery (tRec). We calculated the ratio between total VO 2 during exercise and during recovery (RVO 2 , area under VO 2 curves), the half recovery time of peak VO 2 (½pVO 2 ), the post exercise anaerobic time (PEAT: time during recovery necessary for the respiratory exchange ratio (VCO 2 /VO 2 ) to become &lt;1) and the ratio between exercise duration and PEAT (RPEAT). Patients were divided in 3 subgroups according to their peak VO 2 (&gt;15, &gt;10 and ≤10 ml/min/kg). Result: Contro &gt;15 &gt;10 ≤10 p n 45 88 53 26 Duration exercise s 1299 ± 375 844 ± 171 619 ± 114 445 ± 111 &lt;0.0001 Peak VO 2 ml/min 2641 ± 893 1515 ± 362 995 ± 166 637 ± 176 &lt;0.0001 Peak VCO 2 /VO 2 1.24 ± 0.11 1.26 ± 0.12 1.26 ± 0.12 1.28 ± 0.13 NS RVO 2 5.61 ± 2.48 2.9 ± 0.9 1.97 ± 0.63 1.41 ± 0.65 &lt;0.0001 ½pVO 2 s 70.4 ± 29.4 105 ± 43.4 136 ± 57.7 173 ± 71.8 &lt;0.0001 PEATs 428 ± 147 516 ± 166 535 ± 165 544 ± 208 &lt;0.01 RPEAT 35 ± 189 178 ± 0.61 1.26 ± 0.45 0.97 ± 0.54 &lt;0.0001 tRec s 80.3 ± 26.3 128 ± 120 142 ± 733 204 ± 158 &lt;0.0001 In multiple regression analysis, the parameter most closely correlated with peak VO 2 was the RPEAT (F = 127, P &lt; 0.0001). No relation was found between age or ejection fraction and post exercise parameters. In conclusion, recovery of VO 2 is delayed in patients with DCM and is related to the degree of exercise impairment. Post exercise parameters are a novel marker for exercise intolerance.

Faster force transient kinetics at submaximal Ca2+ activation of skinned psoas fibers from rabbit

The early, rapid phase of tension recovery (phase 2) after a step change in sarcomere length is thought to reflect the force-generating transition of myosin bound to actin. We have measured the relation between the rate of tension redevelopment during phase 2 (r), estimated from the half-time of tension recovery during phase 2 (r = t0.5(-1)), and steady-state force at varying [Ca2+] in single fibers from rabbit psoas. Sarcomere length was monitored continuously by laser diffraction of fiber segments (length approximately 1.6 mm), and sarcomere homogeneity was maintained using periodic length release/restretch cycles at 13-15 degrees C. At lower [Ca2+] and forces, r was elevated relative to that at pCa 4.0 for both releases and stretches (between +/- 8 nm). For releases of -3.4 +/- 0.7 nm.hs-1 at pCa 6.6 (where force was 10-20% of maximum force at pCa 4.0), r was 3.3 +/- 1.0 ms-1 (mean +/- SD; N = 5), whereas the corresponding value of r at pCa 4.0 was 1.0 +/- 0.2 ms-1 for releases of -3.5 +/- 0.5 nm.hs-1 (mean +/- SD; N = 5). For stretches of 1.9 +/- 0.7 nm.hs-1, r was 1.0 +/- 0.3 ms-1 (mean +/- SD; N = 9) at pCa 6.6, whereas r was 0.4 +/- 0.1 ms-1 at pCa 4.0 for stretches of 1.9 +/- 0.5 (mean +/- SD; N = 14). Faster phase 2 transients at submaximal Ca(2+)-activation were not caused by changes in myofilament lattice spacing because 4% Dextran T-500, which minimizes lattice spacing changes, was present in all solutions. The inverse relationship between phase 2 kinetics and force obtained during steady-state activation of skinned fibers appears to be qualitatively similar to observations on intact frog skeletal fibers during the development of tetanic force. The data are consistent with models that incorporate a direct effect of [Ca2+] on phase 2 kinetics of individual cross-bridges or, alternatively, in which phase 2 kinetics depend on cooperative interactions between cross-bridges.

Effects of prolonged exercise on the contractile properties of human quadriceps muscle.

The contractile properties of the quadriceps muscle were measured in seven healthy male subjects before, during and after prolonged cycling to exhaustion. Special efforts were made to obtain measurements immediately after exercise. The exercise intensity corresponded to about 75% of estimated maximal O2 uptake and time to exhaustion was mean 85 (SEM 9) min. At the end of the cycling heart rate and perceived exertion for the legs were 94% and 97% of maximal values, respectively. Maximal voluntary isometric force (MVC) had decreased after 5 min of exercise to a mean 91 (SEM 4)% of the pre-exercise value (P < 0.05) and decreased further to a mean 82 (SEM 6) and mean 66 (SEM 5)% after 40-min cycling and at exhaustion, respectively. A new finding was that during recovery reversal of MVC occurred in different phases where the half recovery time of the initial rapid phase was about 2 min. The MVC was a mean 80 (SEM 2)% of the pre-exercise value after 30 min and was not affected by superimposed electrical stimulation. Maximal voluntary concentric and eccentric forces decreased to 74% and 80% of initial values at exhaustion (P < 0.05). The kinetics of isometric contraction expressed as the time between 5% and 50% of tension (rise time) and the time between 95% and 50% of tension (relaxation time) were not significantly affected by the prolonged cycling. The electromechanical delay measured as the time between the first electrical stimulus and 5% of tension decreased from a mean 32 (SEM 1) ms at rest to a mean 26.6 (SEM 0.6) ms at fatigue (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of swimming behavior in the medicinal leech. IV. Serotonin-induced alteration of synaptic interactions between neurons of the swim circuit.

Serotonin enhances the expression of swimming in the medicinal leech Hirudo medicinalis. These two reports examine the physiological causes underlying this modulation. The initial paper (Mangan et al. 1994) demonstrated that serotonin enhanced the participation of inhibitory swim motor neurons (MNs) in the generation of the swimming rhythm in the isolated nerve cord. In experiments reported here, we examined whether synaptic interactions between neurons of the swim circuit are altered by serotonin. Following exposure to 50 microM serotonin, pairwise intracellular recording revealed the presence of a time-dependent synaptic decrement. Synaptic decrement was characterized by: 1) a substantial decline in synaptic inhibition (half-decay time about 0.4 s) during constant presynaptic excitation; 2) a reduced half-time of recovery from synaptic inhibition; and 3) a strong dependence on the presynaptic neuron's membrane potential. We found little alteration in the physiology of synaptic transmission involving MNs following amine depletion in leech nerve cords. We propose that alterations in synaptic interactions resulting from exposure to elevated serotonin levels, coupled with the changes in MN cellular properties described earlier, are crucial to the increased efficacy of MNs in participating in generating and expressing the leech swimming rhythm.