Post-rest Recovery Research Articles

Walking for a Short Distance at a Brisk Pace Reduces Intraocular Pressure by a Clinically Significant Amount

To determine if walking for a short distance in a natural outdoor setting will have a clinically significant effect on intraocular pressure (IOP). Twenty-five healthy participants (25 eyes) aged 20.8±1.3 years had their IOP measured using noncontact tonometry at baseline, after completing a 1046 m outdoor walking course at a brisk pace and after a 20-minute resting period in a seated position. Repeated-measures analysis of variance was used to compare the average IOP at each time point and Pearson correlation was used to assess relationships between the difference in IOP, baseline IOP, and walking pace. IOP decreased from 16.0±2.6 mm Hg at baseline to 14.6±3.2 mm Hg (-1.4±1.1 mm Hg, P<0.001, 95% confidence interval: +0.7--3.3 mm Hg) after the walk. The IOP remained -0.7 mm Hg below the baseline level (P=0.028, paired t test with Bonferroni correction) after the 20-minute resting period. The decrease in IOP was larger in eyes with a lower baseline IOP (partial Pearson r=0.433, P=0.035, controlled for pace). The average walking pace was 4.7±0.5 km/h and was negatively correlated to the decrease in IOP (partial Pearson r=-0.432, P=0.035, controlled for baseline IOP). The postrest recovery of IOP was greater for participants who demonstrated a greater decrease in IOP during the walking period (Pearson r=-0.427, P=0.033). A short brisk walk caused a clinically significant reduction in IOP by an amount that was related to the relative intensity of the exertion, and it did not recover within a 20-minute period. Clinicians are advised to seek information regarding recent physical activity (including walking) and the subsequent resting period, when highly accurate measurements of IOP are required.

Comparison of the effects of sevoflurane, isoflurane and halothane on rat myocardium

The effects of sevoflurane on myocardial contraction and relaxation are poorly understood. Therefore, we studied the effects of equianaesthetic concentrations (0.5, 1, 1.5, 2 and 2.5 MAC) of sevoflurane, isoflurane and halothane on inotropic and lusitropic (myocardial relaxation) variables, and post-rest potentiation in rat left ventricular papillary muscles in vitro. Sevoflurane and isoflurane caused comparable concentration-dependent negative inotropic effects which were significantly lower than those induced by halothane (P < 0.05). Sevoflurane and isoflurane did not modify lusitropic variables under low or high load, whereas halothane showed a negative lusitropic effect at high concentrations. Halothane suppressed post-rest potentiation, whereas isoflurane and sevoflurane did not. Post-rest recovery was unaffected by halothane, isoflurane or sevoflurane at any concentration. Thus in rat myocardium, sevoflurane and isoflurane caused comparable negative inotropic effects, had no significant lusitropic effects and did not alter post-rest potentiation, suggesting that they did not significantly modify the functions of the sarcoplasmic reticulum.

Regional differences in the regulation of intracellular sodium and in action potential configuration in rabbit left ventricle.

In this study we report measurements of the intracellular sodium concentration ([Na+]i) in cardiac myocytes isolated from sub-endocardial and sub-epicardial regions of the rabbit left ventricle. These measurements show that [Na+]i is significantly higher in sub-epicardial than in sub-endocardial myocytes both at rest and during steady-state stimulation at 0.5 Hz. During a 10-min rest the rate of fall of [Na+]i was identical in cells from the two regions but during post-rest recovery [Na+]i rose significantly faster in sub-endocardial cells. The effect that this difference in sodium regulation may have on the rate of recovery of the calcium transient post-rest is discussed. The steady-state differences in [Na+]i do not appear to have the effect on contraction we would expect i.e. steady-state contraction is larger in sub-endocardial cells where [Na+]i is lower. Changes in [Na+]i brought about by altering the frequency of stimulation are associated with the expected changes of contraction. Action potentials were found to be significantly longer in sub-endocardial cells and following rest action potential duration was shortened although regional differences were maintained. No regional differences in this effect of rest or in recovery of the action potential post-rest were found.

In vitro effects of dantrolene on rat myocardium.

Dantrolene is the only known effective treatment for malignant hyperthermia. However, its effects on myocardial contraction and relaxation remain debatable. The effects of dantrolene (10(-5)-10(-3) M) on the contractility of rat left ventricular papillary muscles were investigated in vitro (Krebs-Henseleit solution, 29 degrees C, pH 7.40, 2.5 and 0.5 mM Ca2+, stimulation frequency 12 pulses/min). The authors studied contraction, relaxation, contraction-relaxation coupling under high and low load, energetics, and postrest potentiation. The effects of dantrolene after depletion of catecholamine stores with reserpine also were studied. Dantrolene induced a moderate concentration-dependent negative inotropic effect at a low calcium concentration (active force at 10(-4) M: 86 +/- 14% of control values, P < 0.05), but not at a high calcium concentration. Dantrolene did not significantly modify the curvature of the force-velocity relation, suggesting that it did not modify myocardial energetics. Dantrolene induced no significant lusitropic effect under low load, suggesting that it did not modify calcium uptake by the sarcoplasmic reticulum. Dantrolene did not significantly modify postrest potentiation and postrest potentiation recovery, suggesting that it did not modify maximum capacity of calcium release by the sarcoplasmic reticulum nor its postrest resetting capacity. Reserpine did not modify the myocardial effects of dantrolene. In rat myocardium, dantrolene did not modify any of the sarcoplasmic reticulum functions tested (uptake, release, postrest recovery). Dantrolene induced a moderate negative inotropic effect, probably mediated by a decrease in transarcolemmal calcium entry, and this negative inotropic effect was blunted by an increase in calcium concentration.

Influence of ryanodine on the mechanical restitution and on the post-extrasystolic potentiation of the guinea-pig ventricular myocardium.

This paper records the results of an investigation into potentiation and staircase phenomena in rightventricular guinea-pig papillary muscles with particular reference to the sarcoplasmic Ca(2+)-channel. As a tool to isolate the second ('late', 'tonic') component of isoproterenol-induced biphasic contractions ryanodine was used. On the evidence at present available the monophasic ryanodine-resistant component of the twitch represents that portion of the activator calcium which reaches the troponin C directly, that is, not taking the roundabout way through the intracellular storage structures. In order to avoid functional instabilities of the isolated muscle preparation a short-time double rest stimulation programme was used which combines a number of different tests and gives information on (1) the post-rest potentiation, (2) the post-extrasystolic potentiation, (3) the mechanical post-rest recovery, (4) the interval-strength relationship, and (5) the mechanical restitution. The results of the present work show that under the influence of ryanodine (1) the Bowditch staircase, a typical feature of normodynamic mammalian ventricular preparations as well as of hypodynamic frog heart preparations, does not exist, (2) the post-extrasystolic potentiation disappears, (3) the curve reflecting the mechanical restitution, under normal in vitro conditions a monotonically increasing function, becomes biphasic within the relative refractory period, (4) the conspicuous depression of the isometric post-rest contraction for long lasting pauses interrupting the regular pacing rhythm, a typical feature of isolated guinea-pig ventricular tissue, is clearly diminished, and (5) the characteristic curve, reflecting the potentiation of the post-extrasystolic post-rest contraction as a function of the delay time preceding the extrastimulus, becomes displaced to the premature interstimulus interval. The concept of an 'extended 2-calcium-store model' is supported by this work.

Regional differences in rest decay and recoveries of contraction and the calcium transient in rabbit ventricular muscle

The rates of rest decay (for rest periods of between 0.5 min and 10 min) and recovery from the rested state (following 10 min of rest) of cell shortening and the amplitude of the intracellular calcium transient were compared in epicardial and endocardial ventricular myocytes isolated from rabbit hearts. The object of these experiments was to determine whether reported transmural differences in action potential duration, myosin type expression and metabolic enzyme content are able to influence the control of contraction. Cells isolated from these two regions of the ventricular wall displayed almost identical twitch shortening and calcium transient characteristics during steady-state electrical stimulation at 0.5 Hz. Despite this, rest decay of cell shortening was faster and recovery from the rested state slower in endocardial cells than in epicardial cells. Neither of these differences could be explained in terms of changes of calcium transient amplitude or time course. We tried to mimic the effect of prolonged rest by application of caffeine to empty the sarcoplasmic reticulum of calcium. The regional differences in recovery of contraction from the rested state were not reproduced in the recovery of contraction after caffeine application, suggesting that the effect is produced by something other than refilling of the sarcoplasmic reticulum. It is suggested that changes in factors that affect myofilament calcium sensitivity produce the regional differences in rest decay and post-rest recovery of contraction.

Cellular mechanisms of endotoxin-induced myocardial depression in rabbits.

We investigated the mechanisms by which endotoxic shock induces intrinsic myocardial depression by studying cardiac myocytes isolated from 10 anesthetized instrumented rabbits given 172 +/- 42 (mean +/- SD) micrograms/kg IV endotoxin. Left ventricular (LV) depression developed 4 +/- 1 hours after endotoxin administration, with a 15 +/- 4% increase in LV internal end-systolic diameter, measured with sonomicrometers at a matched LV end-systolic pressure of 65 +/- 10 mm Hg. Normal LV pressure, arterial PO2, and pH were maintained to minimize confounding effects of ischemia, hypoxia, and acidosis. Cardiac myocytes from endotoxin-exposed rabbits had less unloaded cell shortening and lower peak rates of cell shortening (-dL/dt) and lengthening (+dL/dt) at [Ca2+] levels ranging from 0.5 to 16 mM when compared with myocytes isolated from normal rabbits or rabbits undergoing an identical protocol but without exposure to endotoxin. At 2 mM [Ca2+], cell shortening was depressed by approximately 25% because of a decrease in action potential duration (207 +/- 70 versus 375 +/- 64 milliseconds). In contrast, there was only mild impairment of sarcoplasmic reticulum (SR) function. When myocytes were restimulated after rest periods of 4 to 480 seconds, the decrement in cell shortening (rest decay), peak -dL/dt and peak +dL/dt, and the recovery from rest decay were similar in myocytes from endotoxin-treated and normal rabbits. There was a greater decrement in cell shortening in the second beat of postrest recovery in myocytes from endotoxin-treated rabbits than in normal myocytes. This was partly due to a 12% decrement in action potential duration with rest decay, which did not occur in normal myocytes. The SR Ca2+ content assessed by contractures in 10 mM caffeine was similar in the two groups. We conclude that endotoxic shock produces a LV depression in vivo that persists in isolated myocytes studied in vitro. This intrinsic myocardial depression is largely related to endotoxin-mediated sarcolemmal alterations, which shorten action potential duration, and is not due to alterations in SR function.

Influence of Ca 2+ channel agonists and antagonists on the post-rest staircase

It is now generally accepted that the post-rest staircase consists of two phases, an initial fast phase occurring over the first five to six beats followed by a slow phase which occurs over a period of minutes. In this study, the influence of Ca 2+ channel antagonists (Cd 2+ and nifedipine) and agonists (Bay K 8644 and noradrenaline) on developed tension is investigated to assess the role played by the L-type Ca 2+ current (i Ca) during post-rest recovery. The results show that, at a range of stimulus frequencies, exposure of guinea-pig papillary muscles to either Cd 2+ or nifedipine greatly reduces the fast phase of the staircase and reduces the slow phase of the staircase compared to control (both effects being more prominent at higher stimulus frequencies). Exposure of guinea-pig papillary muscles to Bay K 8644 or noradrenaline potentiated both the fast and slow phases of the staircase with greater proportionate effects observed at higher stimulus frequencies. These results suggest that i Ca plays an important role in both phases of the staircase. The first post-rest beat (the rested state contraction) proved very resistant to Ca 2+ channel blockade suggesting that i Ca plays little role in this contraction which may be the result of entry of Ca 2+ into the cell via a relatively Cd 2+ insensitive pathway, for example the Na +Ca 2+ exchanger.

Ca current facilitation during postrest recovery depends on Ca entry

Whole cell Ca current (ICa) recovery after periods of rest was examined in voltage-clamped rabbit ventricular myocytes with Na and K currents suppressed. To evaluate rest-dependent changes in ICa independent of the effects of sarcoplasmic reticular (SR) Ca release, the intracellular Ca ([Ca]i) transients were usually buffered by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (10 mM) in the patch pipette. When voltage-clamp pulses were resumed (at 0.5 Hz) after a period of rest, several pulses were required to reattain steady-state peak ICa levels. From depolarized holding potentials between -40 and -50 mV, peak ICa of the first pulse was large and gradually decayed to steady-state levels (negative ICa staircase). This potentiation of postrest ICa was mediated by increased recovery from inactivation of Ca channels during the rest period. In contrast, with more negative holding potentials (-70 to -90 mV), the initial postrest ICa was relatively small (rest depression) and facilitation of ICa was then observed for subsequent pulses (positive ICa staircase). This ICa facilitation was mediated by a progressive decrease in the ICa inactivation rate. Depression of the initial postrest ICa required 10-15 s of rest to fully develop and became relatively constant for longer rest intervals (30-300 s). Postrest ICa depression (i.e., subsequent ICa facilitation) was abolished by replacement of extracellular Ca ([Ca]o) with either Ba or Sr. Thus ICa facilitation depends on Ca entry. Increasing [Ca]o increased postrest ICa facilitation and reducing [Ca]o had an opposite effect. When ICa was altered by changing step potential, maximal ICa facilitation occurred when ICa was maximal. Thus ICa facilitation can be graded by the amount of Ca entry. As ICa facilitation was not altered by ryanodine, this response is not likely to be due to SR Ca release. However, increasing [Ca]i buffering by using 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid in the pipette abolished the ICa staircase. Our results indicate that Ca entry can facilitate subsequent ICa, presumably through actions occurring near the sarcolemma. These local changes in [Ca]i lead to a progressive slowing in the rate of ICa inactivation.

In Vitro Effects of Etomidate on Intrinsic Myocardial Contractility in the Rat

Etomidate is available in two different solvents: propylene glycol for induction of anesthesia and ethanol for maintenance of anesthesia. The direct effect of etomidate (1 and 5 micrograms/ml) and of its solvents on cardiac muscle was studied using rat left ventricular papillary muscle. Etomidate induced a slight positive inotropic effect in both solvents, as shown by an increase in maximum unloaded shortening velocity (Vmax) but not in force. At 0.5 mM Ca++ 5 micrograms/ml etomidate increased Vmax (128 +/- 18%, P less than 0.05) but not force (103 +/- 16%, NS). Using various afterloaded twitches, the peak power output (Emax) was calculated: 1 and 5 micrograms/ml etomidate increased Emax (107 +/- 8%, P less than 0.05, and 108 +/- 10%, P less than 0.05, respectively). This increase was related to the increase in Vmax and not in isometric force. Etomidate did not modify the elastic components of papillary muscle, isometric relaxation, and contraction-relaxation coupling under high load. Several findings suggest that etomidate in propylene glycol impaired the sarcoplasmic reticulum (SR) function: 1) it impaired the isotonic relaxation, the contraction-relaxation coupling under low load, and the load sensitivity of relaxation; and 2) it decreased postrest potentiated contraction, which is highly dependent on the SR. Nevertheless, alteration of SR function was only significant at high [Ca++]o and the beat-to-beat postrest recovery was not modified, indicating that the deleterious effects on SR function were moderate. The isotonic relaxation (max Vr) was more impaired by etomidate in propylene glycol (78 +/- 9%, P less than 0.001) and by propylene glycol alone (69 +/- 9%, P less than 0.001) than by etomidate in ethanol (97 +/- 12%, NS) and by ethanol alone (92 +/- 8%, P less than 0.05). This suggests that propylene glycol was responsible for the decrease in SR function. Etomidate in propylene glycol thus has a dual action on rat myocardium: 1) a slight positive inotropic effect due to etomidate per se, and 2) a slight decrease in SR function probably related to propylene glycol. However, because etomidate in propylene glycol induced a slight decrease in isometric force under certain experimental conditions (i.e., after isometric stabilization), etomidate in propylene glycol may induce a slight negative inotropic effect in some clinical conditions as a result of its dual action on the myocardium.

Inotropic effect of ketamine on rat cardiac papillary muscle.

The direct effect of ketamine on cardiac muscle was studied using rat left ventricular papillary muscle. At an extracellular calcium concentration [( Ca++]0) of 2.5 mM, rat myocardial contractility is nearly maximum, and a positive inotropic effect was demonstrated by an increase in maximum shortening velocity (Vmax) with ketamine at 10(-5) M but not 10(-4) M. At a [Ca++]0 of 0.5 mM, ketamine 10(-5) and 10(-4) M had a positive inotropic effect as shown by an increase in Vmax (135% +/- 22% and 147% +/- 33%, respectively) and in isometric active force (AF/s) (120% +/- 10% and 152% +/- 44%, respectively). The positive inotropic effect of ketamine was not related to catecholamine uptake inhibition and/or alpha/beta receptor stimulation because it persisted after phentolamine and propranolol and because ketamine had no relaxing effect. Ketamine 10(-5) and 10(-4) M impaired isotonic relaxation, contraction-relaxation coupling under low loading conditions, and the load sensitivity of relaxation, which suggests impairment of the calcium sequestering systems, especially the sarcoplasmic reticulum (SR). Ketamine modified postrest recovery: the first beat (B1) after a 1-min rest period was decreased by ketamine 10(-4) M but not ketamine 10(-5) M. Moreover, the beat-to-beat postrest recovery has been demonstrated to be exponential, and tau, the time constant of the decay was increased by ketamine 10(-4) M (5.4 +/- 0.3 vs. 3.9 +/- 0.2 beats) but not by ketamine 10(-5) M (3.4 +/- 0.4 vs. 3.7 +/- 0.2 beats). These effects on postrest recovery suggest that ketamine impairs SR function. The authors suggest that ketamine had a dual action on rat myocardium: a positive inotropic effect without any relaxing effect, probably related to an increase in calcium influx, and an impairment of SR function. Nevertheless, impairment of SR is only significant at high concentration (10(-4) M) and might overcome the positive inotropic effect only at supratherapeutic concentration.

Effects of ouabain and low-Na+ perfusion on rest-decay and post-rest recovery of cellular Ca content in ventricular muscle of guinea-pig heart.

Ca2+ shifts in isolated, perfused ventricular muscle of guinea-pig hearts were investigated with the aid of 45Ca under the conditions of complete equilibration of preparations with isotope-containing containing solutions. The content of 45Ca in stimulated preparations (rate 60/min) was 1.30 +/- 0.12 mmol/kg of wet weight (w.w.). 6 min rest resulted in the drop of this content to 0.37 +/- 0.05 mmol/kg w.w. despite continued perfusion with 45Ca containing solution. The difference of 0.93 mmol/kg w.w. is equivalent to fraction Ca2 (15) and is labelled accordingly. Ouabain (1 microM) increased the 45Ca content to 1.53 +/- 0.15 mmol/kg w.w. in the stimulated and to 1.12 +/- 0.23 mmol/kg w.w. in the rested muscle. The respective values after low (50 mM) sodium perfusion were 1.70 +/- 0.11 and 1.07 +/- 0.13 mmol/kg w.w. The differences between the stimulated and rested preparations (Ca2 fraction) were 0.41 and 0.63 mmol/kg, respectively. In the control experiments the force of the first post-rest beat dropped to 20 +/- 5% of the force of steady-state beats. During ouabain and low-sodium perfusion, the force of the first contraction increased markedly and its peak was larger than that of the few subsequent beats. It is concluded that Na-Ca exchange is the important factor in the rate-dependent control of Ca2 fraction content and of contractile force.

Effects of ouabain and low-Na + perfusion on rest-decay and post-rest recovery of cellular Ca content in ventricular muscle of guinea-pig heart

Ca2+ shifts in isolated, perfused ventricular muscle of guinea-pig hearts were investigated with the aid of45Ca under the conditions of complete equilibration of preparations with isotopecontaining solutions. The content of45Ca in stimulated preparations (rate 60/min) was 1.30 ±0.12 mmol/kg of wet weight (w.w.). 6 min rest resulted in the drop of this content to 0.37 ±0.05 mmol/kg w.w. despite continued perfusion with45Ca containing solution. The difference of 0.93 mmol/kg w.w. is equivalent to fraction Ca2 (15) and is labelled accordingly. Ouabain (1 μM) increased the45Ca content to 1.53±0.15 mmol/kg w.w. in the stimulated and to 1.12±0.23 mmol/kg w.w. in the rested muscle. The respective values after low (50 mM) sodium perfusion were 1.70±0.11 and 1.07±0.13 mmol/kg w.w. The differences between the stimulated and rested preparations (Ca2 fraction) were 0.41 and 0.63 mmol/kg, respectively. In the control experiments the force of the first post-rest beat dropped to 20±5% of the force of steady-state beats. During oubain and low-sodium perfusion, the force of the first contraction increased markedly and its peak was larger than that of the few subsequent beats. It is concluded that Na−Ca exchange is the important factor in the rate-dependent control of Ca2 fraction content and of contractile force.

Ca influx and sarcoplasmic reticulum Ca release in cardiac muscle activation during postrest recovery

The recovery of twitch tension (T) and Ca influx after 5-s to 10-min rest intervals was studied in rabbit, rat, and frog cardiac muscle. Extracellular double-barreled Ca-selective microelectrodes were used to assess transsarcolemmal Ca influx. In rabbit ventricle, T at the first postrest beat (B1) exceeded T at the second beat (B2). T and Ca influx then increase toward steady state in a parallel fashion. Since Ca influx is small at B1, this beat may be more dependent on Ca stored in the sarcoplasmic reticulum (SR), and subsequent beats may more closely reflect Ca influx. We have examined this hypothesis using agents that may preferentially inhibit either SR Ca release or Ca influx. SR inhibitors caffeine (5 mM) and ryanodine (100 nM) changed the pattern of T recovery so that B1 was now less than B2 and more closely paralleled the recovery of Ca influx. Caffeine and ryanodine decreased steady-state T to 89 +/- 9 and 78 +/- 3%, respectively. In contrast, B1 was found to be less susceptible to inhibition than B2 when exposed to La or Co (influx inhibitors). These results are consistent with a rabbit ventricle model in which the SR Ca release contributes greatly to B1, the SR contribution declines while the Ca influx component increases, and Ca influx at steady state can account for a large fraction of steady-state T. In adult rat ventricle, caffeine and ryanodine decrease steady-state T to 33 +/- 2 and 13 +/- 3%, respectively, changing the T recovery pattern from a monotonic decrease to a monotonic increase. These results are consistent with a model qualitatively the same as rabbit ventricle. However, the SR can account for most of steady-state T in the rat, and thus its decaying characteristic dominates the control postrest recovery. By inhibition of SR Ca release, the increasing component ascribed to Ca influx becomes apparent. Similar experiments were done to establish an order of relative dependence on SR Ca release: adult rat ventricle greater than rabbit atrium greater than rabbit ventricle greater than frog ventricle.

Calcium fraction correlating with contractile force of ventricular muscle of guinea-pig heart

Ca shifts in the isolated, perfused ventricular muscle of guinea-pig hearts were investigated with the aid of 45Ca under the conditions of complete equilibration of preparations with the isotope-containing solution. In some series of experiments total Ca content was also measured by means of atomic absorption spectrophotometry. The content of 45Ca at the end of 70 min equilibration period during which the ventricles were stimulated at a rate of 60/min was 1.66 +/- 0.09 mmol/kg w.w. This content dropped to 0.42 +/- 0.09 mmol/kg w.w. within 4 min of rest. Contractile force also decreased to 21% of control. Both the content of 45Ca and contractile force returned to the pre-rest values within the 4 min of post-rest stimulation. The difference between the total Ca content in the rested and stimulated muscle was comparable to the respective difference in 45Ca contents. A significant linear correlation between this 45Ca fraction which was lost at rest and recovered during the post-rest stimulation, and contractile force was found under the following experimental conditions: I. post-rest recovery, II. decay during rest, III. post-rest stimulation at various rates. These results are consistent with the hypothesis proposing that this Ca fraction is involved in the frequency-dependent control of contractile force.

The correlation of post-rest recovery in verbal and motor learning.

The correlation of post-rest recovery in verbal and motor learning.