Load Sensitivity Of Relaxation Research Articles

Continuous measurement of the pressure-volume relationship in experimental heart failure produced by rapid ventricular pacing in conscious dogs.

The contractile function of the left ventricle has been defined within the framework of the pressure-volume relationship. We employed a conductance catheter, together with a high-fidelity micromanometer, to obtain accurate pressure and volume data continuously on a beat-to-beat basis in conscious dogs. Reproducibility of conductance volumetry was proven by repeated in situ measurements of left ventricular volume on separate days in the same dog. Heart failure, produced by rapid ventricular pacing, was characterized by impaired systolic shortening, depressed contractility indices and incomplete left ventricular relaxation. The magnitude of the cardiotonic effects of dobutamine was significantly attenuated after development of heart failure. Dobutamine improved left ventricular early relaxation but did not affect chamber distensibility. In heart failure, the load sensitivity of relaxation was enhanced and the force-frequency response attenuated. This may elucidate the mechanisms of early diastolic dysfunction and the deleterious effect of an increase in heart rate in the failing heart. Thus, the conductance catheter provided a reliable and simple method of obtaining left ventricular volume continuously in conscious dogs.

In Vitro Demonstration of the Antidotal Efficacy of Hydroxocobalamin in Cyanide Poisoning

The effects of sodium cyanide (1 mM) and the antidotal action of hydroxocobalamin (1 mM) were studied on rat cardiac papillary muscle. A 10-min period of exposure to cyanide induced a marked decrease in inotropy as shown by a decrease in the maximum unloaded shortening velocity (Vmax: 64 +/- 11% of precyanide values, p <0.01) and active isometric force (AF/s: 35 +/- 13%, p <0.01). The impairment of contraction-relaxation coupling under low load and the nearly complete disappearance of the load sensitivity of relaxation suggested a decrease in sarcoplasmic reticulum function. The proportional acceleration in isometric relaxation suggested a decrease in myofilament calcium sensitivity. There was a nearly complete recovery from cyanide poisoning after 5 min of exposure to hydroxocobalamin, whereas in a control group receiving cyanide alone, the mechanical parameters remained unchanged or were further impaired. The effects of hydroxocobalamin developed very quickly, beat to beat. The main toxic target of cyanide is brain and heart cytochrome oxidase, and brain damage appears only a few minutes after the onset of anoxia. Because hydroxocobalamin is a rapid and powerful antidote, it may be useful in the treatment of acute cyanide poisoning.

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.

Diazepam does not improve the mechanical performance of rat cardiac papillary muscle exposed to chloroquine in vitro

Diazepam has been reported to decrease the cardiac toxicity of chloroquine but the precise mechanism involved remains unknown. Left ventricular papillary muscles from adult Wistar rats were exposed to 10(-4) M chloroquine and assigned to three groups: group I (n = 10) exposed to chloroquine alone; group II (n = 8) exposed to chloroquine and 10(-5) M diazepam; group III (n = 8) exposed to chloroquine and 10(-4) M diazepam. The main mechanical parameters measured were: maximum unloaded shortening velocity (Vmax), maximum lengthening velocity (maxVr), active force normalized per cross-sectional area (AF/s), contraction-relaxation coupling under low load (R1), load sensitivity of relaxation (Isot.A/Isom.A), and peak power output (Emax) determined from Hill's equation of the force-velocity curve. Data are expressed as mean percent of control values +/- SD, for groups I, II, III respectively. No differences between groups I, II, and III were noted for Vmax (87 +/- 13, 82 +/- 9, 86 +/- 7), maxVr (47 +/- 6, 48 +/- 11, 52 +/- 11), AF/s (87 +/- 16, 91 +/- 10, 83 +/- 11), Isot. A/Isom. A (113 +/- 9, 108 +/- 3, 109 +/- 7), or Emax (75 +/- 10, 81 +/- 12, 72 +/- 16). Chloroquine was shown to be a negative inotropic agent since it decreased Vmax, AF/s and Emax, but diazepam did not restore the intrinsic mechanical performance of rat cardiac papillary muscle exposed to chloroquine, therefore 1) the protective cardiovascular effects of diazepam in chloroquine poisoning are not related to an improvement in intrinsic cardiac mechanical properties; 2) inotropic agents are therefore necessary in combination with diazepam for the treatment of severe chloroquine poisoning.

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.

Age-dependent changes of relaxation and its load sensitivity in rat cardiac muscle.

The relaxation phase and its load dependence were studied in papillary muscles isolated from the left ventricle of rats of the following ages: 20 days, 2, 8, 18, and 24 months. The myofibrillar ATPase activity and the force-velocity relation were determined in each age group in order to characterize the kinetic properties of the contractile material. Both shortening velocity and myofibrillar ATPase activity showed a progressive reduction with maturation and aging. This observation suggested an age-dependent decrease in cross bridge formation rate. The relaxation phase was characterized by its duration and the maximum rate of tension decline in isometric conditions, and by the speed of relengthening in isotonic conditions. Relaxation became faster and of shorter duration with maturation from 20 days to 2 months and then became slower and of longer duration with further maturation and aging. The sensitivity of relaxation to changes in length or load was evaluated by measuring how much earlier tension declined in the presence of a given length change. An increase in load sensitivity of relaxation was observed during maturation from 20 days to 8 months. This increase was followed by a reduction during aging from 8 to 24 months. Such a biphasic trend of the age-related changes in load sensitivity of relaxation could result from the interplay between the progressive decrease in cross bridge formation rate and a reduction in activation decay rate. The latter was suggested by the prolongation of the relaxation phase and by the maintenance of developed tension during aging.

Relationship between inotropy and relaxation in rat myocardium.

Myocardial mechanics of 56 rat papillary muscles were investigated in various inotropic states, i.e., early postpartum (1st day, 1st mo) and, in adult, by altering external calcium concentration, [Ca2+]0, stimulation frequency (F), and initial muscle length (L). In all these protocols, the decrease of the inotropic level paralleled a progressive diminution in load sensitivity of relaxation. In such protocols modifying cardiac contractility, peak shortening velocity of the twitch with preload only at Lmax (Vcmax) was always less depressed than peak lengthening velocity (Vrmax), and the ratio R1 = Vcmax/Vrmax always increased. This increase of R1 was linearly related with the decrease of the maximum unloaded shortening velocity (Vmax). The ratio R2 (positive over negative peak force derivatives of the isometric twich at Lmax) was significantly lowered in newborn and was lowered in adult for [Ca2+]0 less than or equal to 1 mM and L less than or equal to 94% Lmax. For a given change in Vmax, each of the experimental protocols gave rise to specific changes in contraction-relaxation coupling tested at low load (R1) and at heavy load (R2).

Relaxation of mammalian heart muscle during chronic cardiac overload.

Cardiac relaxation was studied in rat papillary muscle during hypertrophy induced by different chronic volume and/or pressure overload (aortic insufficiency, aorto-caval fistula, aortic stenosis, spontaneously hypertensive rat). Maximum velocity of lengthening did not depend upon the degree of cardiac hypertrophy, but rather on the type of chronic overload. Cardiac hypertrophy did not modify the load sensitivity of relaxation, whatever the type and stage of chronic overload, although, during acute hypoxia, the load sensitivity disappeared both in normal and in hypertrophied heart muscle.

Load sensitivity of relaxation in the foetal and newborn rabbit heart.

Differences in the mechanism of cardiac relaxation and the influence of changes in the stimulation frequency were studied in foetal and newborn rabbit hearts. In the foetal rabbit heart which lacks a well developed sarcoplasmic reticulum, load sensitivity of relaxation was investigated and compared with that observed in the newborn. Load sensitivity was studied by measuring force and shortening length in twitches with increasing afterloads and also when load clamp steps were rapidly imposed during the twitch. Quantification of the load sensitivity was achieved by the measurement of the time to relaxation "tRi" which was linearly related to the relative developed force. The slope (S) of this linear relation quantifies the load sensitivity: the higher the slope, the more load sensitive is the relaxation. At a frequency of 24 beats X min-1, S was respectively 0.24 in the foetal heart and 0.36 in the newborn heart showing at both ages the existence of a load sensitivity and its significant increase at birth. No further increase in load sensitivity was observed from 1 day to 21 days after birth. Reducing the stimulation frequency from 24 to 10 beats X min-1 abolished the load sensitivity in foetal hearts (S = 0.05) while, in the newborn, a significant load sensitivity could still be observed (S = 0.25). Thus, in rabbit myocardium, the load sensitivity of cardiac relaxation depended upon the age and the stimulation frequency showing a perinatal development of the structures involved in the control of myocardial relaxation.

Load dependence of mammalian heart relaxation during cardiac hypertrophy and heart failure.

Mechanical properties of relaxation were studied in left ventricular rat papillary muscle during cardiac hypertrophy induced by chronic pressure and/or volume overload. Maximum velocity of isotonic lengthening was linearly related to total extent of isotonic shortening and to maximum velocity of isotonic contraction and depended on the type of chronic overloading without correlation with the degree of cardiac hypertrophy. Time to peak shortening was significantly increased in each group of hypertrophied heart muscles as compared to controls. The sensitivity of cardiac relaxation to the loading conditions was determined by the time course of relaxation. To quantify the degree of load sensitivity, we measured the ratio of isotonic area to isometric area, which was the area limited by the afterloaded force vs. time at 50% of the isometric peak tension divided by the area of the force vs. time trace in the isometric twitch below the same level of load. The value of this ratio was about 0.81 in normal rat and did not show any significant differences in hypertrophied heart muscles even at the terminal stage of congestive heart failure. During acute hypoxia the load sensitivity of relaxation disappeared both in normal and in hypertrophied hearts. Thus inadequacy in oxygen supply has more drastic effects, as compared with those induced by chronic overload, probably by affecting the sarcoplasmic reticulum uptake of activating calcium.