Effect of hypokinesia on the contractile function of the myocardium]

Rats were subjected to hypokinesia for two months and the contractile function of isolated papillary muscles was studied. Hypokinesia reduced significantly the isotonic contraction velocity which depended on the ATPase activity of the myofibrils; it also reduced the velocity and index of relaxation which depended on the functional capacity of the Ca++-pump of the sarcoplasmic reticulum. The maximum force of isometric contraction determined by the quantity of actomyosine bridges in the myofibrils did not change after hypokinesia. This complex of changes is contrary to that observed in adaptation to exercise, when the velocity of isotonic contraction and relaxation increases while the force of isometric contraction does not change. The possible mechanism of this stability of the contractile force during adaptation and readaptation of the heart is discussed.     

Experimental hyperthyroidism IV Myocardial muscle mechanics and oxygen consumption in eu-and hyperthyroidism

Myocardial mechanics and oxygen consumption were studied in right ventricular papillary muscles taken from cats pretreated with cristalline L-thyroxine (1 mg/kg/day, i.p.) 8-18 days prior to the examination. Isotonic afterloaded and isometric contractions were employed. Oxygen consumption was determined polarographically. Data obtained were compared with control studies on papillary muscles taken from euthyroid cats. In isotonic afterloaded contractions the extent of shortening was nearly identical in both groups. However, maximum rate of isometric tension development and velocity of isotonic shortening were considerably increased in hyperthyroid myocardium. Myocardial oxygen consumption was significantly increased in hyperthyroidism, primarily due to an increased maximum rate of isometric tension development and-to a lesser extent-to increased isotonic contraction velocity. In isometric contractions maximum tension development (preload near Lmax) was similar in both groups. However, maximum rate of isometric tension development was markedly increased in hyperthyroidism. A close and linear relationship was found between maximum rate of isometric tension development (isometric contraction) and myocardial oxygen consumption. The results demonstrate increases of velocity factors of myocardial performance in experimental hyperthyroidism. Myocardial oxygen consumption is significantly increased. This increase in oxygen consumption quantitatively has its mechanical equivalent in increased isometric contraction velocity and, to a small amount, in increased isotonic contraction velocity.     

Effects of angiotensin II on intrinsic contractibility of the myocardium in the guinea pig]

Analysis of the contraction-relaxation coupling of guinea pig left ventricular papillary muscle was performed with and without angiotensin II (Ang II 10-6 M). The inotropic and lusitropic properties of Ang II were evaluated at 20 degrees C, 30 beats/min, CaCl2 6H20 2 mM and pH 7.4, under low load (isotonic conditions) and high load (isometric conditions). The maximum velocity of contraction (max Vc) and relaxation (max Vr) were calculated from isotonic contraction having as its only load that corresponding to the imposed preload at Lmax. The maximum positive (+dF/dtmax) and negative values (-dF/dtmax) of the derivative of the force were calculated during isometric contraction. The coefficients, R1 = max Vc/max Vr and R2 = (+dF/dtmax)/(-dF/dtmax), were calculated. These two coefficients allow the contraction-relaxing coupling to be assessed at low and high loads respectively. In the presence of Ang II, the increase in the isotonic velocity of relaxation (1.93 +/- 0.26 vs 3.15 +/- 0.35 Lmax/sec; p < 0.001) was greater than that of the isotonic velocity of contraction (0.74 +/- 0.05 vs 1.02 +/- 0.07 Lmax/sec; p < 0.001). This results in a decrease in the ratio of the velocities of isotonic contraction and relaxation (R1) (0.44 +/- 0.06 vs 0.35 +/- 0.05; p < 0.01). Under isometric conditions, Ang II induced a proportional increase in the parameters of contraction and relaxation. Consequently, there was no significant change in the R2 coefficient (1.22 +/- 0.06 vs 1.12 +/- 0.08). Moreover, Ang II did not induce any change in the sensitivity of the relaxation with respect to load.(ABSTRACT TRUNCATED AT 250 WORDS)     

Experimental hyperthyroidism II mechanics of contraction and relaxation of isolated ventricular myocardium

The effect of experimental hyperthyroidism on myocardial mechanics was examined on isolated ventricular myocardium (right ventricular papillary muscle) of cats. 1. Isotonic muscle contraction and isometric tension development were largely unchanged compared with euthyroidism. 2. Isotonic contraction velocity and maximal isometric tension rise velocity showed considerable rises of between 41 and 78%. 3. Force-velocity relations of contraction showed changes with increases of contraction velocity with every degree of load. 4. Force-velocity relations of isotonic relaxation showed increases of isotonic relaxation maxima with comparable loads without any alteration of the typical course of the relaxation curves compared with euthyroidism. 5. Lowering the temperature (from 34 to 24 degrees C) produced a considerable fall of the raised contraction and relaxation velocity in hyperthyroidism whereas the values of muscle contraction and tension development important for the pump function were largely unchanged. It is concluded that the myocardium in experimental hyperthyroidism is characterised by a primarily velocity-related increase of inotropy. Lowering the temperature produces an effective fall of the raised velocity values. The mechanisms of the increase of inotropy and significance of the findings are discussed.     

Reversible alterations in excitation-contraction coupling during myocardial hypertrophy in rat papillary muscle

To investigate the possible role of an alteration in excitation-contraction coupling in cardiac hypertrophy, we compared simultaneously recorded action potentials along with isometric or isotonic contractions of normal and hypertrophied papillary muscles. Hypertrophy was produced by renal hypertension in rats. Hypertrophied papillary muscles were taken from rats that had been hypertensive for 10 [HBP (10)] or 20 [HBP (20)] weeks. Regression of changes induced by hypertrophy was studied in rats that had been hypertensive for 10 weeks and then made normotensive for 10 weeks by removal of the ischemic kidney. Papillary muscles from age-matched, sham-operated rats [SHAM (10), SHAM (20)] were used as controls. We found that HBP (10) rats had significantly longer action potentials than SHAM (10) rats and that difference in the action potential duration recorded during isotonic and isometric contractions was significantly different from SHAM (10) and HBP (10) rats. Peak developed tension was the same in HBP (10) and SHAM (10) muscles, but the duration of isometric contraction and time-to-peak shortening were longer in HBP (10) muscles. Similarly, whereas the peak tension was the same in HBP (20) and SHAM (20) muscles, the duration of the action potential and isometric contraction, as well as the time-to-peak tension, was longer in HBP (20) muscles. The longer values for action potential duration, isometric contraction, and time-to-peak tension in HBP (20) muscles returned to SHAM values in HBP (R) muscles. The functional relationship between contraction and the action potential time course was assessed by plotting action potential duration against four parameters of contraction: peak developed tension, time-to-peak tension, time-to-half relaxation, and time-to-peak shortening. Statistical analysis of these data showed a significant correlation between action potential duration and all four parameters of contraction in SHAM (10) and SHAM (20) muscles. In contrast, HBP (10) muscles showed a significant correlation between action potential duration and only two contractile parameters, whereas action potential duration did not correlate significantly with any of the contractile parameters in HBP (20) muscles. Remarkably, in HBP (R) preparations a significant correlation was restored between action potential duration and three of the four contractile parameters. The results of this study suggest that reversible cardiac hypertrophy is associated with reversible alterations in excitation-contraction coupling. The reversibility of the mechanical and electrical alterations that accompany hypertrophy suggests, in turn, that cardiac hypertrophy is an adaptive process.     

Model dependent behaviour of pressure hypertrophied myocardium

Two animal models with contrasting responses to pressure overloading were used to determine whether cardiac dysfunction is a general property of pressure hypertrophied myocardium or a specific property of a particular model. Chronic progressive cardiac pressure overload was compared in (a) the left ventricle of the adult and aged spontaneously hypertensive rat, in which pressure overloading begins in the pup, and (b) the right ventricle of the adult cat, in which pressure overloading was initiated surgically in the kitten. Nine hypertensive and nine control rats were studied at 1 year of age, when hypertension is stable in this model; five hypertensive and five control rats were then studied at 2 years of age, when both groups of rats are beginning to show appreciable senile mortality. Systolic blood pressure was similarly increased in both hypertensive groups; compared with the normotensive control groups, the ratio of left ventricular to body weight was 36% and 76% higher in the 1 and 2 year old hypertensive groups respectively. During isotonic contractions of left ventricular papillary muscles the extent and velocity of shortening in muscles from the control and hypertensive rats in each group were the same, but shortening and relaxation times were prolonged in muscles from the hypertensive rats in both age groups. During isometric contractions developed tension and the rate of tension rise were the same throughout, but the time integral of active tension was increased in muscles from the hypertensive rats in both age groups. The ratio of oxygen consumption to either external work or developed tension was decreased in muscles from the hypertensive rats. In contrast to these data, previous data from the hypertrophied cat model showed reductions in both the velocity and the extent of isotonic shortening as well as in the rate and amount of isometric tension development, and prolongation of contraction was not observed. A similar but smaller decrease in the oxygen requirements of contraction was found in hypertrophied cat myocardium. These contrasting data suggest not only that pressure induced hypertrophy is more fully compensatory in the rodent model but, more importantly, that general conclusions derived from any particular animal model of hypertrophy may be inappropriate.     

Relaxation in atrial and ventricular myocardium: activation decay and different load sensitivity

Isolated atrial and ventricular preparations from rat heart have been compared. In atrial specimens relaxation is faster than in papillary muscles both in isometric and isotonic conditions. In papillary muscles the tension decay occurs earlier in isotonic than isometric contractions and a stretch applied at or after the peak of isometric twitches promotes a faster relaxation: this load dependence of relaxation is less pronounced in atrial specimens. The decay of activation, evaluated from the decline of the muscle shortening ability, is faster in atrium than in ventricle. These findings suggest that the sensitivity of relaxation to the loading conditions might be determined by both the activation decay rate and the cross bridge kinetics.     

Changes in contraction-relaxation coupling in experimental cardiac hypertrophy in the guinea pig

Guinea pig myocardium resembles human myocardium with respect to the mechanisms which regulate contractility (enzymatic activity of myosine, functional activity of the sarcoplasmic reticulum). Guinea pig left ventricular hypertrophy (LVH) is therefore a good experimental model for the study of human LVH. The mechanical properties of 5 months old female guinea pigs' left ventricular papillary muscle, 3 weeks after constriction of the abdominal aorta (N = 10), were investigated. Ten papillary muscles of operated control animals and eight of normal guinea pigs submitted to 20 minutes hypoxia were also studied. The animals had no signs of cardiac failure after constriction of the abdominal aorta but the increase in the ratio of heart to body weight (p less than 0.001) confirmed the LVH. When compared with the operated controls, there was a decrease of the maximum velocity of contraction at zero load, of the velocity of contraction with preload alone (Vc), of the total isometric force normalized for the section of the muscle(s) and of the positive peak of the derivative of the isometric force normalized for section (+ dF/s) (p less than 0.001 for each parameter). The parameters of relaxation were also abnormal: decreased velocity of isotonic relaxation with preload only (Vr) and of the negative peak of the derivative of the isometric force normalized for section (- dF/s) (p less than 0.001 for each parameter), and an increase in the half relaxation time (t1/2) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiologic aspects of relaxation of the myocardium

To understand relaxation in the intact heart, an appreciation of myocardial relaxation in controlled isometric and isotonic twitches is a prerequisite. Load dependence of myocardial relaxation is manifest as the temporal separation of relaxation in isotonic and isometric twitches, i.e. rapid isotonic lengthening in contrast to slower isometric force decline. Although both isotonic and isometric relaxation modes are governed by the same determinants of crossbridge kinetics (life cycle of individual crossbridges along with regulatory properties of the contractile proteins, and calcium sequestration particularly by the sarcoplasmic reticulum), the contribution of these determinants in controlling onset and rate of relaxation is different in isometric force decline and in isotonic lengthening. In an isometric twitch, cooperative activity will, through a process of force development-induced increased sensitivity of the contractile proteins, upgrade the development and maintenance of force throughout contraction and relaxation. On the other hand, a functional calcium sequestration by the sarcoplasmic reticulum will, in the presence of a reduced effect of cooperative activity in the isotonic twitch, allow for load-induced rapid lengthening. Marked mechanical nonuniformity is observed in intact cardiac muscle. Nonuniformity in cardiac muscle mechanics is usually considered as a nuisance. Uniform behaviour of overall muscle does occur, however, despite or perhaps through nonuniform behaviour of longitudinal muscle segments. A limited but variable degree of nonuniformity therefore probably constitutes an essential property of the heart. A quantitative analysis of nonuniformity in isolated cat papillary muscle is proposed. Pathological considerations require extrapolation of our understanding from isolated muscle relaxation to ventricular relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in load dependence of relaxation between the left and right ventricular myocardium as a function of age in rats

To determine whether the variation in the magnitude of work load sustained by the left and right ventricles during adulthood and senescence affects the load-dependent aspect of relaxation, posterior papillary muscles from the left and right ventricles of rats at 4, 10, and 20 months of age were studied under variably loaded conditions in vitro. Because of differences between the life spans of Fischer and Sprague-Dawley rats, the functional characteristics of relaxation were investigated to evaluate the possibility of a differential age-associated response in these two strains of animals. The kinetic performance of the diastolic phase of myocardial contraction was measured by assessing the relative time during which load bearing occurred in a series of afterloaded isotonic twitches. This measurement was expressed as the ratio of the duration of afterloaded isotonic shortening and relengthening to the time required for isometric force to decline to the same level during isometric relaxation. A ratio of less than unity identified a load-dependent state whereas a value greater than one reflected a load-independent condition. Results showed that the right myocardium was completely load independent whereas the left myocardium was fully load dependent at all physiological afterloads. Aging reduced the load independence of the right ventricle and the load dependence of the left ventricle in Fischer rats. In contrast, no aging effect on the properties of afterloaded isotonic relaxation was seen in Sprague-Dawley rats. In conclusion, distinct differences exist in the mechanical dynamics of inactivation between the left and right ventricular myocardium. Aging reduced these variations in Fischer rats but had no apparent influence in Sprague-Dawley animals up to 20 months after birth.     

Dietary Magnesium Supplementation Attenuates Ethanol-Induced Myocardial Dysfunction

Hypomagnesemia is positively correlated with a number of cardiovascular abnormalities and recent evidence suggests that magnesium supplementation prevents ethanol-induced development of hypertension. The purpose of our study was to assess whether dietary magnesium supplementation effectively reverses or attenuates chronic ethanol-induced cardiac dysfunction, both at the tissue and the cellular level. Therefore, the influence of dietary magnesium supplementation during chronic ethanol ingestion on the mechanical properties of cardiac muscle was studied using isolated papillary muscles and ventricular myocytes from rat heart. In addition, the acute effects of ethanol on cardiac muscle from animals chronically exposed to ethanol in the absence and presence of dietary magnesium supplementation were also examined. Chronic ethanol exposure caused significant cardiac, hepatic, and renal enlargement, increased systolic blood pressure, and produced hypomagnesemia. After chronic ethanol exposure, the baseline force generating capacity of papillary muscles was markedly depressed and was associated with a significant slowing in the maximum velocities of contraction and relaxation. By contrast, in isolated myocytes, long-term ethanol exposure increased the extent of cell shortening associated with a significant reduction in the duration of relengthening and an increase in both the maximum velocities of shortening and relengthening. Dietary magnesium supplementation among animals chronically ingesting ethanol effectively normalized heart size, systolic blood pressure, and reduced plasma ethanol concentration. Magnesium supplementation also attenuated chronic ethanol-induced depression of contractile force and increased the extent of cell shortening. As expected, acute ethanol exposure caused a dose-dependent inhibition of both isometric force and isotonic shortening associated with a decrease in the intracellular calcium transient. However, the extent of the acute ethanol-induced reduction in isometric force and isotonic shortening was always slightly greater among preparations from animals chronically exposed to ethanol. Dietary magnesium supplementation normalized the acute inhibitory action of ethanol on isometric force, isotonic shortening, and the intracellular calcium transient. Our results suggest that dietary magnesium supplementation may attenuate chronic ethanol-induced alterations in baseline myocardial mechanical function and normalize the cardiac response to acute ethanol exposure.     

Sex differences in myocardial contractility in the rat

Summary We examined the intrinsic contractile performance of papillary muscles removed from the left ventricle of male and female Wistar rats. Muscles were studied isometrically and isotonically, stimulated at 0.1 Hz, perfused with Tyrode's solution having an external calcium concentration=2.4 and maintained at 30°C. In addition, we examined muscle response to changes in external calcium, added norepinephrine or verapamil and alterations in contraction frequency. No significant change in peak isometric development tension was observed between male and female preparations. However, muscles from male rats showed a significantly greater isometric time-to-peak tension and time to 1/2 relaxation with a depression of both the maximum rate of tension rise and maximum rate of tension decay. Isotonically, although peak shortening showed no difference between male and female preparations, the maximum velocities of shortening and relaxation were significantly depressed in muscles from male rats. Muscles from male animals also displayed significant prolongation of the time-to-peak shortening and time-to-peak velocity of shortening. These differences in papillary muscle performance were found over a wide range of muscle lengths, stimulus frequencies and bath concentrations of calcium, norepinephrine and verapamil. Thus differences in intrinsic contractile performance between papillary muscle from male and female rats have been characterized.Supported in part by NIH grants #HL 21933-02, #HL 07071-05 and a Herman Raucher Investigatorship Award of the New York Heart Association to Dr. J. M. Capasso.     

β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model

A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca²⁺ transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by β-adrenergic stimulation (β-AS). β-AS effect on sarcoplasmic reticulum Ca²⁺ handling, Ca²⁺, K⁺ and Cl⁻ currents, and Na⁺/K⁺-ATPase properties was included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca²⁺ sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental β-AS responses on action potentials and Ca²⁺ transient amplitude and kinetics. It also replicated the behavior of force–Ca²⁺, release–restretch, length–step, stiffness–frequency and force–velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The β-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing β-AS effects on L-type Ca²⁺ channels or phospholamban limited Ca²⁺ transients and contractile responses in parallel, while blocking phospholemman and K⁺ channel (I_Ks) effects enhanced Ca²⁺ and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca²⁺ (due to greater Ca²⁺ buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca²⁺ transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of β-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. β-AS effects on XBCa and XBcy have greater impact on isometric and isotonic contraction, respectively.     

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

Summary 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 relenthenning 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 evaluted 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.     

Altered pattern of post-rest contractions in hypertrophied rabbit ventricle

Summary The pattern of contractions elicited after rest periods of 0.25–10 min duration was investigated in right ventricular papillary muscles from control and hypertrophied rabbit hearts. Hypertrophy was induced by pressure overload following coarctation of the pulmonary artery. In control hearts, the first post-rest contraction was always of a smaller amplitude than the preceding steady-state (0.5 Hz stimulation) contractions, and the amplitude of this first post-rest contraction decreased as the rest interval increased. In contrast, the amplitude of the first post-rest contraction of muscles from hypertrophied hearts exceeded the steady-state amplitude for rest durations of up to at least 2 min. In the hypertrophied muscles, force in the first post-rest contraction (expressed as a percentage of the pre-rest steady-state) was potentiated compared to the control muscles at all rest intervals studied. There was no significant difference in the second post-rest contraction between control and hypertrophied muscles at any rest interval. Following the second post-rest contraction, force increased monotonically toward the steady-state levels in all the muscles. The recovery of force was, however, somewhat faster in the hypertrophied muscles. Upon resumption of 1-Hz stimulation following rest intervals of 2 min or greater, pulsus alternans were invariably observed in the hypertrophied muscles but never in the control muscles. These differences in the non-steady-state contractile behavior of ventricular muscle from normal and hypertrophied hearts are suggestive of some alteration in the normal pattern of Ca²⁺ translocation in pressure overload hypertrophy of rabbit ventricle. This may involve a change in the rate at which Ca²⁺ is lost from the sarcoplasmic reticulum during periods of quiescence.Supported by a Project Grant (87/0095) from the National Health and Medical Research Council of Australia.     

Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis

Familial hypertrophic cardiomyopathy (FHC) is a leading cause of sudden cardiac death among young athletes but the functional effects of the myofilament mutations during FHC-associated ischemia and acidosis, due in part to increased extravascular compressive forces and microvascular dysfunction, are not well characterized. We tested the hypothesis that the FHC-linked tropomyosin (Tm) mutation Tm-E180G alters the contractile response to acidosis via increased myofilament Ca²⁺ sensitivity. Intact papillary muscles from transgenic (TG) mice expressing Tm-E180G and exposed to acidic conditions (pH 6.9) exhibited a significantly smaller decrease in normalized isometric tension compared to non-transgenic (NTG) preparations. Times to peak tension and to 90% of twitch force relaxation in TG papillary muscles were significantly prolonged. Intact single ventricular TG myocytes demonstrated significantly less inhibition of unloaded shortening during moderate acidosis (pH 7.1) than NTG myocytes. The peak Ca²⁺ transients were not different for TG or NTG at any pH tested. The time constant of re-lengthening was slower in TG myocytes, but not the rate of Ca²⁺ decline. TG detergent-extracted fibers demonstrated increased Ca²⁺ sensitivity of force and maximal tension compared to NTG at both normal and acidic pH (pH 6.5). Tm phosphorylation was not different between TG and NTG muscles at either pH. Our data indicate that acidic pH diminished developed force in hearts of TG mice less than in NTG due to their inherently increased myofilament Ca²⁺ sensitivity, thus potentially contributing to altered energy demands and increased propensity for contractile dysfunction.     

Experimental hyperthyroidism III: Contractile responses to propranolol of the intact heart and of the isolated ventricular myocardium

The effect of propranolol on cardiac mechanics and haemodynamics was examined on isolated papillary muscle as well as in situ in the closed thorax in euthyroid and hyperthyroid cats. Under propranolol there occurred on isolated papillary muscle significant decreases of muscle contraction, contraction velocity, isometric tension rise velocity and load and velocity values of simultaneously determined force-velocity relations. The 50% decrease of the values found was demonstrable at ca. 5--8 mu/ml for euthyroidal muscles, at 0.3--0.5 mug/ml for hyperthyroidal muscles. Contractility indices determined in situ (dp/dtmax, VCEmax, extrapolated Vmax) showed in hyperthyroidism at equal propranolol concentration a decrease about twice as great as in euthyroidism. The findings, showing a raised responsiveness of the ventricular myocardium in experimental hyperthyroidism to the negative inotropic effect of propranolol are discussed with regard to the therapeutic use of propranolol in hyperthyroidism.     

Cultured embryonic chick heart cells: Photometric measurement of the cell pulsation and the effects of calcium ions,electrical stimulation and temperature

With a new mîcroscope system (Zeiss Axiomat) single cell pulsation was photometrically measured on cell cultures of 7 to 9-day-old embryonic chick hearts. The time course of pulsation of cells with well-developed attachment is similar to the tension development under isometric conditions. The spontaneous frequency (Tyrode's solution 37°C) varies between 40 and 200/min with a maximum around 120/min. At 27°C the frequency is reduced by a factor of 3. Cooling at constant pulsation frequency (electrical stimulation) prolongs time to peak and contraction time. Peak pulsation remains unchanged but incomplete relaxation develops. Therefore pulsation amplitude only decreases during cooling. A linear relationship was found between pulsation amplitude and the extracellular Ca²⁺-concentration in the range of 0.8 to 3.4 mm. A plateau is reached at 5 mm Ca²⁺. Higher Ca²⁺-concentrations cause dysrhythmic activity. Stimulation frequencies above the spontaneous frequency have little if any influence on pulsation maximum but cause incomplete relaxation. In cultured cells a positive correlation between pulsation amplitude and stimulation frequency was regularly found at lower range of frequencies. The typical mechanical transients following extrastimuli were also found on single cells.     

Comparison of the effects of inotropic interventions on isometric tension and shortening in isolated ferret ventricular muscle

In this study, we have compared the effects of a range of positive and negative inotropic interventions on isometric tension and shortening at low load in isolated ferret papillary muscles. It was found that the majority of interventions produced broadly similar effects on tension and shortening. Positive inotropic interventions which behaved in this way included increasing extracellular calcium and increasing frequency at moderate stimulation rates. Acidosis, the addition of cyanide, and metabolic blockade produced by the addition of iodoacetic acid and cyanide, all produced negative inotropic effects which showed a similar pattern. For all these interventions, it was noted that the fractional effect on tension was 1.5-2 times larger than the fractional effect on shortening. This was attributed to the shape of the tension-length relation for cardiac muscle in different inotropic states. When frequency was increased to a high rate, tension rose to an initial peak, but then showed a marked decline, while shortening rose to a new level and was then well maintained. When protocols consisting of varying amounts of isometric and isotonic contraction were applied, the amount of the secondary decline for both tension and shortening was related to the period spent doing isotonic contractions, and hence to the energy consumption of the muscle. Thus the difference in the behaviour of tension and shortening under these conditions can be accounted for by the lower energy requirements of shortening, rather than by other factors. Over the range of inotropic interventions studied, peak shortening velocity was a more sensitive index of contractility than shortening, being roughly comparable to isometric tension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of alpha adrenergic stimulation on the mechanical properties of the myocardium

The mechanical effects of phenylephrine at 2 x 10(-6) M (PE1, n = 8), 2 x 10(-5) M (PE2, n = 10) and 2 x 10(-4) M (PE3, n = 6) were studied on rat left ventricular papillary muscle, in the presence of propranolol (4 x 10(-7) M) and 0.5 mM of (Ca2+)e. The contraction-relaxation coupling was studied under isotonic and isometric conditions. The maximal velocity of contraction (max Vc) and relaxation (max Vr) were calculated during isotonic contraction with preload only at L max. The positive (+ dF/dt max) and negative (- dF/dt max) peaks of the derivative of the force were calculated during isometric contraction. Two coefficients, R1 = max Vc/max Vr and R2 (+ dF/dt max)/(- dF/dt max) provided an appreciation of the contraction-relaxation coupling at low and high loads respectively. The positive inotropic effect observed in the three groups was accompanied by a significant decrease of the coefficient R1 (PE1: - 11 +/- 2% p less than 0.001; PE2: - 15 +/- 2%, p less than 0.001; PE3: -20 +/- 2%, p less than 0.001). On the other hand, no significant variations of the coefficient R2 were observed (PE1: 3 +/- 3%; PE2: 1 +/- 4%; PE3: 5 +/- 3%). The proportionally greater improvement in the velocity of relaxation compared to the velocity of contraction at low loads suggests that the sarcoplasmic reticulum is involved in the expression of positive inotropic and positive lusitropic effects of alpha-adrenergic stimulation.