Mechanical responses of chromium-deficient developing rat heart.

Mechanical responses were compared between controls, developing Sprague-Dawley rat papillary muscle and age-matched weanlings fed with Torula yeast, a food source deficient in chromium. At 8 weeks postnatal, deficient rats differed in significant ways from their normal counterparts. Deficient rats in contrast to controls weighed less, their interval-force (I-F) relationship was more negative and their inotropic response to high calcium concentrations was greater. At this time, however, deficient and control rats responded equally to alpha (phenylephrine) and beta (isoproterenol) agonists. At 10 weeks of age, the controls exhibited a less negative I-F and a negative inotropic response to high calcium concentrations while the response to alpha and beta agonists was unchanged. In contrast, at 10 weeks of age, the chromium-deficient rats exhibited a highly negative I-F response and significant inotropic response to high calcium concentrations. The response of the deficient hearts to beta-agonists diminished. At 13 weeks postnatal, control hearts showed only a 10-15% negative I-F response, a persistent response to catecholamines and negative inotropic responses to high calcium concentrations. In deficient hearts, the negative I-F response was reduced and the response to beta-agonists was further diminished but a positive inotropic response to phenylephrine and high calcium concentrations persisted. These observations in deficient animals are explained in terms of a retarded development of the calcium handling elements in the heart and a lack of an insulin-like growth factor.

The determinants of contractility in the heart.

The contraction-relaxation cycle of the heart represents the combined action of a variety of different components of the myocytes. For many years an 'index' of contractility has been sought as a means of describing and integrating the large amount of information available from the studies of heart muscle contraction. This review will undertake to show that dF/dt, recorded from the whole heart, and dT/dt, recorded in isometric studies of isolated heart muscle preparations, should not be considered as the 'index' of contractility. Examples will be presented in which an increasing dT/dt is paradoxically accompanied by a lower tension, while a decreasing dT/dt can occur concomitantly with an increased contractile tension. Arguments are further presented in support of the concept that Ca2+, in conjunction with troponin C, is the main determinant of cardiac contractility and that dT/dt reflects a dynamic equilibrium between free and troponin-bound Ca2+. Peak tension is thus the net result of overlapping events competing for Ca2+ during the latter part of contraction, that is, during Phase II of contraction as defined below. These suggestions are based upon the following considerations: (a) The Ca2+ pumps are active even during rest and serve to maintain low cytosolic Ca2+ levels. (b) As cytosolic Ca2+ concentration increases, Ca2+ pump activity also increases. (c) In addition, the Na+/Ca2+ exchange is activated by elevated Ca2+ concentrations and serves to decrease cytosolic Ca2+ levels. (d) The net result is a decline in free Ca2+ concentration during Phase II and a reduction in the rate of cross-bridge formation until peak tension is reached. Thus, the Ca2+ handling elements of the myocyte serve as a finely tuned feedback device, regulating troponin C-Ca2+ interactions controlling the Ca2+ concentration of the cytosol and as a result, the actin and myosin interaction. Factors which influence the function of these elements will change the contractility of the heart.

A relationship between circulating natural glucocorticoids and the mechanical responses of the heart in atricial and precocial rodents.

1. A comparison was made of the mechanical performance of heart muscle from mouse, an atricial mammal, with corticosterone as glucocorticoid and spiny mouse (Acomys cahirinus), a precocial mammal, with cortisol as glucocorticoid. 2. Force-frequency responses were negative in mouse and positive in spiny mouse. 3. During recovery, there was a gradual increase and an overshoot in the mouse, while in the spiny mouse there was an initial enhanced response, diminishing gradually with time. 4. High calcium concentration inhibited contractile tension in mouse heart, while it was positively inotropic in spiny mouse heart. Changes in the concentration of calcium did not change the patterns of force-frequency response. 5. Lowering the experimental temperature increased the time course and amplitude of the tension curve. However, various parameters exhibited different temperature sensitivity. 6. There was a significant difference in the levels of circulating cortisol between male and female spiny mice. 7. It is proposed that the differences in the mechanical responses of mouse and spiny mouse hearts may be explained in terms of the effects of the specific glucocorticoid hormone on the development of the sodium-calcium exchanger.

Electrical properties of developing rat heart. Effects of dexamethasone.

Action potentials recorded from perinatal rat ventricles exhibited a plateau (phase 2), followed by a rapid repolarization characteristics of all mammalian ventricular cells. Within the second postnatal week, a number of distinct changes occurred in the contour of action potentials. An early slow depolarization, at the foot of the action potential, preceded the beginning of phase zero. The early slow depolarization was observed until day 12 and disappeared by day 13. A second slow depolarization occurred during the terminal phase of the rapid upstroke of the action potential, persisted through day 13 and disappeared by day 14. On day 12, what had been a homogeneous contour of action potentials seen during the first week converted into a heterogeneous contour. Occasionally, action potentials similar to those recorded from Purkinje fibres in adult heart were recorded from hearts as young as 12 days. By day 14, signs of a spike (the hallmark of action potentials from adult heart) were apparent in some fibres. Treatment of newborn rats with dexamethasone on the second day after birth prevented the disappearance of the second slow depolarization. In adult and aged rat hearts, dexamethasone treatment induced a slow depolarization and a plateau in the region of overshoot. In view of the time-dependent change of the second slow depolarization it is suggested that this phase of the action potential is influenced by the levels of circulating glucocorticoid in developing heart and by changes in calcium sensitivity observed in this species. Heterogeneity of action potentials observed on day 12 postnatal may precede structural differentiation of myofilaments.

Cytosolic glucocorticoid receptors in the developing rat heart.

Glucocorticoid hormones alter functional cardiac responses in the rat heart. In the neonatal rat heart, glucocorticoid treatment on post-natal day 2 alters heart function for up to 3 weeks post-injection, which suggests that cardiac glucocorticoid receptors mediate cardiac function in neonates. However, glucocorticoid receptors have not been identified in neonatal rat heart. Glucocorticoid receptor binding was measured in neonatal rat heart cytosol extract using [3H] dexamethasone as ligand, and characterized by competition assays and Scatchard analysis. Saturable, specific, high affinity glucocorticoid receptor binding was found in the cytosol of the neonatal rat heart. We then examined the effects of a single, post-natal day 2 injection of hydrocortisone acetate on glucocorticoid receptor binding in 12 to 14-day-old rat heart. While this injection paradigm results in altered cardiac function in 12-day-old rat hearts, cytosol glucocorticoid receptor binding in 12 to 14-day-old heart was not altered by treatment on post-natal day 2 with hydrocortisone acetate. It is postulated that exposure to elevated glucocorticoid levels on neonatal day 2 may alter cardiac function by producing permanent organizational effects on cardiac tissue.

Effects of glucocorticoids and catecholamines on maturing rat heart.

1. The negative force-frequency response of normal rat heart was accentuated when the animals were adrenalectomized. Treatment of adrenalectomized animals with dexamethasone restored the normal force-frequency response. 2. Total adrenalectomy increased the sensitivity of rat heart to calcium. 3. Adrenalectomized-dexamethasone-treated hearts were more responsive to epinephrine and ouabain. 4. Total adrenalectomy caused independent myocardial disturbances in calcium handling elements (glucocorticoid effect) and beta receptors (catecholamine effect).

Mechanical responses of developing Fisher rat heart. Effects of steroid hormone.

Age-dependent changes in the mechanical responses of developing Fisher rat heart during the first three postnatal weeks were studied in relation to the hypothesis that the abnormality observed in the mechanical responses of the rat heart might be calcium related. Therefore the effect of frequency of stimulation as well as the response to calcium, epinephrine and ouabain on hearts of untreated and cortisol-treated rats was compared. The positive force-frequency response observed in fetal rat heart reverted to a highly negative response by the 12th to 14th postnatal day. The biphasic mechanical responses directly paralleled reported changes in circulating glucocorticoid levels in developing rat. The force-frequency response was maximally negative when the circulating levels of glucocorticoids were lowest. The reversion of the negative force-frequency responses coincided with a gradual increase reported in the circulating levels of glucocorticoids. The negative force-frequency response was absent in the cortisol-treated developing rat heart and a definite positive pattern was observed as the rats developed. A high sensitivity to free calcium concentration, seen in control fetal and and newborn hearts, diminished after the second postnatal week. By the third postnatal week, the sensitivity to high extracellular calcium concentrations was significantly reduced. The sensitivity to calcium persisted in the cortisol-treated hearts during the 3 postnatal weeks. Cortisol-treated hearts were more responsive to epinephrine than controls. The abbreviation of time to peak tension, a hallmark of the catecholamine effect, was observed at a younger age in the cortisol-treated hearts. Cortisol-treated hearts were more responsive to the inotropic effects of ouabain than controls. The possible involvement of glucocorticoids in the control of calcium handling elements of the myocardium is discussed.

Mechanical properties of developing swine myocardium.

Mechanical responses of myocardium from 16 piglets were studied from 18 hr to 12 days after birth. Tension, time and velocity parameters of contraction and relaxation were determined for every contraction cycle. Increasing the frequency of stimulation in step-changes induced negative inotropy in some muscles regardless of age. Doubling extracellular calcium ion concentration induced a positive force-frequency response in all muscles. Epinephrine increased tension and velocities without affecting contraction time. The ultrastructure was immature even on the 12th postnatal day. We concluded that in newborn piglet hearts, the mechanisms for calcium delivery are not fully developed. Thus, the heart undergoes a transient phase during which at least a principal portion of calcium for the myofibers is supplied by the extracellular fluid. While receptors for catecholamines are present, the time course for their response is immature.

Alterations in mechanical response of aged rat myocardium. Effects of dexamethasone.

1. Mechanical responses of young and old rat myocardium to increasing rates of stimulation were compared. As the animals aged, we found a significant enhancement of the negative force-frequency response and a decline in the velocities of contraction and of relaxation. 2. At 6 months of age, there were no differences between rats obtained from commercial sources and a group of rats obtained from a colony maintained at the National Institute of Aging. 3. At 24 months, the negative force-frequency response was considerably greater in the former group of animals than in the latter. 4. The sensitivity to the calcium concentration in the tissue bathing solution was significantly increased in aged heart preparations. Increasing the calcium concentration reduced the negative inotropy and the decline in the velocities of contraction and relaxation. The enhancement by calcium was directly proportional to the concentration of the metal in the bathing solution. 5. When aged animals were pretreated with pharmacological doses of dexamethasone, the age-induced alterations in the mechanical responses were reversed. The aged, dexamethasone-treated myocardium also became refractory to calcium concentrations above 2.7 mM in the bathing solution. 6. It is suggested that aging induces multifocal defects and that steroid hormones play a role in the maintenance of integrity of the myocardium. The action of the steroids is on the sarcolemma, the contractile proteins and the sarcoplasmic reticulum.