Abstract. The intrinsic contractile properties of isolated cat papillary muscles and myocardial high energy phosphate stores were examined at three levels of thyroid activity and correlated with hemodynamic measurements in the intact animal. In addition, the relationship of thyroid state to endogenous norepinephrine stores and myocardial responsiveness to certain inotropic in-.terventions were studied. In muscles from hyperthyroid cats, the velocity of shortening and the rate of tension development were markedly augmented, while duration of active state was decreased, compared to euthyroid muscles. These findings occurred in the presence and absence of intact norepinephrine stores and over a wide range of temperature and contraction frequency. The opposite changes occurred in muscles from hypothyroid cats. Isometric tension was slightly higher in muscles from hyperthyroid and lower in muscles from hypothyroid cats. The inotropic response to both norepinephrine and strophanthidin varied inversely with the level of thyroid state and allowed all three groups of muscles to reach a common ceiling of isometric tension regardless of thyroid state. Creatine phosphate and adenosine triphosphate stores were intact at all three levels of thyroid state. Thus, the level of thyroid activity profoundly affects the intrinsic contractile state of cardiac muscle, independent of both norepinephrine stores and alterations in high energy phosphate stores, and, in addition, modifies the responsiveness of cardiac muscle to inotropic agents.

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Four apparently healthy young adults with vague chest symptoms during the day, two of whom had infrequent syncope while ambulatory at night, had periods of asystole up to nine seconds in duration occurring repeatedly during rapid-eye-movement (REM) sleep. Extensive evaluations, including electrophysiologic studies in two patients, were normal. It is therefore suggested that the underlying pathophysiology involved autonomic dysfunction. REM sleep-related sinus arrests such as these, which may occur in apparently healthy subjects but are undetected, may explain some cases of sudden, unexpected death during sleep. Polygraphic monitoring during sleep may be helpful in delineating the pathophysiology of the sleep-related arrhythmia in persons with daytime cardiac arrhythmias thought to be secondary to abnormal vagal tone. The possibility of nocturnal asystole should be considered in patients such as those described here.

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The utilization of creatine phosphate (CP) and adenosine triphosphate (ATP) was studied in the iodoacetate (IAA) and nitrogen (N 2 )-treated cat papillary muscle. Under these conditions the net production of ATP does not occur, and the net utilization of ATP is reflected in a fall in CP concentration. The rate of energy utilization of the IAA-N 2 -treated cat papillary muscle resting without tension was 0.68 mole CP/g/min. This rate was increased to 1.07 umole/g/min when muscles were passively stretched with 2 g of tension. In a series of isometrically contracting muscles CP utilization was found to be proportional to the number of activations and the summated contractile element work. These rates of CP utilization were 0.083 /Amole/g/activation and 0.0059 tumole/g-cm of work. The calculated mechanochemical coupling efficiency was 33 %.

The present study was undertaken to evaluate the influence of heart failure on the cardiac stores of norepinephrine, and to elucidate the mechanisms responsible for the changes observed. Congestive heart failure was produced in the guinea pig by supravalvular aortic constriction. Significant reductions in both the concentration and content of norepinephrine in the ventricles were observed, the magnitude of changes being related to the severity of the constriction. The renal concentration of norepinephrine was not usually affected. Infusions of large quantities of norepinephrine produced elevations of ventricular norepinephrine concentrations which were significantly less in guinea pigs with heart failure than in normal animals. Injections of lesser quantities of radioactive norepinephrine also resulted in smaller amounts of this material in the hearts of animals with failure. Measurement of the decay of specific activity indicated that heart failure did not alter the net turnover of norepinephrine in the left ventricle. From these findings it has been concluded that a defect in the uptake and/or retention of norepinephrine exists in these hearts and that this defect may be responsible for the depletion of norepinephrine.

Although it is clear that cardiac norepinephrine stores are often markedly reduced in congestive heart failure, the mechanism responsible for this depletion has not been elucidated. The objective of this study was to investigate cardiac synthesis of norepinephrine in experimental right-sided heart failure by measuring the activity of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of norepinephrine. In homogenates of the right ventricles of 6 dogs with congestive heart failure and 2 with chronic cardiac denervation, myocardial tyrosine hydroxylase activity was severely reduced, averaging 0.4 ±0.1 (SE) and 0.2 iryunole/g per hour respectively as compared to a normal value of 3.3 ± 0.7 m/tmole/g per hour. Tyrosine hydroxylase activity was normal in reserpine-treated, norepinephrine-depleted dogs. These data provide evidence for a mechanism severely limiting norepinephrine biosynthesis in congestive heart failure.

The sympathetic innervation of the rabbit heart, as a function of age, was studied by measuring the cardiac concentration of catecholamines and observing the anatomic distribution of sympathetic nerves by die monoamine fluorescense technique. The cardiac concentration of norepinephrine in late gestation was quite low; the levels rose progressively after birth to reach adult levels by about three weeks of age. Similar small amounts of epinephrine were found in the hearts at all ages. Substantially less change in adrenal catecholamines accompanied advancing age. At all ages a close correlation was noted between the norepinephrine levels and the histochemical demonstration of sympathetic innervation. Intensely fluorescent, terminal varicosities were observed within large preterminal nerve trunks only in the youngest animals, suggesting that the sympathetic nerves move into, rather than form within, die heart. Chromaffin cells were observed in the hearts at all ages.ADDITIONAL KEY WORDS norepinephrine epinephrine adrenal chromaffin cells myocardial catecholamines• Although the adrenergic nervous system plays an important role in the control of cardiac contractility in the mature mammal, its significance in the perinatal period is not clear. Physiologic and pharmacologic studies undertaken to assess the maturation of the autonomic control of the circulation have been largely concerned with the ability of young animals to respond to various physiologic stimuli, such as hypoxemia and carotid sinus hypotension, or to the injection of catecholamines (1). A number of observations in rabbits of varying ages suggest that the circulaFrom the Cardiology Branch, National Heart Institute, Bethesda, Maryland, and the Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania.This investigation was supported in part by U. S. Public Health Service Research Grant 1R01NB0-6707. Dr. Jacobowitz was a recipient of a Research Career Program Award, 5-K 3-N B-13, 935-02, from the National Institutes of Health.Accepted for publication April 29, 1968. tion of the newborn is under no (2), a lesser (3), or a comparable (1) degree of neural control, as compared to the adult. The development of the separate factors constituting an integrated circulatory response-the afferent, central, and efferent components of a vascular reflex, the responsiveness of the peripheral vasculature, and the direct inotropic and chronotropic effects on the myocardium -have not yet been analyzed quantitatively. The objective of the present investigation was to define more clearly the development of sympathetic innervation of the rabbit heart. The cardiac concentration of norepinephrine in fetal, neonatal, and adult animals was employed as an index of the maturity of sympathetic innervation because the heart's stores of norepinephrine are localized almost exclusively in intraceilular storage sites within the terminations of the sympathetic nerves (4). In addition, the monamine fluorescence technique of Falck and O...