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...
The effect of encainide on chronic pacing thresholds was evaluated in 10 patients, age 64-89, who were exposed to weekly increased encainide dosing (25 mg TID, 50 mg TID, 75 mg TID). Median pacing threshold (mujoules) increased modestly at each period compared to placebo and returned rapidly to baseline after discontinuation. (table; see text) No patient experienced a pacing-related clinical event. One patient had a large threshold increase (566%), but no failure to capture on 24-hour ECG, and one patient whose threshold increased minimally had clinically insignificant capture failure, the longest event being 3 beats. No other failure to capture was noted. Thus, encainide, like a number of other antiarrhythmic drugs, appears to affect pacing thresholds. At the highest dose of 225 mg/day (75 mg TID, which exceeds the generally recommended dose of 50 mg TID), but not at lower doses, some patients may experience loss of capture that does not appear related to the change in threshold energy required. Increases in the duration of the paced QRS induced by encainide did not predict increases in threshold. Therefore, when higher doses of encainide are required in patients with pacemakers, clinical observation and ambulatory electrocardiographic monitoring should be carried out.
The contractile properties of right ventricular papillary muscles from the hearts of 15 rats which had developed hypertension 6 weeks following renal artery ligation were compared with those from 14 normal litter-mates. In the experimental group, the heart weight-body weight ratio was increased by 39%, while the right ventricular weight-body weight ratio increased 20%. Right ventricular papillary muscles from the hypertensive rats demonstrated increased tension development at the apex of the length-active tension curve (P less than 0 X 0001), elevated maximal rate of tension development (P less than 0 X 001), and increased maximal velocity of contraction at muscle lengths corresponding to both a light preload and at Lmax (P less than 0 X 05). Resting tension and time-to-peak tension in the muscles from the hypertensive group were not significantly different from the normal group. Thus, improved right ventricular performance, in the presence of increased left ventricular afterload, may indicate the existence of a stimulus to increased function in hypertrophied muscle not yet negated by the adverse effects of direct exposure to stress.
The aim of this study was to evaluate utilization of chemical energy in relation to myocardial mechanics in variably afterloaded contractions of cardiac muscle by determining total energy utilization (-P) in the absence of energy production. Right ventricular papillary muscles of cats were equilibrated at 26°C in a myograph in Krebs' solution while contracting isometrically (12/ min). Following treatment with iodoacetate and N 2 to inhibit completely ATP production from glycolytic and aerobic metabolism, the muscles were stimulated to contract isotonically 20 to 75 times with varying afterloads. They were then rapidly frozen in liquid N 2 -cooled isopentane, and concentrations of ATP, creatine phosphate, inorganic phosphate and creatine were measured.The efficiency of energy utilization for the performance of internal work was 0.0067 ^unoles 1 --P/g-cm of work and for external work was 0.0031 /imoleŝ -•P/g-cm. In addition, resting energy utilization was 0.662 /zmoles/g/min and activation energy was estimated to be 0.040 /imoles/g/ contraction. These findings provide a demonstration of the Fenn effect in cardiac muscle and explain the well-known discrepancy in energy cost when cardiac work is increased by increasing pressure load as opposed to increasing volume load.ADDITIONAL KEY WORDS adenosine triphosphatc cat papillary muscle energetics creatine phosphate muscle mechanics• Hill (1, 2) has demonstrated in skeletal muscle that during isometric contraction, the liberation of energy is related directly to tension development. Similarly, several studies of the intact heart have shown a direct correlation between oxygen utilization and various derivatives of tension development, such as the product of pressure and heart rate (3-6), integrated pressure and heart rate (7), or developed ventricular wall tension, as calculated from the Laplace relation (6,8,9). In isolated papillary muscle preparations, oxygen utilization and developed tension have also been correlated (10, 11), and more recently, the utilization of high energy phosphates in Dr. Chandler's present address is Victoria General Hospital, Halifax, Nova Scotia.Dr. Sonnenbllck's present address is Peter Bent Brigham Hospital, Boston, Massachusetts.Accepted for publication January 22, 1968. isometric contractions has been related to contractile element work, which is a function of tension (12). The results of the last of these investigations agree with those from studies on isometrically contracting skeletal muscle (13-15) and extend these findings directly to heart muscle. However, the manner in which shortening and the performance of external work affect the utilization of energy is less clear. Fenn demonstrated that when skeletal muscle shortens and performs external work, the total energy released is greater than that which is released if it develops tension alone and does not perform external work (16). The total energy released during contraction can then be described by Fenn's equation: E = A+ Bt + kW, where E = energy liberated; A = energy ...
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