Norepinephrine turnover in the heart and spleen of the cardiomyopathic Syrian hamster.

Abstract

Although a reduction in myocardial norepinephrine stores in cardiac hypertrophy and congestive failure is well documented, norepinephrine turnover has been inadequately studied in such hearts. We compared norepinephrine turnover in control and cardiomyopathic hamsters by following the decline in specific activity of myocardial norepinephrine after labeling with an intraperitoneal tracer dose of 3 H-norepinephrine. Adult myocardial norepinephrine concentrations were not attained until 4 weeks of age in both strains. There was no difference in the rate constant (K) for myocardial norepinephrine turnover (0.107 ± 0.004 hours" 1 vs. 0.100 ± 0.005 hours" 1 ) in the two strains of hamsters during the neonatal period. In young control hamsters, K fell to 0.064 ± 0.004 hours" 1 , but that for age-matched hamsters with mild cardiac hypertrophy was 0.102 ± 0.001 hours" 1 (P < 0.001). There was little change in K as control hamsters aged. With the development of more severe hypertrophy in cardiomyopathic hamsters, cardiac norepinephrine decreased and resting K rapidly increased to approach the value obtained when hamsters were subjected to immobilization stress (0.302 ± 0.013 hours" 1 ). The maximum achievable K remained the same for both control and dystrophic hamsters even during terminal disease. Prolonged immobilization led to a reduction in cardiac norepinephrine in both strains. Ganglionic blockade of failing hamsters completely restored the levels of both cardiac norepinephrine and K to control values. Splenic noradrenergic nerves showed no change in K, norepinephrine content, or maximum K during cardiac decompensation. We conclude that, in the late stages of hamster cardiomyopathy, there is a progressive and possibly specific increase in cardiac sympathetic tone which leads to a concomitant decrease in cardiac norepinephrine. With the loss of sympathetic reserve, congestive failure supervenes.• The normal heart is richly supplied with noradrenergic sympathetic nerves. This innervation contributes little to intrinsic myocardial function (1) but is a most important mechanism for the elevation of cardiac output in response to a physiological stress such as exercise (2). In the absence of a catecholamine stimulus, cardiac output can be increased solely by the Frank-Starling mechanism (3). Dilated or noncompliant hearts, however, cannot take further advantage of the length-tension relationship and thus depend on sympathetic support to maintain cardiac output (4). This paper won the Young Investigators' Award given by the Canadian Cardiovascular Society.Dr. Sole was a Hunter Fellow of the Ontario Heart Foundation.Please address reprint requests to Dr. Michael J. Sole, Clinical Sciences Division, Medical Sciences Building, University of Toronto, Toronto, Canada M5S 1A8.Received May 1, 1975. Accepted for publication October 2, 1975.Circulation Research, Vol. 37, December 1975 There is considerable evidence for sympathetic dysfunction in the hearts of humans with congestive heart failure and animals with experime...

Nuclear proteins in the heart of the cardiomyopathic Syrian hamster. Phosphorylation of phenol-soluble nonhistone proteins.

“…It is well known that norepinephrine is a potent stimulus for cyclic AMP production in the heart. 36 Sole et al 37 found a considerable increase in cardiac norepinephrine turnover as early as the myolytic phase of hamster cardiomyopathy. Furthermore, Nair and co-workers 24 described a similar increase in myocardial adenyl cyclase activity.…”

Low Serum Dopamine β-Hydroxylase Activity

“…There is evidence that both in humans, and in animal models, heart failure is associated with depletion of cardiac norepinephrine stores and augmented generalized sympathetic activity (1)(2)(3)(4). Marked increases in rates of norepinephrine turnover have been reported in this disorder (5). Under normal conditions the rate-limiting step in the biosynthesis of norepinephrine is the hydroxylation of tyrosine, which is catalyzed by the enzyme tyrosine hydroxylase (6).…”

“…Alternatively, normal amounts of DBH are synthesized and released but the enzyme is peripherally inactivated. It is of considerable interest that in cardiomyopathic hamsters with heart failure there is accumulation of dopamine in the myocardium (5). This suggests that in this animal model there may be reduced availability of DBH to catalyze the hydroxylation of dopamine to norepinephrine.…”

Introduction to Cardiac Neuronal Imaging: A Clinical Perspective

“…In the 20th century, improvements in analytic techniques allowed more accurate in vitro measurements of neurotransmitters such as acetylcholine, epinephrine, and norepinephrine, which provided further understanding of the interactions and responses of the parasympathetic and sympathetic systems (2,3). The use of radiolabeled versions of these neurotransmitters later offered a means to monitor in vivo pharmacodynamics and provided the first quantitative estimates of uptake and clearance of these compounds in living tissues (4,5). Research with compounds labeled with tritium ( 3 H), 14 C, and 125 I laid the groundwork for the development of compounds labeled with g-and positron-emitting radioisotopes (6).…”

“…Much of this research involved measurement of norepinephrine turnover, a quantitative method for estimating sympathetic nerve function that has been widely used in both animal and human subjects (6). The best validated method of measuring norepinephrine turnover involves injecting radiolabeled 3 H-norepinephrine and measuring its initial uptake and then its disappearance from the heart and other organs over several hours (5,11). Studies in animals have shown that, in a variety of physiologic and pathophysiologic situations, 3 H-norepinephrine disappearance from the heart follows first-order kinetics, which can be characterized in terms of a fractional turnover rate, k, or turnover half-time, T1 (12).…”