Tyrosine hydroxylase activity in the heart of the cardiomyopathic Syrian hamster (original) (raw)

A possible change in the rate-limiting step for cardiac norepinephrine synthesis in the cardiomyopathic Syrian hamster

Circulation Research, 1977

The development of heart failure in the cardiomyopathic hamster is associated with a decrease in norepinephrine stores and parallel increases in cardiac sympathetic tone and tyrosine hydroxylase activity. Despite the increase in tyrosine hydroxylase, cardiac norepinephrine synthesis does not increase in heart failure. In this study, we have shown that an accumulation of cardiac dopamine accompanies the decline of cardiac norepinephrine. The abnormal content of norepinephrine and of dopamine in the decompensating hamster heart is restored to normal by peripheral ganglionic blockade. The acute increase in cardiac sympathetic tone induced by immobilization stress in control hamsters mimics the alterations in cardiac catecholamine distribution found in heart failure. Other investigators have demonstrated similar alterations in the catecholamine content of the rat submaxillary gland and adrenal medulla following an increase in sympathetic input to these organs. We conclude that the incre...

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

Circulation Research, 1975

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 labelling with an intraperitoneal tracer dose of 3H-norepinephrine. Adult myocardial norepinephrine concentrations were not attained until 4 weeks of age in both strains. There was no difference in the rate of 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 less than 0.001). There was little change in K as control hamsters aged. With the development of more severe hypertrophy in...

Increased dopamine in the failing hamster heart: Transvesicular transport of dopamine limits the rate of norepinephrine synthesis

The American Journal of Cardiology, 1982

An earlier study demonstrated an increase in dopamine and a decrease in norepinephrine in the failing myopathic hamster heart. There was evidence to suggest that this abnormal distribution of catecholamines was secondary to a marked increase in cardiac sympathetic nerve traffic rather than a peculiarity of hamster cardiomyopathy. In this study the hamster model was used to dissect further the step limiting the conversion of dopamine into norepinephrine. In heart failure, cardiac norepinephrine was reduced from a mean value (& standard error of the mean) of 1,192 f 176 to 441 f 61 rig/g (probability [p] <O.OOS) and cardiac dopamine was increased from 51 f 5 to 456 f 70 rig/g (p <O.OOl). Cardiac decompensatlon also induced increases in both cardiac tyrosine hydroxylase (64 percent, p <O.OOl) and cardiac dopamine-beta-hydroxylase (46 percent, p <O.OOl) relative to values In the control hearts. In preparations of noradrenergic granules 44 percent of norepinephrine stores and 33 percent of dopamine stores were associated with the vesicular pellet of normal hearts. Congestive heart failure led to a significant decrease in norepinephrine, particularly in the intravesicular compartment, whereas dopamine exhibited an approximately 20-fold rise, reflected exclusively by the supernatant (extravesicular) fraction. Ganglionic blockade restored catecholamine content and distribution to normal. Inhibition of monoamine oxidase doubled the norepinephrine content of failing hearts (p <O.Ol) in the absence of a change in dopamine. Catecholamine histofluorescence observations revealed a marked reduction in the number of nerves in apposition to the muscle of myopathic hearts In addition to a sprouting of new adrenergic fibers into connective tissue and in the lipofuscin pigment debris.

Measurement of Sympathetic Nervous System Activity in Heart Failure: The Role of Norepinephrine Kinetics

2000

Recent demonstration that the level of sympathetic nervous drive to the failing heart in patients with severe heart failure is a major determinant of prognosis, and that mortality in heart failure is reduced by beta-adrenergic blockade, indicate the clinical relevance of heart failure neuroscience research. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with the application of isotope dilution methods for measuring cardiac norepinephrine release to plasma indicating that in untreated patients cardiac norepinephrine spillover is increased as much as 50-fold, similar to levels of release seen in the healthy heart during near maximal exercise. This preferential activation of the cardiac sympathetic out¯ow contributes to arrhythmia development and to progressive deterioration of the myocardium, and has been linked to mortality in both mild and severe cardiac failure. Although the central nervous system mechanisms involved in the sympathetic nervous activation at present remain uncertain, increased intracardiac diastolic pressure seems to be one peripheral re¯ex stimulus, and increased forebrain norepinephrine turnover an important central mechanism. Additional neurophysiological abnormalities present in the failing human heart include release of the sympathetic cotransmitters, epinephrine and neuropeptide Y, at high levels more typical of their release during exercise in healthy subjects, and the possible presynaptic augmentation of norepinephrine release from the cardiac sympathetic nerves by the regionally released epinephrine. Following on the demonstrable bene®t of beta-adrenergic blockade in heart failure, additional antiadrenergic measures (central suppression of sympathetic out¯ow with imidazoline binding agents such as clonidine, blocking of norepinephrine synthesis by dopamine-b-hydroxylase inhibition, antagonism of neuropeptide Y) are now under active investigation.

Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine

Circulation, 1991

Background. We have previously shown that chronic elevation of plasma norepinephrine leads to a functional independent increase in left ventricular weight. The goals of the present study were to determine quantitatively the component of the myocardium that accounted for the observed structural changes and to determine the function of the hypertrophied myocardium. Methods and Results. Mongrel dogs were chronically' instrumented for measurement of arterial and left ventricular pressures, left ventricular internal diameter, and left ventricular wall thickness. Subcutaneous osmotic pumps were implanted to release norepinephrine continuously for 28 days. Hemodynamics were measured with dogs in the quietly resting state and during infusions of isoproterenol at 0.1 and 0.5 ,ug/kg/min before and on days 14 and 28 during the infusion of norepinephrine. The hemodynamic response to 10 jig/kg phenylephrine, given as a bolus, was also assessed before norepinephrine and 28 days during the infusion of norepinephrine, and the end-systolic pressure-diameter or wall stress-diameter relations were calculated. On day 28, hearts were arrested in diastole and perfusion fixed in situ. Tissue samples were prepared for electron microscopy and morphometry. Hemodynamic studies showed that isoproterenol (0.5,g/kg/min) reduced mean arterial pressure (MAP) to the same point on each experimental day, and the increases in indexes of contractility were reduced during norepinephrine infusion. Left ventricular dP/dt.,,. increased 131±24% on control day, only 67±20%o on day 14, and 55±18%o on day 28. Similar changes were observed in dP/dt/DP40 and dP/dt/end-diastolic circumference. However, E.., the slope of the end-systolic pressurediameter or wall stress diameter relations, was unchanged, suggesting that inotropic state was not altered. Morphometric studies showed that the cross-sectional area of myocytes increased by 55%, but myocyte and capillary densities decreased by 34% and 29%o, respectively (p<0.05) in dogs with high norepinephrine levels. There were no differences in volume fractions of myocytes, capillary lumen, or interstitium or capillary-to-myocyte ratio. Conclusions. The myocardium of dogs with high norepinephrine levels shows reduced inotropic response to,B-adrenergic stimulation despite the increases in left ventricular mass and left ventricular wall thickness, which are a result of growth of the cardiac myocytes and characteristic of concentric hypertrophy. These data suggest that chronic adrenergic stimulation of the heart reduces the ,B-receptor coupling to the contractile response without importantly compromising left ventricular function. (Circulation 1991;84:2091-2100) M s j~y ocardial hypertrophy of different etiolo-ventricular wall.89 Plasma norepinephrine levels in giesl-4 is associated with several pathologthis model are similar to those seen during mitral ical conditions.5-7 We have recently valve prolapse,l0 pheochromocytoma,ll and congesshown that chronic infusion of subpressor doses of tive heart failure.7 On structural analysis, pressure norepinephrine in mongrel dogs results in increased overload leads to concentric hypertrophy in which mass of the myocardium and thickening of the left wall thickness increases'2 through the lateral expan-From the Departments of Physiology (M.

Different response of the rat left and right heart to norepinephrine

Cardiovascular Research, 1996

The in vivo hemodynamic and morphologic responses of the rat left (LV) and right (RV) ventricle to continuous long-term i.v. infusion of norepinephrine (NE) at different dosages and for different durations of infusion were studied. Female Sprague-Dawley rats received continuous intravenous infusion of norepinephrine from infors" syringe pumps for 24, 48 and 12 h at a dose of 200 pg. kg-'. h-l. Furth ermore, NE was infused for 72 h at dosages of 50, 100 and 200 pg. kg-' . h-'. The beta-adrenergic blocker and vasodilator with alpha,-blocking activity carvedilol (0.5 mg . kg-' . h-'> was coinfused with NE for 72 h. The hemodynamic effects were measured on intact, anesthetized rats with special Millar'@ ultraminiature. pressure tip catheters, and the weights of the left and right ventricles were measured. NE increased heart rate at any time or dose, whereas cardiac output and total peripheral resistance remained unchanged. LV and RV d P/d t,, were nearly doubled as compared to control values and RVSP was elevated by more than 100%. The effect of NE on LVSP was much less pronounced ( < 20%) and only significant at 50 pg . kg-' h-' for 72 h. Neither LV nor RV end-diastolic pressures were elevated, indicating that cardiac failure had not occurred. The LV developed hypertrophy with an increase of the ventricular weight/body weight ratio (LVW/BW) of 22% even after only 2 days of NE (200 pg. kg-' . h-'). The RV showed no hypertrophy at any time of the experiments. The NE-induced changes in HR, d P/d t,, , RVSP and LVW/BW were completely prevented by the coinfusion of carvedilol. These studies show that the hemodynamic responses to continuous infusion of NE are more pronounced in the RV than in the LV. Conversely, NE induced hypertrophy only in the LV, not in the RV. The hemodynamic effects of chronic NE infusion did not change significantly between 1 and 3 days of infusion. The in vivo responses to exogenous NE therefore were unaffected by adaptive effects such as downregulation of adrenergic receptors.

Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure

Journal of the American College of Cardiology, 1994

Objectives. The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to Investigate the Influence of the cause of heart failure, heal udynamic variables and central nervous system catech trine rely use on cardiac sympathetic tone. Backgmmnd. Although head failure is generally accompanied by symp,%thoexcitation, the integrity of cardiac sympathetic nerve fuadion in hod failure remains controversial, particularly in relstflon to nerve firing activity and to the capacity of sympathetic nerves to recapture pore pinephrive. Additionally, the location of the affirrent and central neural pathways implicated in heart failure-Induced sympathoexcitation remains unclear. Whodh InulkArv,er techniques were applied in 41 patients with severe head failure and IS healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic Indexes of cardiac performance were measured In the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was Inessured to study the central noudrenergle control of sympathetic outflow. The development of congestive heart failure is accompanied by activation of a variety of neural and hormonal counterregulatory systems. These include the sympathetic nervous system (1-4) and the renin-angiotensin-aldosterone axis (5-7), with accompanying increased release of vasopressin (8) and endothelin (9). Evidence for activation of the sympathetic nervous system in heart failure includes increased plasma norepineph-From the Alfred and Baker Medical Unit. Baker Medical Research Institute. Melbourne and

Depletion of cardiac norepinephrine during two forms of hemolytic anemia in the rat

Circulation Research, 1976

Knowledge of the status of cardiac norepinephrine (NE) during anemia could lead to a better understanding of the role the sympathetic nervous system plays in cardiac function during anemia. Rats were made anemic by treatment with phenylhydrazine (PHZ). After the rapid onset of anemia, 60% of the stored NE in the heart was lost within 48 hours after treatment. Associated with the loss of cardiac NE was an increase in the wet weight of the heart, which reached a value 40% above control 48 hours after treatment. PHZ itself probably does not directly mediate this depletion of NE, since the vas deferens, brain and spleen had a normal store of NE at 48 hours. This contention was supported when rats, treated with PHZ, were transfused with normal rat red blood cells. This transfusion resulted in PHZ-treated rats which were not anemic. The hearts of these rats were not depleted of NE, but the hearts of the nontransfused, PHZ-treated controls were. Anemia also was induced by treating rats wit...