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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 increase in cardiac sympathetic tone in the late stages of hamster cardiomyopathy appears to lead to a shift in the rate-limiting step for norepinephrine synthesis from the hydroxylation of tyrosine to the hydroxylation of dopamine. There is evidence that this shift which results in an accumulation of dopamine in the noradrenergic nerve terminals of the heart is a general manifestaion of augmented sympathetic nerve traffic rather than a peculiarity of hamster cardiomyopathy.
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PMID:A possible change in the rate-limiting step for cardiac norepinephrine synthesis in the cardiomyopathic Syrian hamster. 2 58

Choline acetyltransferase activity, which is rate limiting in acetylcholine biosynthesis, was measured in the four heart chambers of guinea pigs subjected to (1) sham surgery, (2) constriction of the ascending aorta, (3) constriction of the descending thoracic aorta, and (4) constriction of the pulmonary artery. After 30 days when hypertrophy and heart failure were fully established, choline acetyltransferase was quantified in vitro by a radiochemical assay. In the sham-operated group, enzyme activity expressed in terms of unit weight of cardiac tissue was greatest in the right atrium and the right ventricle and lower in th left atrium and the left ventricle (3.62 plus or minus 0.30, 2.96 plus or minus 0.52, 1.64 plus or minus 0.15, and 1.67 plus or minus 0.22 nmoles/min g-1, respectively). Enzyme activity was reduced (P less than 0.05) in the right atria and the right ventricles of guinea pigs with constriction of the pulmonary artery (1.68 plus or minus 0.37 and 1.31 plus or minus 0.29 nmoles/min g-1, respectively). Enzyme activity also tended to be reduced in the left atria and the left ventricles of guinea pigs with constriction of the aorta. These changes represented a relative dilution of enzyme activity per unit weight but not an absolute depletion, since choline acetyltransferase activity per ventricle was not reduced. The absence of significant changes in the total amount of the neuronal enzyme, choline acetyltransferase, per ventricle contrasted with the observed increases in the myocardial enzyme, carnitine acetyltransferase. These results confirm the presence of significant parasympathetic innervation of the ventricles as well as the atria but do not demonstrate alterations in parasympathetic neurotransmitter biosynthesis in hypertrphied and failing myocardium. The absence of absolute reductions in choline acetyltransferase activity in hypertrophied and failing ventricle contrasts strikingly with the previously reported reductions in tyrosine hydroxylase, which is rate limiting in sympathetic neurotransmitter biosynthesis.
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PMID:In vitro acetylcholine biosynthesis in normal and failing guinea pig hearts. 16 10

The sympathetic nervous system is markedly activated in most patients with congestive heart failure, but it is not clear whether such activity is clinically beneficial (and should be enhanced) or detrimental (and should be blocked). Some insights into this question can be gained by reviewing the results of clinical trials with beta-adrenergic agonists and antagonists. Long-term treatment with agents that stimulate the beta-receptor (prenalterol and pirbuterol) has not proved to be useful in the treatment of chronic heart failure; moreover, prolonged treatment with beta-agonists (dobutamine and pirbuterol) may adversely affect survival. Most of the studies with beta-agonists, however, have employed agents that interact nonselectively and with a high degree of intrinsic activity with both beta 1-and beta 2-receptors. It is possible that the problems that have been encountered with the use of beta-agonists could be minimized by agents that are more selective and have less intrinsic activity. Yet, such agents may actually function as beta-adrenergic antagonists (rather than agonists) in states of heightened sympathetic activity. Indeed, sustained therapy with drugs that attenuate the effects of the sympathetic nervous system (by blocking tyrosine hydroxylase or beta-adrenergic receptors) may produce hemodynamic and clinical improvement and may reduce long-term mortality in chronic heart failure. Although beta-adrenergic blockade carries important risks, these might be minimized by the use of drugs that spare myocardial and vascular beta 2-receptors or possess some intrinsic agonist activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Is activation of the sympathetic nervous system beneficial or detrimental to the patient with chronic heart failure? Lessons learned from clinical trials with beta-adrenergic agonists and antagonists. 247 8

Although the sympathetic nervous system is markedly activated in most patients with congestive heart failure, it is not clear whether such activity is clinically beneficial (and should be reinforced) or detrimental (and should be pharmacologically blocked). Some insights pertinent to this important question can be gained by reviewing the results of clinical trials with beta agonists and antagonists. Neither beta 1-selective (prenalterol) nor beta 2-selective (pirbuterol) agonists have been shown to be effective in treating heart failure in double-blind, placebo-controlled studies; moreover, research has indicated that prolonged stimulation of beta receptors with oral or intravenous catecholamines may adversely affect survival. In contrast, sustained therapy with drugs that attenuate the effects of the sympathetic nervous system (by blocking either tyrosine hydroxylase or beta-adrenergic receptors) may produce hemodynamic and clinical improvement and may favorably affect long-term prognosis. These potential benefits of beta-adrenergic blockade contrast strikingly with the lack of efficacy (with respect to clinical status and survival) of agents that block alpha-adrenergic receptors. Beta-adrenergic blockade carries important risks in the patient with heart failure, however. The risk-to-benefit ratio cannot be delineated accurately until the outcome of additional randomized clinical trials is known.
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PMID:Modulation of functional capacity and survival in congestive heart failure. Effects of activation of the sympathetic nervous system. 289 67

The effects of sino-aortic denervation (SAD) on cardiac noradrenaline stores, turnover and neuronal re-uptake were examined in normotensive rabbits and rabbits with two-kidney, two wrapped hypertension. Ten to 12 days after SAD, left ventricular (LV) noradrenaline stores were reduced in renal hypertensives to 43% of that of the sham-operated rabbits, although there was no overt evidence of heart failure. This did not occur after SAD of normotensive rabbits. The reduction in noradrenaline content was accompanied by a reduction in [3H]-noradrenaline turnover time (4.4 h) compared with renal hypertensive (7.4 h) and the normotensive subgroups (9.3 h). Noradrenaline turnover rates were elevated by 25% in hypertensive compared with normotensive rabbits. Left ventricular tyrosine hydroxylase, dopamine-beta-hydroxylase and type A monoamine oxidase activities were similar in normotensive and hypertensive rabbits and were unaffected by SAD. Following SAD of hypertensive rabbits cardiac neuronal uptake for alpha-methylnoradrenaline was reduced by 33% compared with either the hypertensive or the normotensive rabbits. Sino-aortic denervation did not affect neuronal uptake in normotensives. These results suggest that following SAD of hypertensive rabbits, cardiac noradrenaline stores are depleted by enhanced cardiac sympathetic activity (reduction in [3H]-noradrenaline turnover time) and a reduction in neuronal re-uptake. It appears that the hypertensive hypertrophied heart is less able to tolerate chronic sympathetic overactivity and/or liability in coronary oxygen supply brought about by SAD.
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PMID:Differential effects of sino-aortic denervations on cardiac noradrenaline stores, turnover and neuronal re-uptake in normotensive and renal hypertensive rabbits. 377 95

Sympathetic neurochemical indices in heart are increased in Syrian golden hamsters with skeletal and cardiac myopathy. The possibility that parasympathetic neurochemical indices might be altered was investigated in myopathic and normal hearts by measuring activity of choline acetyltransferase involved in acetylcholine synthesis. Confirming a previous report, tyrosine hydroxylase activity increased in failing myopathic hearts and norepinephrine concentration decreased. Extending previous work, tyrosine hydroxylase and dopamine-beta-hydroxylase activities in myopathic hearts demonstrated progressive, age-related increases. These changes were associated with reduced choline acetyltransferase activity in hearts of older myopathic hamsters (180 to 300-plus days). Decreases tended to be more pronounced in hamsters with cardiac hypertrophy and fluid retention (290-360 days old). Neurochemical evidence of increased sympathetic indices (dopamine-beta-hydroxylase activity) was detected at 30 days of age. Evidence of decreased parasympathetic indices (choline acetyltransferase activity) was detected at 180 days of age and persisted through terminal phases of heart failure. This study demonstrated that there are abnormalities in cardiac parasympathetic as well as cardiac sympathetic indices in myopathic hamsters.
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PMID:Changes in parasympathetic and sympathetic neurochemical indices in hearts of myopathic hamsters. 612 32

Heart failure is associated with a reduction in tissue norepinephrine concentration, catecholamine fluorescence, and tyrosine hydroxylase activity. We hypothesized that this attrition of sympathetic nerve function might also be associated with a reduction in the ability of the neuronal membrane to sequester catecholamines. Since the heart does not release epinephrine, the cardiac extraction of epinephrine should be an index of the membrane uptake system. In 12 patients with documented left ventricular failure (pulmonary edema) secondary to mechanical overload and in 10 patients with no history of heart failure, we measured simultaneous plasma catecholamine concentrations in the aorta, coronary sinus, and femoral vein. The aortocoronary sinus extraction of epinephrine was 43 +/- 17% in the group with no evidence of heart failure but 0 +/- 14% in the group with failure. Net norepinephrine outflow (release minus extraction) was significantly higher in the group with failure, possibly because of reduced extraction. There was neither a reduction in the ability of the lower limb to extract epinephrine nor an increased norepinephrine outflow from the limb. These findings suggest that the sympathetic neuronal membrane uptake system is also depressed in the failing heart and that if the mechanism of catecholamine sequestration in the heart is related to that in the lower limb, the ablation of sympathetic nerve function is specific to the heart and is not a result of a generalized depression of the peripheral sympathetic nervous system.
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PMID:Reduced aortocoronary sinus extraction of epinephrine in patients with left ventricular failure secondary to long-term pressure or volume overload. 686 2

Depletion of cardiac norepinephrine has been reported in cardiac hypertrophy. This depletion causes less support for cardiac output in response to sympathetic nerve activation. The central nervous system is thought to be involved in this abnormality. Correction of this abnormality is expected to restore proper support for the heart. Clipping of the ascending aorta or a sham operation was performed in 10-week-old rats. At 4 weeks after the operation, the left ventricular norepinephrine concentration in clipped rats decreased (p<0.01). The clipped rats and sham-operated rats were treated with either guanabenz (1 mg/kg) or a vehicle for 4 weeks starting from fifth postoperative week. The level of left ventricular norepinephrine increased more in clipped rats treated with guanabenz (469+/-37 ng/g) than in clipped rats treated with a vehicle (325+/-28 ng/g). The norepinephrine concentration in the left ventricle recovered significantly after the treatment with guanabenz (p<0.001). Tyrosine hydroxylase activity in the left ventricle also recovered after treatment with guanabenz (p<0.01). Modulation of sympathetic nerve tone by the alpha2-adrenoceptor agonist restored cardiac norepinephrine concentration and tyrosine hydroxylase activity. This could be a new approach to the treatment of heart failure.
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PMID:Recovery of cardiac norepinephrine concentration and tyrosine hydroxylase activity by the central alpha2-adrenoceptor agonist guanabenz in rats with aortic constriction. 1006 76

Cardiac sympathetic nerve terminal dysfunction plays an important role in the downregulation of myocardial beta-adrenoceptors in heart failure. To determine whether chronic angiotensin-converting enzyme (ACE) inhibition improved cardiac sympathetic nerve terminal function and hence increased myocardial beta-adrenergic responsiveness, we administered ACE inhibitors to dogs with chronic right-sided heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. The RHF animals exhibited fluid retention, elevated right heart filling pressures, blunted inotropic response to isoproterenol, and reduced beta-adrenoceptor density. These changes were accompanied by decreases in right ventricular norepinephrine (NE) uptake and neuronal NE histofluorescence and tyrosine hydroxylase immunoreactive profiles. ACE inhibitors had no effect on the production of heart failure but greatly reduced the attenuation of cardiac NE uptake, neuronal NE histofluorescence, and tyrosine hydroxylase immunoreactive profiles. ACE inhibition also improved the inotropic response to isoproterenol and restored myocardial beta-adrenoceptor density. The changes probably are caused by reduction of cardiac NE release by ACE inhibition and may contribute to the beneficial effects of ACE inhibitor therapy in patients with chronic heart failure.
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PMID:ACE inhibition improves cardiac NE uptake and attenuates sympathetic nerve terminal abnormalities in heart failure. 1051 1

Experiments were performed to determine if there is regional heterogeneity in sympathetic neural activation of peripheral tissues in rats with chronic heart failure (HF; 6-8 wk after coronary artery ligation). Norepinephrine (NE) turnover, an index of sympathetic activation, was determined on the basis of the decline in tissue NE levels that occurs during the 8-h after tyrosine hydroxylase inhibition (alpha-methyl-DL-p-tyrosine, 300 mg/kg ip at 4-h intervals). Compared with sham-operated rats, NE turnover was increased in the cardiac left ventricle, skeletal muscle, duodenum, and kidney of rats with HF, but was unaltered in liver and spleen. The increased renal NE turnover in HF was largely a reflection of increased turnover in the cortex, with no change evident in the medulla. Blockade of sympathetic ganglionic traffic (hexamethonium, 2 mg/kg sc at 2-h intervals) eliminated the tissue-specific effects of HF on tissue NE levels measured 8-h after tyrosine hydroxylase inhibition. These data support the contention that chronic HF evokes a central nervous system-mediated increase in basal sympathetic tone that exhibits regional heterogeneity (both between and within organs), a phenomenon that likely contributes to the functional consequences of this pathophysiological state.
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PMID:Norepinephrine turnover in peripheral tissues of rats with heart failure. 1071 72


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