Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.14.16.2 (tyrosine hydroxylase)
14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Assessments were made of the tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) activities as well as the noradrenaline (NA) content of samples excised from right auricular tissue during cardiac surgery on a total of 55 patients with ischaemic heart disease (IHD), valvular heart disease (VHD), uncomplicated atrial septal defect (ASD) or congestive heart failure (CHF). The NA content was significantly higher in the IHD group than in the other three groups. The TH activity was highest in the IHD group although the difference was statistically significant only compared with the ASD and CHF groups. The DBH activity was also highest in the IHD group, but again the difference was statistically significant only compared with the ASD and CHF groups. In the whole material there was a significant positive correlation between the NA content and TH or DBH activity, as well as between TH and DBH activity. In the IHD group there was a significant positive correlation between heart volume and TH activity. The results suggest that at least compared with ASD and CHF, the sympathetic tone is relatively high in IHD, possibly involving an enhanced NA turnover.
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PMID:Auricular tyrosine hydroxylase and dopamine-beta-hydroxylase activities and noradrenaline content in ischaemic heart disease. 2 85

To study further the pathophysiology of radiation-induced cardiomyopathy, we investigated resting hemodynamics, myocardial catecholamine synthesis and storage, and beta-adrenoceptor density after local heart irradiation. In Wistar rats, a radiation dose of 20 Gy eventually leads to compromised myocardial function which is characterized by a reduction in cardiac output to 43 +/- 11% and in the left ventricular ejection fraction to 66 +/- 7.5%, and an increase in the left ventricular end-diastolic volume to 187 +/- 17% of control values. This reduction in function is correlated with focal degeneration of 23 +/- 4% of the myocardium. Measurement of tyrosine hydroxylase activity and catecholamine content revealed that catecholamine biosynthesis is unchanged in the adrenals but is significantly reduced in the hearts of irradiated animals, while cardiac beta-adrenoceptor density is increased to about 140% of that in age-matched controls. This is in contrast to findings in dilated or ischemic cardiomyopathy. Time-course studies showed that the development of myocardial degeneration starts simultaneously with the decrease in cardiac output and ejection fraction and the increase in beta-adrenoceptors at 50-80 days postirradiation. Myocardial degeneration is maximal in extent and severity at 100 days and does not progress thereafter. Cardiac output decreases at 80-100 days postirradiation to 60 +/- 7% of control values. A significant further decrease is seen only when congestive heart failure becomes manifest at 249 +/- 21 days after 20 Gy. Thus there is a delay between structural myocardial injury and hemodynamic deterioration which could be due to a compensatory increase in beta-adrenoceptor density during the initial stages of the cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Radiation-induced heart disease: morphology, changes in catecholamine synthesis and content, beta-adrenoceptor density, and hemodynamic function in an experimental model. 131 62

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

Myocardial noradrenaline (NA) content, together with the activities of the enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) was measured in biopsy specimens taken during cardiac surgery from patients with various heart diseases. Fluorescence histochemical studies were also performed on comparable specimens. The mean NA content in patients with symptomatic ischaemic heart disease (IHD) was significantly higher than that in patients with valvular heart disease (VHD), atrial septal defect (ASD) or congestive heart failure (CHF). The lowest mean NA content was found in patients with CHF. The activities of TH and DBH were highest in the IHD group, although the differences between IHD and VHD groups were not significant. Histochemical investigations of adrenergic structures showed less fluorescence intensity in the CHF than in the other 3 groups. On the other hand, the density of the adrenergic nerve net and the size and number of varicosities were greatest in patients suffering from IHD. The significance of these results is discussed in relation to the pathophysiological mechanisms underlying these various disease conditions. In IHD the high myocardial NA content creates local conditions for excessive NA release into the myocardial interstitium at the onset of ischaemia, which is known to result in several adverse local consequences.
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PMID:Myocardial catecholamines and their biosynthetic enzymes in various human heart diseases. 612 8

The adrenergic nervous system is chronically activated in patients with congestive heart failure (CHF). One consequence of this is depletion of the normally high levels of myocardial norepinephrine. In this study, myocardial norepinephrine and dopamine concentrations from the left ventricular walls of 3 patients undergoing cardiac transplantation for severe refractory CHF are reported. The dopamine/norepinephrine ratios were high in all 3 patients (29, 58 and 26%). This finding supports data from animal studies suggesting a change in the rate-limiting step for myocardial norepinephrine synthesis in CHF. Conversion of tyrosine to dopa by tyrosine hydroxylase is replaced as the rate-limiting step by inability to hydroxylate dopamine to norepinephrine. Thus, dopamine accumulates while norepinephrine is depleted.
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PMID:Elevated left ventricular myocardial dopamine in preterminal idiopathic dilated cardiomyopathy. 635 60

The development of dystrophic cardiac muscle is related to increases in sympathetic nervous system activity but little is known regarding possible central neural mechanisms that may be involved in cardiomyopathy. The inbred cardiomyopathic hamster is an animal model for studying the development and mechanisms of necrosis in cardiac muscle which resemble non-vascular myocardial diseases of man. Because monoamines are known to play a major role in central regulation of the cardiovascular system, we compared the distribution and density of tyrosine hydroxylase (TH) and 5-hydroxytryptamine (5-HT) immunostaining in the brains of cardiomyopathic hamsters (strain CHF-146), a related strain (CHF-148) of non-cardiomyopathic albino hamsters, and golden Syrian hamsters for possible differences in neurochemical organization. At the time of sacrifice, the cardiomyopathic hamsters exhibit small, calcified lesions on the surface of the ventricular cardiac muscle (early necrotic phase). Brain sections from each group were processed identically and simultaneously. The results show that there were significant differences among strains in the parabrachial nucleus with respect to the two neurochemicals examined. In golden Syrian and albino hamsters, TH and 5-HT immunoreactive axons were lightly-to-moderately stained in the lateral parabrachial nucleus. In the cardiomyopathic hamster, there were significantly more densely stained TH and 5-HT immunoreactive axons in the lateral parabrachial nucleus, in particular the inner part of the external lateral subnucleus. Because the lateral parabrachial nucleus, including the external lateral subnucleus, is known to be involved in regulation of the cardiovascular system, the differential distribution of TH and 5-HT in the parabrachial nucleus of cardiomyopathic hamsters in comparison to normal hamsters suggests that the parabrachial nucleus could be involved in sympathetic mechanisms related to the development of necrosis in cardiac muscle of the cardiomyopathic hamster.
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PMID:Monoamines in the parabrachial nucleus of the cardiomyopathic hamster. 766 67

Congestive heart failure is associated with cardiac adrenergic nerve terminal changes and beta-adrenoceptor density downregulation. To study the temporal sequence of these changes, we performed studies in rabbits at 2, 4, and 8 wk of cardiac pacing (360 beats/min) and at 1, 2, and 4 wk after cessation of pacing. Rapid pacing produced left ventricular (LV) dysfunction and an increase in plasma norepinephrine (NE) in 1-2 wk. At week 2, NE uptake activity, NE uptake-1 density, and adenylyl cyclase responses to isoproterenol, 5'-guanylyl imidodiphosphate [Gpp(NH)p], and forskolin reduced. However, immunostained tyrosine hydroxylase profile, beta-adrenoceptor density, and NE histofluorescence did not reduce until 4-8 wk of pacing. After cessation of cardiac pacing, LV function normalized quickly, followed by return of tyrosine hydroxylase and NE profiles in 1 wk and adenylyl cyclase responses to agonists and NE uptake activity in 2 wk. Myocardial beta-adrenoceptor density returned to normal by 4 wk after cessation of pacing. Our results suggest that there is no permanent structural neuronal damage in the myocardium within the first 8 wk of rapid cardiac pacing. Abnormal myocardial NE reuptake mechanism may play an important pathophysiological role in heart failure.
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PMID:Alterations in cardiac adrenergic terminal function and beta-adrenoceptor density in pacing-induced heart failure. 1077 52

Sympathetic neurotransmitters are diminished in cardiac efferent nerve endings in congestive heart failure (CHF). Similar changes occur after exogenous norepinephrine (NE) infusion. Since NE reduces nerve growth factor (NGF) in cultured cardiomyocytes, we proposed to determine whether the loss of noradrenergic transmitters in the failing heart is caused by the NE-mediated reduction of NGF or its neurotrophic receptor tyrosine kinase A (TrKA). Dogs were assigned to receive either rapid ventricular pacing (225 beats/min) or NE infusion (0.5 microg/kg/min) for 8 wk. Control animals received either cardiac pacing of 100 beats/min or saline infusion. We measured NGF and TrKA proteins by Western blot and immunocytochemistry and measured NGF and TrKA mRNAs by reverse transcription polymerase chain reaction, neuronal catecholaminergic histofluorescence, tyrosine hydroxylase-immunostained profiles, and plasma NE. Rapid ventricular pacing produced CHF with increased plasma NE, decreased myocardial NGF protein (0.61 +/- 0.07 vs. 1.04 +/- 0.04, P < 0.05), TrKA protein (0.75 +/- 0.08 vs. 0.98 +/- 0.06, P < 0.05), NGF and TrKA mRNAs and reduced catecholaminergic histofluorescence (197 +/- 23 vs. 485 +/- 43, P < 0.05), and tyrosine hydroxylase profiles (360 +/- 51 vs. 773 +/- 36, P < 0.05). Decreases in tissue NGF and TrKA protein were also noted by immunocytochemistry. Similar changes occurred in NE-treated animals. Tissue NGF and TrKA levels correlated closely with the noradrenergic transmitter profiles. We conclude that cardiac NGF and TrKA are reduced by rapid ventricular pacing and NE infusion, and that these changes correlate with decreases of cardiac catecholaminergic and tyrosine hydroxylase profiles. Findings indicate that decrease of cardiac sympathetic transmitters in heart failure is associated with NE-mediated reduction of NGF and TrKA.
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PMID:Loss of cardiac sympathetic neurotransmitters in heart failure and NE infusion is associated with reduced NGF. 1174 83

Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.
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PMID:Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy. 1621 45


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