Reduction of Cardiac Tyrosine Hydroxylase Activity in Experimental Congestive Heart Failure

Pool, Peter E.; Covell, James W.; Levitt, Morton; Gibb, James W.; Braunwald, Eugene

doi:10.1161/01.res.20.3.349

Cited by 137 publications

(40 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tyrosine hydroxylase is the rate-limiting step in the biochemical synthesis of NE. Early studies have demonstrated that cardiac tyrosine hydroxylase activity is reduced in both human CHF (18) and animals with experimental CHF (44). More recently, we have shown that tyrosine hydroxylase content is diminished in animals with CHF using either immunohistochemistry (27,29,33,35) or Western blot analysis (unpublished data).…”

Section: Discussionmentioning

confidence: 81%

See 1 more Smart Citation

Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Liang

Yatani

Himura

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

. Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion. Am J Physiol Heart Circ Physiol 284: H1729-H1736, 2003. First published January 23, 2003 10.1152/ajpheart. 00853.2002We reported recently that inhibition of neuronal reuptake of norepinephrine (NE) by desipramine prevented the reduction of sympathetic neurotransmitters in the failing right ventricle of right heart failure animals. In this study, we studied whether desipramine also reduced the sympathetic neurotransmitter loss in animals with left heart failure induced by rapid ventricular pacing (225 beats/min) or after chronic NE infusion (0.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Desipramine was given to the animals for 8 wk beginning with rapid ventricular pacing or NE infusion. Animals receiving no desipramine were studied as controls. We measured myocardial NE content, NE uptake activity, and sympathetic NE, tyrosine hydroxylase, and neuropeptide Y profiles by histofluorescence and immunocytochemical techniques. Effects of desipramine on NE uptake inhibition were evidenced by potentiation of the pressor response to exogenous NE and reduction of myocardial NE uptake activity. Desipramine treatment had no effect in sham or saline control animals but attenuated the reduction of sympathetic neurotransmitter profiles in the left ventricles of animals with rapid cardiac pacing and NE infusion. In contrast, the panneuronal marker protein gene product 9.5 profile was not affected by either rapid pacing or NE infusion, nor was it changed by desipramine treatment in the heart failure animals. The study confirms that excess NE contributes to the reduction of cardiac sympathetic neurotransmitters in heart failure. In addition, it shows that the anatomic integrity of the sympathetic nerves is relatively intact and that the neuronal damaging effect of NE involves the uptake of NE or its metabolites into the sympathetic nerves. neuronal uptake activity; histofluorescence; tyrosine hydroxylase; neuropeptide Y; protein gene product 9.5 EARLIER STUDIES FROM OUR LABORATORY have shown that right heart failure produced by progressive pulmonary constriction and tricuspid valve avulsion is associated with a selective reduction of norepinephrine (NE) reuptake and downregulation of myocardial ␤-adrenoceptor density in the failing right ventricle (33). The sympathetic nerve terminal profiles, as measured by catecholaminergic histofluorescence, and tyrosine hydroxylase and neuropeptide Y immunocytochemistry are also reduced only in the failing right ventricle (27). These findings suggest that the reductions of myocardial ␤-adrenoceptors and sympathetic nerve neurotransmitters in congestive heart failure (CHF) are caused by local mechanisms occurring only in the failing myocardium; the correspondent left ventricle is relatively unaffected despite exposure to the same systemic elevation of plasma catecholamines (33). A similar chamber specific reduction of myocardial ␤-adrenoceptors was reported in humans with right heart fail...

show abstract

Section: Discussionmentioning

confidence: 81%

“…This reduction of myocardial NE is caused by a number of factors, including increased release, decreased synthesis, and reduced reuptake of NE (11,18,27,44,45). Tyrosine hydroxylase is the rate-limiting step in the biochemical synthesis of NE.…”

Section: Discussionmentioning

confidence: 99%

Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Liang

Yatani

Himura

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…The lack of correlation between NE uptake activity and myocardial NE depletion in the left ventricles of RHF dogs in our present study, however, suggests that NE depletion cannot be accounted for by abnormal NE uptake alone. Alternatively, myocardial NE depletion could have resulted from decreased NE synthesis, as heart failure has been shown to be associated with a decrease in cardiac tyrosine hydroxylase activity (48)(49)(50), or other ratelimiting steps for cardiac NE synthesis (51).…”

Section: Resultsmentioning

confidence: 99%

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

Liang¹,

Fan

Sullebarger³

et al. 1989

J. Clin. Invest.

124

View full text Add to dashboard Cite

The reduction of myocardial beta-adrenoceptor density in congestive heart failure has been thought to be caused by agonistinduced homologous desensitization. However, recent evidence suggests that excessive adrenergic stimulation may not produce myocardial beta-receptor downregulation unless there is an additional defect in the local norepinephrine (NE) uptake mechanism. To investigate the association between betaadrenoceptor regulation and NE uptake activity, we carried out studies in 30 dogs with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary artery constriction and 23 sham-operated control dogs. We determined NE uptake activity by measuring accumulation of IHINE in tissue slices, NE uptake-i carrier density by V3Hlmazindol binding and beta-adrenoceptor density by VHJdihydroalprenolol binding. Compared with sham-operated dogs, RHF dogs showed a 26% decrease in beta-adrenoceptor density, a 51% reduction in NE uptake activity, and a 57% decrease in NE uptake-i carrier density in their right ventricles. In addition, right ventricle beta-receptor density correlated significantly with NE uptake activity and NE uptake-i carrier density. In contrast, neither NE uptake activity nor beta-receptor density in the left ventricle and renal cortex was affected by RHF. Thus, the failing myocardium is associated with an organ-and chamber-specific subnormal neuronal NE uptake. This chamber-specific loss of NE uptake-i carrier could effectively reduce local NE clearance, and represent a local factor that predisposes the failing ventricle to beta-adrenoceptor downregulation.

show abstract

“…15 Other observations suggest that heart failure may impair sympathetic neurotransmitter production and/or release. [33][34][35][36] Clinical Implications…”

Section: Modulation Of Sympathetic Activity In Heart Failurementioning

confidence: 99%

Sympathetic vasoconstriction during exercise in ambulatory patients with left ventricular failure.

et al. 1989

View full text Add to dashboard Cite

In patients with heart failure, exercise is thought to increase sympathetic vasoconstrictor tone. To investigate the extent of this sympathetic activation, we studied the effect of maximal exercise on nonexercising vascular beds in 35 patients with left ventricular failure (ejection fraction, 21 +/- 8%; peak exercise oxygen uptake (VO2), 12.3 +/- 3.5 ml/min/kg). In 28 patients, cardiac output and leg blood flow were measured during maximal upright bicycle exercise. Total flow to nonexercising tissue was then calculated as cardiac output--(2 x leg flow). In seven patients and six normal subjects, forearm blood flow was measured during supine bicycle exercise before and after alpha-adrenergic blockade with intravenous phentolamine. Maximal upright exercise increased the vascular resistance of nonexercising tissue from 34 +/- 16 units at upright rest to 45 +/- 25 units (p less than 0.02) but did not affect total flow to nonexercising tissue (rest, 2.9 +/- 1.0; maximal exercise, 2.8 +/- 1.4 l/min; p = NS). Supine exercise had no significant effect on forearm blood flow or vascular resistance in the normal subjects. In the patients with heart failure, supine exercise increased forearm vascular resistance from 45 +/- 17 to 58 +/- 25 mm Hg/ml/min/100 ml (p less than 0.02), again with no change in tissue flow (rest, 2.4 +/- 0.1; maximal exercise, 2.4 +/- 0.9 ml/min/100 ml; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

Reduction of Cardiac Tyrosine Hydroxylase Activity in Experimental Congestive Heart Failure

Cited by 137 publications

References 20 publications

Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

Sympathetic vasoconstriction during exercise in ambulatory patients with left ventricular failure.

Contact Info

Product

Resources

About