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

Abstract

. 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...

Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents

“…TH + nerves are reduced in hearts after CHF, leading to the assumption that the SNS is anatomically denervated (5,(27)(28)(29). Conversely, Liang reported that there was a discrepancy between anatomical integrity and the catecholaminergic properties of the cardiac SNS in CHF, and that nerve fibers expressing the general neuronal marker, protein gene product 9.5, are intact, despite an overall reduction in catecholaminergic neurotransmitters (30). We have previously shown that in the cardiac SNS in CHF, the expression of TH and DBH is downregulated, with concomitant upregulation of GAP43 or PSA-NCAM proteins (6).…”

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells

“…Using confocal microscopy, we observed the absence of tyrosine hydroxylase, a well-established marker of sympathetic nerves, in tumor blood vessels visualized by injecting FITC-lectin to the tumor-bearing animals (Fig. 1A); this finding indicates the absence of sympathetic nerves in the blood vessels of these tumors (23)(24)(25)(26). Then, to determine the effect of sympathectomy on the status of DA in these tumor tissues, we measured the concentration of DA in tumor tissues by HLPC with electrochemical detection (27).…”

Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy

“…Tyrosine hydroxylase, a rate-limiting enzyme in NE biosynthesis (37), is reduced in heart failure (16,53), which may account, at least in part, for the reduced production of NE. Recently, we observed in several animal models of experimental CHF (23,30,39,41) that the sympathetic nerve profiles as measured by NE histofluorescence and tyrosine hydroxylase immunocytochemistry are reduced in CHF, but there is no significant reduction of protein gene product 9.5 (PGP9.5) (41), a panneuronal marker (20,29,57). Thus the anatomic integrity of the cardiac sympathetic nerves probably is intact in CHF, and the changes of sympathetic neurotransmitters within the nerve endings are caused by functional abnormalities that are potentially reversible with either effective therapy or removal of primary insult that causes heart failure as discontinuation of cardiac pacing in tachycardiainduced cardiomyopathy (30).…”