Elsevier

Journal of Cardiac Failure

Volume 12, Issue 7, September 2006, Pages 577-583
Journal of Cardiac Failure

Basic Science and Experimental Studies
Preserved Norepinephrine Reuptake but Reduced Sympathetic Nerve Endings in Hypertrophic Volume-Overloaded Rat Hearts

https://doi.org/10.1016/j.cardfail.2006.05.006Get rights and content

Abstract

Background

In congestive heart failure (CHF), an activation of the cardiac sympathetic nervous system results in depleted cardiac norepinephrine (NE) stores. The underlying regulatory mechanisms are discussed controversially and were investigated in the present study in CHF resulting from volume overload.

Methods and Results

Aorto-caval shunt (AVS) was performed in rats. Plasma NE levels were determined by radioenzymatic assay, left ventricular NE by high-performance liquid chromatography, endothelin-1 by enzyme-linked immunosorbent assay. Tyrosine-hydroxylase (TH)– and nerve growth factor (NGF)–mRNA was determined by Northern blot analysis and ribonuclease-assay. Cardiac [3H]-NE uptake was measured in isolated perfused hearts. Glyoxylic acid–induced histofluorescence was used to quantify cardiac sympathetic nerves. Compared with sham-operated animals (SH), AVS rats were characterized by depleted cardiac NE stores and enhanced NE plasma levels. Neither TH-mRNA levels in stellate ganglia, nor cardiac [3H]-NE-uptake were reduced in AVS. The left ventricular density of sympathetic nerves was markedly decreased. Gene expression of myocardial NGF (a positive regulator of NE reuptake and cardiac sympathetic nerve density) and left ventricular endothelin-1 (a negative regulator of NE reuptake and positive regulator of cardiac NGF expression) were unchanged.

Conclusion

In volume-overloaded hypertrophic hearts, depletion of cardiac NE stores is caused by a reduction of the sympathetic nerve density, whereas cardiac NE reuptake is preserved.

Section snippets

Experimental Animals

The experiments were performed in male Wistar rats (Thomae, Biberach/Riss, Germany) and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was officially approved by the authorities at the Regierungspräsidium Karlsruhe, Germany.

Induction of Congestive Heart Failure

AVS was performed in male Wistar rats by a modified method of Garcia and Diebold,13 as previously described.10 Rats with a body weight of about 180 g were

Baseline Characterization of Aorto-Caval Shunt Rats

Six weeks after induction of AVS, peripheral shunt volume was 84 ± 4% of abdominal aortic blood flow, corresponding to a central shunt volume of approximately 55% of total cardiac output. The animals presented a doubled left ventricular end-diastolic pressure, marked left ventricular hypertrophy, and an increased lung wet weight as compared to SH rats, indicating a severe pulmonary congestion (Table 1). Furthermore, signs of more severe CHF such as ascites, or pleural effusions were observed at

Discussion

In the present study, we demonstrate that depletion of cardiac NE stores in volume overload–induced heart failure is caused by a reduction of sympathetic nerve fibers within the hypertrophic left ventricle and not by an impairment of NE reuptake, as it was shown previously in pressure overload.2 Experimental CHF was induced by infrarenal AVS, resulting in biventricular myocardial hypertrophy and overt heart failure. In contrast to other established animal models of heart failure, a major

Conclusions

Depletion of cardiac NE stores in volume overload–induced CHF is caused by a reduction of cardiac sympathetic nerve fibers. In contrast to other forms of CHF, an impairment of NE reuptake does not mediate depletion of cardiac NE stores in volume overload.

Acknowledgment

The expert technical assistance of Silvia Harrack, Jutta Krebs, and Michaela Oestringer is gratefully acknowledged.

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    J.B. was supported by a grant from the Young Investigator Program of the University of Heidelberg.

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