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European Journal of Heart Failure 2005 7(6):1003-1010; doi:10.1016/j.ejheart.2004.11.001
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© 2005 European Society of Cardiology

Decreased renal sympathetic activity in response to cardiac unloading with nitroglycerin in patients with heart failure{star}

Magnus Peterssona,*, Peter Fribergb, Gavin Lambertc and Bengt Rundqvista

a Department of Cardiology, The Cardiovascular Institute, Sahlgrenska University Hospital S-413 45 Göteborg, Sweden
b Department of Clinical Physiology, Sahlgrenska University Hospital Göteborg, Sweden
c Baker Medical Research Institute Prahran, Australia

* Corresponding author. Tel.: +46 31 3424222; fax: +46 31 827614. E-mail address: magnus.petersson{at}wlab.gu.se


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: To examine changes in renal sympathetic outflow in response to cardiac unloading with nitroglycerin (GTN) in patients with chronic heart failure (CHF) and healthy subjects (HS).

Methods and Results: Renal (RNAsp) and total body (TBNAsp) noradrenaline (NA) spillover were measured with radiotracer methods in 16 patients with CHF (50±3 years, LVEF 20±1%) and nine HS (57±2 years) during right heart and renal vein catheterisation. Low dose GTN decreased mean pulmonary artery pressure (PAm: CHF –7±2 mm Hg, HS –4±1 mm Hg, p<0.05 vs. baseline) but not mean arterial pressure (MAP: CHF –2±1 mm Hg, HS –2±1 mm Hg) and did not affect RNAsp in any of the study groups. High dose GTN lowered MAP (CHF –12±1 mm Hg, HS –12±2 mm Hg, p<0.05 vs. baseline) and PAm (CHF –13±2 mm Hg, HS –5±1 mm Hg, p<0.05 vs. baseline) and was accompanied by a significant reduction in RNAsp only in CHF (1.3±0.1 nmol/min baseline to 0.9±0.2 nmol/min, p<0.05), whereas RNAsp in HS remained unchanged.

Conclusions: In spite of a reduction in both arterial pressure and cardiac filling pressures, renal sympathetic activity decreased in CHF and did not increase in HS. These findings suggest that the altered loading conditions resulting from high-dose GTN infusion have renal sympathoinhibitory effects.

Key Words: Heart failure • Congestive • Sympathetic nervous system • Renal circulation • Cardiovascular physiology • Baroreflex

Received July 30, 2004; Revised September 16, 2004; Accepted November 11, 2004


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The autonomic changes that characterise heart failure are generalised sympathetic activation, blunted baroreflexes and decreased vagal tone-changes that have been associated with adverse prognosis [1–4]. Patients with chronic heart failure (CHF) have been shown to have increased renal noradrenaline (NA) spillover consistent with an increased renal sympathetic nerve activity [5,6]. The underlying mechanisms causing this increased activity have not been elucidated. Evidence from experimental heart failure in rats has demonstrated an attenuated response in efferent renal nerve activity to various baroreflex stimuli [7], but information is sparse regarding baroreflex control of renal sympathetic activity in human CHF as well as in healthy subjects.

We hypothesised that the renal sympathetic response to a decrease in cardiac filling pressures, rather than a reduction in arterial pressure, would be blunted in patients with CHF compared to that in healthy subjects. Thus, this study was designed to examine changes in systemic and renal sympathetic activity, as determined by NA spillover measurements, to sequential changes in cardiac filling pressures and arterial pressures during infusion with nitroglycerin (GTN) in patients with CHF. For adequate comparison, healthy subjects were examined with the same experimental protocol, including right heart and renal vein catheterisations.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The local ethics and isotope committees at Sahlgrenska University Hospital approved all studies, and written informed consent was obtained from each subject after the purpose and procedures of the study had been fully explained. Although patients with CHF of both sexes were screened for participation, only males were eventually included, and accordingly, only male healthy subjects were studied as controls.

2.1. Patients with CHF
The study population (Table 1) comprised patients in a stable clinical condition with CHF (n=16), referred for evaluation by the cardiac transplant unit at Sahlgrenska University Hospital between January 1998 and April 2001. Consecutive patients in stable sinus rhythm, left ventricular ejection fraction <35% by echocardiography, with clinical history of pulmonary congestion and/or peripheral oedema and no evidence of primary renal disease were included. The aetiology of CHF was classified as ischemic heart disease in seven and idiopathic dilated cardiomyopathy in the remaining nine patients. Patients with diabetes mellitus, neuropathy or known primary autonomic dysfunction were excluded. Because our protocol included the use of nitroglycerin, only patients with systolic blood pressure >95 mm Hg at rest were included in the study. Symptoms in all patients were classified as New York Heart Association functional class III. Concomitant medications are detailed in Table 2.


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  		Table 1 Baseline characteristics

 


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  		Table 2 Individual medications in the CHF group

 
2.2. Healthy subjects
Healthy subjects (n=9) of similar age as the CHF patients were studied (Table 1). None had a history of neurological or cardiovascular disease, and all were normotensive. All healthy subjects were without medication. A comprehensive clinical evaluation in conjunction with haematology, routine serum biochemistry, blood pressure and resting electrocardiogram was all within the normal range.

2.3. Catheterisation procedure
All patients and healthy subjects underwent a combined right heart and right renal vein catheterisation with simultaneous measurements of cardiac hemodynamics and arterial and renal venous blood sampling. The studies were performed in the morning after an overnight fast and were performed with the subjects in supine position. All regular medications were given as usual to the CHF subjects except diuretics (withheld >12 h) and oral nitroglycerin (withheld >48 h) before the investigations. All subjects refrained from smoking and coffee drinking for the 12 h preceding the study. A cannula was introduced percutaneously into the left radial artery for blood pressure monitoring and blood sampling. A balloon-tipped thermodilution catheter, inserted via the right jugular vein, provided measurements of cardiac pressures and flows. A similarly inserted multipurpose catheter was advanced to the proximal part of the right renal vein. The positioning of the catheter in the renal vein was confirmed by fluoroscopy and blood gas analysis. Healthy subjects were studied under similar conditions, except that they were not hospitalised.

2.4. Infusions
A tracer dose of [3H]NA (L-2,5,6-[3H]NA; 40 Ci/mmol; New England Nuclear, Boston, MA, USA) was delivered via an antecubital vein at a rate of 1.3 µCi/min. The infusate contained acetic acid (2 mM) and ascorbic acid (1 mM) to stabilise the radiolabelled NA. Renal plasma flow was determined by infusing paraaminohippurate (PAH) to steady state, using a dose adjusted to the patient's serum creatinine concentration [8].

2.5. Experimental protocol
After obtaining baseline hemodynamics, blood samples were taken simultaneously from the radial artery and the right renal vein at steady state ≥30 min after placement of the catheters, and the radiotracer and PAH infusions were begun. All subjects then received a continuous infusion of GTN, initially titrated to primarily affect cardiac filling pressures without significant changes in mean arterial pressure (MAP), i.e., preferential cardiopulmonary baroreceptor unloading. The infusion rate was increased by 25% every 20 min until the continuous pressure recorder indicated a reduction in diastolic pulmonary artery pressure by at least 10%. This low-dose GTN level was kept for 17±1 min in healthy subjects, GTN infusion rate of 0.08±0.01 ìg/kg/min, and for 21±1 min in CHF patients, GTN infusion rate 0.4±0.1 ìg/kg/min, before measurements, and blood samples were taken. GTN infusion rate was then increased stepwise until a stable reduction in mean arterial pressure of 10 mm Hg was reached. This high-dose GTN level was achieved at a GTN infusion rate of 0.13±0.02 ìg/kg/min in healthy subjects and 1.6±0.5 ìg/kg/min in CHF patients, kept for 15±1 and 14±2 min, respectively, before samples and measurements. Blood samples were transferred immediately into ice-cold tubes containing reduced glutathione and heparin. Plasma was separated by centrifugation and stored at –80 °C until assayed for catecholamines.

2.6. Assays
Catecholamines were extracted from plasma (1 ml) and samples of infusate (10 µl) using alumina adsorption and separated by high-performance liquid chromatography. Timed collection of [3H] eluate leaving the electrochemical cell permitted separation of [3H] labelled NA for subsequent counting by liquid scintillation spectroscopy. Interassay coefficients of variation were 4.6% for endogenous NA and 3.2% for [3H]NA [6,9]. Plasma PAH concentrations were estimated by chemical analyses using a modified method of Brun [10].

2.7. Calculations
Total body NA spillover into plasma and total body plasma clearance (TBCL) were calculated according to Esler et al. [11]:


Formula



Formula

where I is the infusion rate of NA (dpm/min), [3H]NA is the arterial concentrations of tritiated NA (dpm/ml) and NAA the arterial endogenous NA concentrations (pmol/ml).

Renal spillover of NA into plasma and the renal fractional extraction of NA (EXrenal) were calculated as:


Formula



Formula

where Q is the renal plasma flow (ml/min), NAV is renal venous NA concentrations (pmol/ml) and [3H]NAV is renal venous concentrations of tritiated NA (dpm/ml).

For determination of renal plasma flow, standard curves relating optical density to the concentration of PAH were determined and used to calculate infusion clearance, which was then corrected for fractional extraction to obtain plasma flow.

2.8. Statistical methods
Results are expressed as mean±standard error of the mean (S.E.M.). Between-group comparisons of baseline characteristics were performed with an unpaired t test for normally distributed variables and the Mann–Whitney U test for variables expressing a skewed distribution. Within-group comparisons of the effect at the low-dose nitroglycerin level and at the high-dose nitroglycerin level were made by one-way repeated measures ANOVA with the use of the Newman–Keuls test for post hoc comparisons. The logarithms of variables with skewed distribution were used in the ANOVA-tests. Between-group comparisons of the effects were performed with the use of two-way repeated measures ANOVA. Spearman rank correlation was used to assess the relationship between the change in NA spillover and the change in and baseline values of hemodynamic variables. A statistically significant difference was defined as p<0.05.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Baseline measurements
Patients with CHF had higher heart rate and cardiac filling pressures compared to healthy subjects (p<0.05) and lower mean arterial pressure (p<0.05; Table 1). Cardiac index was lower in patients compared to healthy controls (p<0.05). Total body NA spillover was increased twofold compared to healthy subjects (p<0.05; Table 1). Renal plasma flow was 24% lower in patients with CHF vs. healthy subjects (p<0.05). In the patients with CHF, total body NA spillover, but not renal NA spillover, correlated with mean pulmonary artery pressure at baseline (Spearman r=0.56, p<0.05).

3.2. Responses during intravenous nitroglycerin
3.2.1. Hemodynamic responses
The low-dose GTN level decreased cardiac filling pressures (p<0.05 vs. baseline; Tables 3 and 4) but not mean arterial pressure (MAP, p=NS vs. baseline). Renal plasma flow remained unchanged in both study groups. Systemic vascular (SVR) and renal vascular resistance (RVR) index tended to decrease in both groups (Tables 3 and 4).


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  		Table 3 Responses to nitroglycerin in healthy subjects

 


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  		Table 4 Responses to nitroglycerin in heart failure group

 
The high-dose GTN level lowered MAP (p<0.05 vs. baseline) and the mean pulmonary artery pressure (p<0.05 vs. baseline). At this dose level, renal plasma flow remained similar in CHF patients, while it increased by 13% vs. baseline in healthy subjects (p<0.05). RVR and SVR decreased at the high-dose GTN level in both study groups (p<0.05).

In healthy subjects, heart rate increased already at the low-dose GTN level (p<0.05 vs. baseline), with a further increase (p<0.05 vs. low-dose GTN level) at the higher infusion rate (high-dose GTN level). CHF patients had similar heart rates during both interventions.

3.2.2. Renal and total body NA kinetics
In CHF patients, renal NA spillover remained unchanged at low-dose GTN level but was significantly reduced when MAP was lowered at the high-dose GTN level (p<0.05; Fig. 1). Renal NA spillover was similar at all levels in the healthy subjects. The arterio-venous step-up in NA concentrations across the kidney followed the same pattern as renal NA spillover in both study groups. There was a statistically significant correlation between the change in renal NA spillover and the change in MAP (Spearman r=0.53, p<0.05) but not with the change in mean pulmonary artery pressure.


Figure 1
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  		Fig. 1 The graph illustrates the relative changes in renal and total body noradrenaline spillover rates (upper panel) and hemodynamics (lower panel) vs. baseline during low-dose GTN and high-dose GTN infusion rates. Vertical bars denote±S.E.M. *p<0.05 vs. baseline and {dagger}p<0.05 vs. low-dose GTN (ANOVA test).

 
The total body NA spillover tended to be higher compared to baseline at both infusion rates of GTN in the healthy subjects, although not statistically significant (p=0.06, ANOVA), while it did not change in the CHF patients.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The new and main finding in this clinical experimental study, performed in patients and healthy subjects, was a reduction in renal NA spillover in response to GTN infusion in CHF and an absence of response in healthy subjects. The observed decrease in renal NA spillover in patients with CHF occurred in spite of a clear decrease in both MAP and cardiac filling pressures and seems to be organ specific, with reference to the systemic sympathetic response since the reduction in renal sympathetic activity was not paralleled by a decrease in total body NA spillover. New and unexpected was also the absence of an increased renal NA spillover in the healthy subjects during the interventions. Instead of an expected increase in renal sympathetic activity [12], we observed an unchanged or even a trend to decrease in renal NA spillover, thus indicating either similar intrarenal effects of GTN, differentiated central effects of this drug or an unexpected baroreflex response as compared to animal data [13]. As anticipated, heart rate increased progressively during the experiment in healthy subjects, indicating adequate cardiac baroreflex activation, but was blunted in the CHF patients consistent with reduced baroreflex sensitivity. The lack of response in total body NA spillover in the patients with CHF, as compared to the healthy subjects, corroborates previous findings of an abnormal overall sympathetic response in CHF [14–16].

In the present study, there was neither any correlation between renal NA spillover and cardiac filling pressures at baseline nor between the fall in pulmonary artery pressure and changes in renal NA spillover in any of the study groups. Although we achieved a firm reduction in cardiac filling pressures at the low infusion rate of GTN, the absence of significant changes in renal NA spillover argues against a sympathoexcitatory reflex coupled to cardiopulmonary baroreceptors as mechanism behind the increased renal sympathetic activity in this CHF population. Thus, reflex modulation of sympathetic activity in the kidney may differ from the heart where a correlation exists between both baseline cardiac NA spillover and cardiac filling pressures [17] and between decreased cardiac NA spillover and LBNP-induced reduction in cardiac filling pressures [18].

The finding of a reduced renal sympathetic activity in the present CHF group, in spite of a significant blood pressure reduction, was unexpected as was the lack of reflex increase in total body NA spillover in this study group. In animal CHF models, renal sympathetic response to atrial distension and volume expansion has been shown to be attenuated [7,19,20] but not to decrease. However, in subgroups of patients with severe CHF, previous studies have shown evidence for a paradoxical decrease in peripheral sympathetic response to LBNP and orthostatic stress [21,22]. Stimulation of left ventricular mechanoreceptors, by means of diastolic ventricular interaction, has been suggested by Atherton et al. as one possible explanation for such paradoxical response in patients with severe CHF [21,23]. Although our patient population had similar functional status, pulmonary artery pressures and left ventricular ejection fraction as in the studies by Atherton et al., right heart filling pressures were lower in our material [21,23], and a renal sympathetic response already at the low-dose GTN level would have been expected if this reflex mechanism would be a major contributor to the observed response. Other mechanisms responsible for the blunted or paradoxical baroreflex response in CHF have been proposed, such as stimulation of mechanically sensitive cardiac vagal afferents thought to participate in the cardiac depressor response [24]. Although a depressor response could result in a rapid fall in sympathetic activity, it should be emphasized that the reduction of renal NA spillover in our CHF subjects occurred from a high level down to a level similar to that observed in healthy subjects. In addition, total body NA spillover and heart rate did not decrease. Thus, it seems unlikely that such a mechanism could explain our findings.

In patients with CHF, a reduced renal function is common, probably due to decreased renal perfusion. Renal dysfunction is associated with an increased sympathetic activity that seems to be related to activation of renal afferent signalling [25]. The regional response with a selective decrease in renal sympathetic activity in the present study suggests that renal effects such as improved renal perfusion might mediate a decrease in afferent signalling from renal chemoreceptors [26]. We have in previous studies, both in healthy subjects and in patients with hypertension, demonstrated selective increases in renal NA spillover with no concomitant change in total body NA spillover in response to vasodilatation, with and without blood pressure reduction, induced by enalaprilat [9,27]. These findings support the contention that renal afferents and hemodynamics contribute to short-term regulation of renal sympathetic outflow. The observed differences between these results and the present could be an effect of either differing effects on the renal vasculature between the two drugs or, possibly, by other sympathoinhibitory effects related to GTN per se [28]. The high-dose GTN-level in the present study was associated with a decrease in both systemic and renal vascular resistances in both study groups, contrasting the increase in these hemodynamic parameters during LBNP-induced hypotension in a study by Azevedo et al. [18], thus suggesting an influence of improved peripheral perfusion by means of a tentative decrease in afferent sympathetic signalling.

Our findings corroborate a recently published study on the effects of brain natriuretic peptide (BNP) on sympathetic nervous activity in CHF patients and healthy subjects [29], in which high doses of BNP resulted in a decrease of arterial blood pressure and cardiac filling pressures of similar magnitude as our high-dose GTN level. These authors observed a reduction in renal NA spillover in the CHF group, whereas no change in renal or total body NA spillover was found in healthy subjects. These findings suggest similar sympathoinhibitory effects of BNP and GTN and may indicate, in adjunct to peripheral effects, important central interactions of GTN [28].

Although total body NA spillover increased in the healthy subjects when cardiac filling pressures were lowered, there was surprisingly no further increase in total body NA spillover during blood pressure reduction. Prolonged steady state levels of the nonhypotensive and hypotensive interventions were used in the present study in order to obtain reliable measurements for PAH-clearance. Thus, blood samples for PAH and NA were taken at least 15 min after steady-state hypotension, in contrast to most previous baroreflex studies in which no hemodynamic steady-state levels have been utilized. Although GTN given as bolus doses has been used extensively in baroreflex studies and has repeatedly induced expected reflex increases in sympathetic outflow similar to those after nitroprusside and LBNP [30–32], our approach with steady-state infusion of GTN might be unable to detect an early increase in renal sympathetic activity. This possibility is supported by a study by Nordin et al. who found an initial increase in muscle sympathetic nerve activity (MSNA) during hypotension induced by GTN in healthy subjects, but after approximately 15–20 min, MSNA decreased to baseline values in spite of sustained hypotension [33]. Whether such an effect is related to central sympathoinhibitory effects of GTN per se or other mechanisms is unclear.

4.1. Limitations of the study
Although neither chronic treatment with metoprolol or enalapril in subjects with ischemic heart disease nor single doses of these medications in healthy subjects seem to influence GTN induced forearm dilatation [34], these therapies may theoretically have confounding effects with respect to renal NA spillover responses. Available results indicate that chronic therapy with metoprolol in CHF may have less effect on NA release than unselective beta blockade [35], and studies on spontaneously hypertensive rats suggests that late onset treatment with metoprolol does not alter renal sympathetic nerve activity as assessed with ramp infusions of phenylephrine and GTN [36]. Also, ACE-inhibitors and angiotensin receptor blockers have important interactions with the autonomic nervous system and may thus have influenced the results. Stimulation of facilitatory prejunctional angiotensin II receptors can enhance NA release from peripheral sympathetic nerves [37,38]. In the present study, renal NA spillover decreased during the high-dose nitroglycerin in patients whether or not they were receiving metoprolol or an ACE-inhibitor. Given these results, it is unlikely that the concomitant treatment influenced the relative changes in NA spillover in the present study. Central effects of GTN have been described in animal experiments [28] resulting in decreased sympathetic outflow and could thus introduce a confounding effect when interpreting the results. In the present study, additional blood sampling were performed in four subjects at the low-dose GTN level, about 10 min post the original study samples, and no changes in NA kinetics were found (data not shown). Thus, we do not believe that central effects of GTN per se dominate the changes in NA spillover rates.

In conclusion, these results demonstrate inhibitory effects of cardiac unloading with GTN on renal sympathetic activity in patients with CHF and also an unexpected absence of renal sympathetic response in healthy subjects. The similarity to previous findings with brain natriuretic peptide suggests either a common biochemical pathway for these substances or that the renal reflex response differs from other vascular beds. The attenuation of renal sympathetic activity may, apart from the reduction in cardiac pre- and afterload, contribute to the beneficial acute effects of GTN in CHF.


   Acknowledgements
 
The authors are grateful for the invaluable technical assistance of Gun Bodehed Berg and Sven-Eric Hägelind and to the staff of the Cardiology Laboratory and the Cardiopulmonary Transplant Unit at Sahlgrenska University Hospital. The authors are much obliged to Professor Gerald F. DiBona for valuable comments on this manuscript.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} This study was supported by grants from the Swedish Heart Lung Foundation, The Sahlgrenska Academy at Göteborg University and Göteborg Medical Society. No conflict of interest exists. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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J. S. Floras
Sympathetic nervous system activation in human heart failure: clinical implications of an updated model.
J. Am. Coll. Cardiol., July 28, 2009; 54(5): 375 - 385.
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