The Effects of Dobutamine on Renal Sympathetic Activity in... : Journal of Cardiovascular Pharmacology (2024)

INTRODUCTION

Renal dysfunction in the setting of the heart failure, known as the cardiorenal syndrome, affects 25 to 45% of hospitalized patients.^1,2 Apart from presenting an obstacle to the management of these patients, it is now recognized as a strong and independent predictor of mortality.^3,4 The pathophysiology of the cardiorenal syndrome is still poorly understood.

Heart failure is characterized by an increase in sympathetic activity, and the kidney is a primary target of this activation by virtue of its central role in homeostasis.⁵ This sympathetic activation contributes to the sodium avid state, renal vasoconstriction, and reduction in glomerular filtration rate (GFR).⁶ These findings suggest that sympathetic activation is at least partially responsible for the development of the cardiorenal syndrome. However, the reflex control of renal sympathetic activity remains largely unexplored in human heart failure.

Arterial baroreceptor control of renal sympathetic activity is blunted in human heart failure.⁷ To our knowledge, there are no data concerning the impact of positive inotropic therapy on renal sympathetic activity in human heart failure. Animal models suggest that inotropic activation of ventricular mechanoreceptors is associated with a reduction in efferent sympathetic activity.⁸ We have previously shown that activation of these receptors was associated with a reduction in cardiac sympathetic activity in the setting of heart failure.⁹ We used the norepinephrine spillover technique to test the hypothesis that inotropic therapy with dobutamine would reduce renal sympathetic activity in patients with heart failure.

EXPERIMENTAL PROCEDURES

We studied 11 male patients with systolic heart failure (age, 64 ± 3 years; ejection fraction, 25 ± 4%). Six subjects had coronary artery disease, and five patients had idiopathic dilated cardiomyopathy. The patients had preserved renal function (creatinine, 88 ± 6 μmol/L). The patients were on maximally tolerated doses of angiotensin-converting enzyme inhibitiors, and β-adrenergic receptor blockers. All medications were held on the morning of the study. The subjects were referred for cardiac catheterization as part of their heart failure work-up.

The Mount Sinai Hospital Research Ethics Board for experimentation involving human subjects approved the protocol, and written informed consent was obtained from all participants.

A diagnostic left and right heart catheterization from the femoral approach was performed without sedation. After the diagnostic procedure, a 7F micromanometer-tipped catheter (Millar Industires, Houston, Texas) was placed in the left ventricle. A 6F Judkins left diagnostic catheter was inserted via the femoral vein and positioned under fluoroscopic guidance in the right renal vein for blood sampling. Femoral artery pressure was monitored via an 8F side-arm sheath (Cordis Laboratories).

Sympathetic activity was estimated by the measurement of renal and total-body norepinephrine spillover.^10,11 For these measurements, tritiated norepinephrine (1 to 1.2 μCi/min with a 16 μCi priming bolus of L-[2,5,6-3H]norepinephrine; New England Nuclear) was infused into a peripheral vein to steady-state concentration in plasma. Norepinephrine clearance and spillover rates were calculated as previously described.^7,9

Renal plasma flow (RPF) was measured by use of the P-aminohippurate clearance technique. GFR was measured by use of inulin clearance.⁷P-Aminohippurate (PAH) and inulin priming boluses were followed by a steady-state infusion into a peripheral vein. Arterial and renal vein concentrations of PAH and inulin were determined to measure RPF and GFR, respectively.

Plasma catecholamine concentrations were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. Fractions from the HPLC effluent containing tritium-labeled norepinephrine were assayed by liquid scintillation spectroscopy. These analyses were performed by established methods in our laboratory by personnel blinded to patient status.⁹

After the diagnostic heart catheterization and insertion of catheters for hemodynamic monitoring, the patient was left undisturbed for a minimum of 20 minutes for tritium-labeled norepinephrine to reach steady state. Baseline hemodynamic measurements were obtained, along with measures of total-body and renal norepinephrine spillover. Subsequently, an intravenous infusion of dobutamine was initiated, starting at 2.5 μg/kg/min. The dobutamine infusion rate was increased until the LV +dP/dt has increased by 20%. Hemodynamic and total-body and renal norepinephrine spillover were reassessed 30 minutes after this increase had been achieved.

Data are presented as mean ± SEM. The effects of dobutamine were assessed by a paired t test for normally distributed data and by the Wilcoxin-Mann-Whitney Rank sums test for nonparametric data. P < 0.05 was considered statistically significant.

RESULTS

Hemodynamic Responses

Dobutamine at a final infusion dose of 4.3 ± 0.9 μg/kg/min increased LV + dP/dt by 23 ± 5% (1088 ± 128 to 1447 ± 181 mm Hg/sec) (Table 1). During the dobutamine infusion, LVEDP was reduced (−30 ± 8%, P < 0.02) and Tau was shortened (−17 ± 2%, P < 0.0001). Systemic arterial blood pressure was unchanged.

Renal plasma flow increased by 11 ± 3% (P < 0.03) during dobutamine infusion, and GFR increased by 12 ± 4% (P < 0.04).

Neurohormonal Responses

There was a 50 ± 13% reduction in renal norepinephrine spillover (P < 0.003), and a 34 ± 9% reduction in total body norepinephrine spillover (P < 0.003) in response to dobutamine (Table 2 and Figure 1). The sympatholytic response was preferentially directed at the kidneys as the contribution of renal sympathetic activity to total body sympathetic activity was reduced from 27 ± 4% to 18 ± 3% (P < 0.03).

This renal sympatholytic response was not accompanied by a reduction in renal renin release as we observed a trend towards an increase in both arterial and renal vein renin levels.

DISCUSSION

The salient findings of the present investigation are (1) a renal sympatholytic response; and (2) an improvement in renal function in response to dobutamine infusion in the acute setting. This information is relevant to the current use of dobutamine in the management of acute heart failure.

The kidneys are subserved with abundant sympathetic innervation to renal vasculature, renal tubules, and the juxtaglomerular apparatus.¹² Renal sympathetic activation increases renin secretion via activation of β₁-receptors, reduces sodium excretion via activation of tubular α₁-receptors, and reduces renal plasma flow via activation of α₁-receptors in a frequency-dependent manner.¹³

Ventricular mechanoreceptor activation is associated with a withdrawal of sympathetic outflow to the periphery and an increase in cardiac parasympathetic activity.^8,14,15 We have previously shown that an infusion of dobutamine was associated with a cardiac sympatholytic response and attributed it to the increase in cardiac parasympathetic activity associated with ventricular mechanoreceptor activation.⁹ In this experiment, we extended our observation to the control of renal sympathetic activity in human heart failure. We observed a 50% reduction in renal sympathetic activity during dobutamine infusion. This sympatholytic response is not explained by arterial baroreceptor unloading, as systemic arterial blood pressure was unchanged in response to dobutamine. Furthermore, we have previously shown that baroreceptor control of renal sympathetic activity is impaired in human heart failure patients.⁷ Similarly, this sympathoinhibitory response is unlikely to be attributed to a reduction in left ventricular filling pressures and unloading of cardiopulmonary low-pressure baroreceptors. Middlekauff et al have described an intact cardiopulmonary reflex control of renal sympathetic activity and blood flow in human heart failure.¹⁶ Therefore, isolated unloading of cardiopulmonary receptors should have been associated with a renal sympathoexcitatory response and a reduction in renal blood flow (RBF), contrary to the responses we observed.

It is important to acknowledge some of the limitations of our observation. We observed an increase in renal plasma flow and GFR in response to renal sympathoinhibition. However, the contribution of cardiac output augmentation to this increase in RBF cannot be excluded. Despite a significant sympathoinhibitory response, we observed a trend toward an increase in renal renin release. This observation in not unexpected given the direct stimulatory effects of dobutamine on the juxtaglomerular apparatus β₁-adrenergic receptors.^13,17 We did not measure the effects of this alteration in renal sympathetic activity on tubular sodium handling. However, we believe this sympatholytic response should have a beneficial effect on renal sodium handling for multiple reasons. First, there was an increase in GFR. Second, the observed increase in RBF suggests that the sympathoinhibitory response was of enough magnitude to reduce tubular sodium absorption.¹² Lastly, other investigators have shown that pharmacological and physiological intervention associated with a reduction in sympathetic activity, similar in magnitude to the changes observed in our experiment, to have a beneficial effect on renal sodium handling. ^18-20

CONCLUSION

We have demonstrated that a short-term infusion of a positive inotropic agent caused a significant reduction in efferent renal sympathetic activity in patients with heart failure. This effect is probably related to an activation of ventricular mechanoreceptors. These observations are relevant given the negative impact of renal sympathetic activation on outcomes in patients with heart failure.²¹ Our observation does not address the controversy surrounding the utility and safety of positive inotropic agents when used routinely or intermittently in decompensated heart failure.^22,23

REFERENCES