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(Hypertension. 1997;30:392.)
© 1997 American Heart Association, Inc.

Articles

Sympathoinhibitory Response to Clonidine Is Blunted in Patients With Heart Failure

Chim C. Lang; C. Michael Stein; Richard A. Nelson; Huai B. He; Frank J. Belas; Ian A. Blair; Margaret Wood; Alastair J. J. Wood

From the Departments of Pharmacology and Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Dr Alastair J.J. Wood, Room 550, MRB 1, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.

	Abstract

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Abstract To determine whether ₂-adrenergic–mediated sympathoinhibition was altered in chronic heart failure, sympathoinhibitory sensitivity was assessed using the ₂-adrenergic agonist clonidine in 7 patients with heart failure and in 10 healthy control subjects. Basal norepinephrine spillover was significantly higher in patients with heart failure (1.3±0.3 µg/min) than in control subjects (0.7±0.1 µg/min, P=.05). Compared with control subjects, the decrement in norepinephrine spillover to cumulative doses of clonidine (1, 2, and 3 µg/kg administered intravenously) was significantly less in patients with heart failure (P<.05). Blood pressure also tended to decrease less in patients with heart failure (P=.06). The doses of clonidine required to produce a 10% decrease in blood pressure and a 25% decrease in norepinephrine spillover were significantly higher in heart failure (P<.01 and P=.05, respectively). Thus, although clonidine lowers norepinephrine spillover significantly in patients with heart failure, such patients are less sensitive to clonidine than healthy control subjects. This difference in sensitivity suggests that doses of clonidine provide effective sympathoinhibition will need to be selected for studies that will evaluate the potential therapeutic effect of clonidine in heart failure.

Key Words: -adrenergic receptors • congestive heart failure • clonidine • norepinephrine

	Introduction

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Abnormalities in sympathetic function occur in patients with chronic heart failure, resulting in increased urinary excretion of catecholamines and increased plasma levels of norepinephrine (NE).^{1 2} Systemic and regional [³H] NE kinetic studies have demonstrated that increased NE spillover, mainly from the heart and kidneys, and a decreased clearance of NE from the plasma^{3 4} both contribute to the increase in plasma NE in heart failure. Increased sympathetic activity in heart failure has been confirmed using peroneal nerve recordings of sympathetic efferent nerve traffic.⁵ This sympathetic activation would tend to restore circulatory pressure and volume by stimulating myocardial contractility and increasing peripheral vasoconstriction. Although these changes may be beneficial in the short term, they may in the long term lead to increased afterload and preload with possible detriment to the failing myocardium⁶ and predispose these patients to lethal ventricular arrhythmias.

Thus, pharmacological inhibition of sympathetic activation is a rational therapeutic approach to explore. Sympathetic blockade with peripheral adrenergic blockers has had a history fraught with problems because vasodilation results in reflex sympathetic activation with an increase in overall sympathetic activity. Thus, initial benefits with ₁-adrenergic blockers such as prazosin were found to be short-lived,^{7 8} with no demonstrable effect on mortality.⁹ Until recently, clinicians have been reluctant to prescribe ß-adrenergic blockers for patients with heart failure out of concern that they will further impair contractile function. However, it is now recognized that long-term ß-adrenergic blockade may in fact enhance the cardiac reserve in heart failure,¹⁰ and studies with various ß-adrenergic blockers have produced symptomatic improvement in terms of exercise capacity and quality of life, although long-term survival studies have produced inconsistent results.^{11 12}

The principal drawback of this adrenoceptor antagonistic approach is its limited objective, which is to shield the heart, kidney, and peripheral vasculature from the potentially harmful effects of neuronally released NE rather than to attenuate sympathetic outflow to these organs. Moreover, the neuroeffector response to other neurotransmitters released by noradrenergic neurons will not be blocked by these antagonists. Thus, to attain additional benefits, it may be necessary to attenuate adrenergic drive directly. The recent demonstration of increased activity of central noradrenergic neurons with increased rates of cardiac NE spillover in patients with heart failure¹³ has renewed interest in the use of central sympathoinhibition, such as with clonidine, as a potential modifier of the poor prognosis of heart failure.¹⁴ Clonidine is highly lipophilic and acts centrally on ₂-adrenoceptors on sympathoinhibitory neurons in the brain stem^{15 16} as well as on noradrenergic neurons of the forebrain¹⁷ to inhibit their firing. In addition, clonidine has effects on imidazoline receptors,¹⁸ baroreceptor reflex, and parasympathetic function.¹⁹

Prolonged sympathetic stimulation has been shown to alter both ₁- and ₂-adrenergic responsiveness of certain target organs.^{20 21} Despite the importance of ₂-adrenoceptors in the pathophysiology of heart failure,²² their regulation and function have not been studied. In this study, we have compared the sensitivity of the sympathoinhibitory response to ₂-adrenergic stimulation with clonidine in patients with heart failure and in normal healthy control subjects.

Plasma concentration of NE is an inadequate measure of sympathetic activity because it depends not only on the rate of release of NE but also on the clearance of NE from the plasma. The overall effects of clonidine on plasma NE may be influenced not only by its effects on the release of NE but also by the clearance of NE, which may be altered by its hemodynamic effects. Thus, sympathetic activity was measured in this study with the isotope dilution techniques.²³

	Methods

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Study Population
Seven patients with heart failure aged 60±6 (mean±SEM) years were studied. The cause of heart failure was ischemic heart disease in all 7 patients, and all had a documented history of one or more previous myocardial infarctions that occurred at least 6 months before the study. Only patients with well-compensated mild to moderate chronic, stable heart failure (New York Heart Association [NYHA] functional classes II and III) were studied. Left ventricular ejection fraction (LVEF) as assessed by radionuclide ventriculography ranged from 10% to 30% (mean, 20.0±2.7%). All were receiving regular therapy for heart failure: furosemide (n=6; dose range, 40 to 200 mg/d), digoxin (n=3), angiotensin-converting enzyme inhibitors (n=7), and long-acting nitrates (n=3). Digoxin and angiotensin-converting enzyme inhibitors were both withheld for 48 hours before the study, and diuretics and nitrates were withheld on the morning of the study.

The control group included 10 normal subjects aged 57±6 years. Medical history, physical examination, routine blood tests, and electrocardiogram established that each subject was free of medical illness, heart disease, and diabetes mellitus. Five of the control subjects also acted as controls in a study of interethnic differences in -adrenoceptor sensitivity.²⁵ No subject was taking regular medications, and all refrained from caffeinated beverages on the day of the study. Written informed consent was obtained from all participants, and the study was approved by and the procedures followed were in accordance with the guidelines of the Vanderbilt University Committee for the Protection of Human Subjects.

Experimental Protocol
All studies were performed in the morning after fasting and resting supine overnight in the Vanderbilt University Clinical Research Center. Subjects were studied resting in the supine position. An intravenous cannula was placed in the antecubital fossa in each arm for subsequent blood sampling and intravenous infusion of [³H] NE and drugs. After placement of these cannulae, an intravenous infusion of [³H] NE (norepinephrine levo-[ring-2,5,6-³H] 70.1 Ci/mmol, New England Nuclear) in normal saline was administered into the nondominant arm. An initial loading dose of 25 µCi [³H] NE was administered over 2 minutes followed by a constant infusion of 0.9 µCi/min of [³H] NE, an infusion regimen that we have shown to achieve constant plasma concentrations of [³H] NE within 30 minutes.²⁴ The [³H] NE was prepared for human administration by the Vanderbilt Hospital Radiopharmacy, and appropriate sterility and pyrogen testing were performed. It was reconstituted in normal saline containing ascorbic acid 1 mg/mL immediately before use.

Venous blood samples were drawn for determination of plasma NE and [³H] NE after 50 and 60 minutes of the [³H] NE infusion. Blood pressure and heart rate were measured at the same time by a semiautomatic sphygmomanometer (Dinamap 1846, Critikon Inc). Sixty, 90, and 120 minutes later, subjects received three 10-minute infusions of the vehicle (normal saline, volume [mL] equals body weight [kg] divided by 3), followed at 150, 180, and 210 minutes by clonidine (Catapres, Boehringer Ingelheim Pharmaceuticals) administered by slow intravenous infusion over 10 minutes, in cumulative doses of 1 2, and 3 µg/kg. The maximum dose of 3 µg/kg was determined from previous studies in healthy subjects.²⁵ The infusions were administered in single-blind fashion. Venous blood was drawn and hemodynamic recordings were made 30 minutes after each infusion.

Blood Collection and Analysis
Blood was collected into cooled tubes with ethyleneglycol tetra-acetic acid (EGTA) and reduced glutathione (Amersham Corp), placed on ice, and centrifuged at 3000 revolutions per minute at 4°C and the plasma stored at -20°C until assayed in duplicate. Samples of the [³H] NE infusate were also collected, stored, and later assayed in quadruplicate, as described for the blood samples, to allow determination of the actual rate of [³H] NE infusion. During the clonidine infusion period, plasma was also collected for determination of clonidine concentrations.

NE concentrations were measured by high-performance liquid chromatography using electrochemical detection with ³H-dihydroxybenzylamine as the internal standard as we have previously described.²⁶ All plasma samples for each subject were assayed in the same assay run in duplicate. The high-performance liquid chromatography effluent coinciding with the NE peak was collected and counted in a liquid scintillation counter. This allowed determination of plasma [³H] NE concentration without interference from tritiated metabolites. The intra- and inter-day coefficients of variation were 7.8% and 7.6%, respectively. Plasma clonidine concentrations were determined using a modification of a previously described gas chromatography electron capture negative chemical ionization mass spectrophotometry method (GC-ECNCI/MS).²⁷ The assay was linear over a range of 173 to 3457 pg/mL. Standard curve correlation coefficients of .99 or better were obtained throughout the validation. The intra- and interassay precisions were within 8.5% relative standard deviation for quality control samples in the lower, middle, and upper quality control portions of the standard curve.

Determination of NE kinetics
NE kinetics were determined as described by Esler et al.²³ (1) NE plasma clearance was determined as follows:

NE Clearance=[³H] NE infusion rate÷V*

where V* is the venous concentration of [³H] NE. (2) The rate at which NE entered (NE spillover) was determined as follows:

NE Spillover=NE ClearancexV

where V is the venous concentration of endogenous NE.

Data Analysis
The mean of the values obtained after 50 and 60 minutes of the [³H] NE infusion was used as the baseline, and the mean of the values obtained at the end of the vehicle infusion at 90, 120, and 150 minutes of the [³H] NE infusion was used as the pre-clonidine value. The responses to clonidine were determined by comparison of the individual area under the change in hemodynamic or NE parameter/time curve for each individual. Sensitivity to clonidine was also determined by analysis of the individual dose-response curves to clonidine, fitted using an allosteric Hill equation and a computer program (Fig.P Version 6.0, Biosoft Software Corp). The doses of clonidine required to produce a 10% decrease in mean arterial pressure (ID10 MAP), a 25% decrease in plasma NE (ID25 NE), and a 25% decrease in systemic NE spillover (ID25 NESO) were then determined for both patients and control subjects. ANOVA and Student’s paired (for within-group comparisons) and unpaired (for between-group comparisons) t tests were used for statistical analysis as appropriate. Measures of potency (ID10 MAP, ID25 NE, and ID25 NESO) were log-transformed before statistical analysis and expressed as geometric means (95% confidence intervals). All other data are expressed as mean±SEM. A value of P<.05 was the minimal level considered significant.

	Results

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Table 1 summarizes the baseline hemodynamic and NE kinetics in the two groups. The two groups were well matched for age and body weight. Baseline systolic and diastolic blood pressures, mean arterial pressure, and heart rate did not differ between the two groups. Baseline plasma NE and systemic NE spillover were significantly higher in patients with heart failure. Systemic NE clearance did not differ between the patients with heart failure and normal control subjects.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical, Hemodynamic, and [3H] Norepinephrine Kinetics Data in Patients With Heart Failure and in Normal Control Subjects

Hemodynamic Responses to Clonidine in Patients With Heart Failure and in Normal Control Subjects
All subjects tolerated the intravenous clonidine. The administration of intravenous clonidine resulted in a decrease in mean arterial pressure in both patients and normal control subjects (Table 2), although the response was somewhat blunted in patients with heart failure (P=.06). Analysis of the dose-response curves showed that the ID10 MAP was significantly higher in heart failure compared with normal control subjects (P=.05, Table 3). Clonidine did not alter heart rate in either group.

View this table: [in this window] [in a new window]   Table 2. Hemodynamic and Sympathetic Responses to Intravenous Clonidine in Patients With Heart Failure and in Normal Control Subjects

View this table: [in this window] [in a new window]   Table 3. Doses of Clonidine Required to Produce a 10% Decrease in Mean Arterial Pressure (ID10 MAP) and a 25% Decrease in Norepinephrine (NE) Spillover (ID25 NESO) and Plasma NE (ID25 NE) in Patients With Heart Failure and in Normal Control Subjects

[³H] NE Kinetics and Clonidine in Patients With Heart Failure and in Normal Control Subjects
Increasing doses of clonidine resulted in a decrease in NE spillover in both heart failure and normal control subjects (Table 2). However, when compared with healthy control subjects, the decrease in NE spillover was significantly less in patients with heart failure (P<.05, Figure). Furthermore, analysis of individual dose-response curves showed that the ID25 NESO was significantly higher, reflecting decreased sensitivity in patients with heart failure compared with normal control subjects (P<.01, Table 3). The relative decrease in venous plasma NE was smaller than the relative decrease in spillover in normal subjects because NE clearance was also decreased significantly by clonidine in normal control subjects (Table 2). Systemic clearance did not change in heart failure patients (Table 2). Thus, the plasma NE response does not adequately reflect the changes produced by clonidine because of relative differences in the effect of clonidine on NE clearance and spillover between patients with heart failure and normal control subjects.

View larger version (11K): [in this window] [in a new window]   Figure 1. The effect of clonidine on norepinephrine (NE) spillover in patients with heart failure (n=7) and in normal control subjects (n=10). The values are expressed as % change from pre-clonidine NE spillover values and are mean±SEM.

Plasma Clonidine Concentrations
Plasma clonidine concentrations achieved were similar in patients with heart failure and healthy control subjects (Table 4).

View this table: [in this window] [in a new window]   Table 4. Plasma Concentrations of Clonidine Achieved During Cumulative Doses of Intravenous Clonidine of 1, 2, and 3 µg/kg in Patients With Heart Failure and in Normal Control Subjects

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The principal finding of this study is that increasing doses of clonidine resulted in a decrease in NE spillover in both patients and in healthy control subjects, demonstrating the beneficial sympathetic suppressant effects of clonidine in patients with heart failure. However, the decrease in NE spillover was significantly less in the patients with heart failure, which suggests that the sensitivity to ₂-adrenergic stimulation is decreased in patients with heart failure. In clinical studies that evaluate the therapeutic place of clonidine in the treatment of heart failure, it will be important to use doses of clonidine that will adequately reduce sympathetic activity.

The concept of altering the pathophysiology of heart failure with centrally acting drugs is not new. Early short-term studies of clonidine in heart failure demonstrated beneficial effects on vascular resistance and ventricular filling pressures.^{28 29} However, as a result of a report of a presumed negative inotropic effect³⁰ and the prevailing opinion at the time that heart failure should be treated with positive inotropic agents such as amrinone, as well as the lack of commercial interest in clonidine,³¹ studies of clonidine in heart failure were abandoned. It is now apparent that persistent sympathetic stimulation in heart failure is harmful and that reduction in myocardial stimulation may in fact enhance the cardiac reserve and lead to a favorable long-term outcome.¹⁰ This has led to a resurgence of interest in central sympathoinhibition in the treatment of heart failure. In a recent pilot study, Manolis et al¹⁴ demonstrated beneficial hemodynamic and neurohormonal effects in 20 patients with moderate to severe heart failure who were maintained and further improved after one week of therapy with oral clonidine 0.15 mg given twice daily. However, none of these studies evaluated the sensitivity to clonidine in patients with heart failure.

Since clonidine acts on ₂-adrenoceptors present both centrally and peripherally on the presynaptic nerve terminal,^{15 32 33} our findings of decreased sensitivity in heart failure could be explained by decreased sensitivity of both central and/or peripheral ₂-adrenoceptors in heart failure. The few studies that have examined peripheral presynaptic ₂-adrenergic responses in heart failure, with the ₂-adrenoceptor antagonist yohimbine in the forearm³⁴ and with the nonselective -blocker phentolamine in the myocardium,³⁵ have suggested that increased peripheral sensitivity to antagonists may be present. However, because studies in animals and tetraplegic humans with preganglionic sympathetic denervation³⁶ show that both the sympatholytic and hypotensive effects of clonidine are largely mediated through central mechanisms, these studies cannot be extrapolated to predict the effects of clonidine. As the peripheral mechanisms of actions of clonidine are minimal, our findings are best explained by decreased central ₂-adrenoceptor sensitivity in heart failure.

The mechanisms for this attenuation of central ₂-adrenergic responses are not known but may be due to desensitization consequent to the prolonged sympathetic activation within the brain in heart failure. Whether the desensitization is due to downregulation of central ₂-adrenoceptor numbers is not known. Selective downregulation of ß₁ but not ß₂ adrenoceptors and uncoupling of ß₁ and ß₂ adrenoceptors occur in failing myocardium.^{20 21} There is little information on the regulation and function of the -adrenergic system despite its important physiological role in heart failure.²² ₁-Adrenoceptor density has been reported to be unchanged or increased in the failing human heart.³⁷ On the other hand, ₂-adrenoceptor density has been reported to be decreased on platelets obtained from patients with heart failure.³⁸ Clearly, further studies are required to examine the mechanisms underlying decreased central ₂-adrenergic responsiveness in heart failure.

The lack of change in NE clearance after clonidine in patients with heart failure is of interest. This was in contrast to the significant decrement in NE clearance in healthy control subjects. The reasons for the differences in response in the two groups are not clear. Esler and coworkers³⁹ examined the clearance of [³H] NE in healthy volunteers and found that 60% to 80% of NE is cleared in the heart and hepatomesenteric circulation and, somewhat less, 35% to 55% in the kidneys and skeletal muscle. NE clearance is therefore dependent to a large extent on the relative perfusion of these various organs. Thus, one explanation for the different response in NE clearance to clonidine in the two groups may be the greater decrease in blood pressure in healthy control subjects, which would lead to a decrease in perfusion pressure to the various organs and result in a decrease in NE clearance in these subjects. On the other hand, a differential effect of clonidine on cardiac output in the two populations, such as an increase in cardiac output with clonidine in heart failure,¹⁴ may lead to an increase in regional blood flow, which would increase NE clearance. Such an effect would counteract the decrement in NE clearance caused by the decrease in blood pressure and result in the lack of change in NE clearance to clonidine in patients with heart failure.

Pathophysiologic Implications
The precise signal for sympathetic activation in heart failure is not known. There is evidence to show that this heightened sympathetic activity is not merely a reflex compensatory response but that it is also a reflection of abnormalities in parasympathetic function,⁴⁰ baroreceptor afferent traffic,⁴¹ and increased central nervous sympathetic outflow.^{11 42} Sympathetic tone is regulated by a stream of afferent neural signals that are integrated centrally. The sustained sympathetic activation seen in heart failure partially reflects a breakdown in this control system and may be the result of an attenuation in feedback inhibition.⁴³ ₂-Adrenoceptors are found in abundance in the central nervous system^{32 44} and also on the peripheral presynaptic nerve terminal^{32 33} where they play an important role in local feedback inhibition of NE release. Thus, our findings of a decreased central ₂-adrenergic sensitivity in heart failure may result in a loss of feedback inhibition and contribute to the sustained sympathetic activation seen in heart failure.

Study Limitations
Interpretation of our results requires the following considerations. First, the mean plasma NE was only modestly elevated (394 pg/mL) in these patients with well-compensated mild to moderate heart failure. Whether these results can be extrapolated to more severely affected patients is unknown. Strengthening our findings, in a subsequent study⁴⁵ we have examined the effect of the 2 µg/kg clonidine dose administered intravenously, as in this study, to another group of patients (n=15) with more severe heart failure (NYHA functional class III-IV) who had been referred for heart failure and heart transplantation evaluation. The basal plasma NE in this group was 474 pg/mL (range 219 to 1017 pg/mL), and clonidine 2 µg/kg decreased the plasma NE by 38% compared with the 42% decrease observed in the present study. When the two groups were combined to make a total of 10 normal control subjects and 22 patients with varying degrees of heart failure (LVEF range, 10% to 35%; plasma NE range, 211 to 1017 pg/mL), we found a significant inverse correlation between the clonidine-induced decrement in plasma NE and the baseline plasma NE level (r=-.40, P<.05). Since clonidine-induced sympathoinhibition is a measure of ₂-adrenergic sensitivity, these findings would suggest that the decreased ₂-adrenergic sensitivity is associated with the increased level of sympathetic activity and the sustained sympathetic activation in heart failure.

A second consideration is that clonidine has other actions besides its activity at ₂- adrenoceptors. An effect of clonidine on the baroreceptor reflex and parasympathetic function has been reported.¹⁹ The lack of change in heart rate in response to the decrease in blood pressure might be evidence of the effect of clonidine on baroreceptor function. Clonidine may also act on imidazoline receptors¹⁸ to lower blood pressure and sympathetic activity. Thus, our findings do not exclude the possibility that there might also be altered sensitivity of imidazoline receptors in heart failure.

Finally, it should be emphasized that our observations were made over a short period of time. Since the circadian variation in sympathetic activity is attenuated in patients with heart failure,⁴⁶ it is not clear whether the reduction in sympathetic activity over a 24-hour period will be different. Greater decreases in blood pressure may also occur in patients with advanced heart failure who are dependent on sympathetic tone to maintain blood pressure. However, it should be noted that in the study of Manolis et al,¹⁴ patients with more severely decompensated heart failure who had higher plasma NE and worse hemodynamic parameters not only tolerated oral clonidine but the hemodynamic parameters showed a tendency toward greater improvement with clonidine.

Conclusions
In conclusion, this study demonstrates that clonidine significantly lowers NE spillover in patients with heart failure but to a lesser extent than in healthy control subjects. The sympathoinhibitory effect of clonidine suggests a possible therapeutic role for clonidine in the treatment of heart failure. However, the decreased sensitivity to clonidine suggests that doses of clonidine that result in effective sympathoinhibition will need to be selected in future clinical trials of this drug in heart failure. This decreased sensitivity to central ₂-adrenergic–mediated sympathoinhibition may also result in an attenuation of central feedback inhibition of sympathetic activity, thus contributing to the sustained sympathetic activation seen in chronic heart failure.

	Acknowledgments

 
This study was supported in part by grants from the American Heart Association and United States Public Health Service grants HL 56251 and GM 5MO1-RR00095. C.C. Lang was the recipient of a Merck International Fellowship in Clinical Pharmacology Award. C.M. Stein is the recipient of a Faculty Development Award in Clinical Pharmacology from the Pharmaceutical Research and Manufacturers of America Foundation.

Received November 18, 1996; first decision December 20, 1996; accepted February 21, 1997.

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