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(Circulation. 2002;106:e222.)
© 2002 American Heart Association, Inc.

Correspondence

Plasma Catecholamines and Chronic Congestive Heart Failure

Fuad Lechin, MD, PhD

Departamento de Ciencias Fisiologicas, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas, Venezuela

Marcel Lechin, MD

Texas A & M University, College Station, Tex

Bertha van der Dijs, MD

Seccion de Neuroquimica y Neurofarmacologia, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas, Venezuela

To the Editor:

We read with great interest the paper by Swedberg et al.¹ With respect to it, we will supply additional information that might aid in the understanding of the failure of imidazoline’s agonists to improve chronic congestive heart failure (CCHF) in patients.

We have assessed all plasma neurotransmitters in some 30 000 normal and diseased subjects. Included were noradrenaline (NA), adrenaline (Ad), dopamine (DA), platelet serotonin, free serotonin in the plasma, and tryptophan. These parameters were measured during supine-resting, 1-minute orthostasis, 5 minutes of moderate exercise,² and after the administration of clonidine.³ We found that the normal NA/Ad ratio >4.5. This ratio is greatly reduced in stressed mammals and severely diseased humans (<1).² With respect to the above, neural sympathetic activity (sympathetic nerves) is constituted by NA (80%) and DA (20%), whereas adrenomedullary sympathetic secretion is constituted by Ad (80%) and NA+DA (20%). Neural sympathetic activity depends on the firing rate of the locus coeruleus (LC)-NA pontine nucleus, whereas adrenomedullary sympathetic activity depends on the C1 medullary nuclei (located at the rostral ventrolateral medulla).⁴ Although both central sympathetic nuclei display associated and/or alternating activities during normal situations, dissociation of activities occurs during uncoping stress experimental situations and human diseases.⁴ Exhaustion of the LC-NA nucleus activity is the rule during these circumstances, which is reflected in deep reductions of the NA/Ad plasma ratio.⁴

All ₂ and imidazoline I₁ agonists act on the rostroventrolateral medullary area (C1) nuclei preferentially.⁵ For this reason, clonidine provokes deep reduction of plasma catecholamines and blood pressure during the first challenges; however, these effects tend to lessen after repeated administration of the drug in normals. This phenomenon should be attributed to down-regulation (subsensitivity) of the ₂ and/or imidazoline I₁ receptors located at this area. However, considering that the C1-adrenomedullary nuclei send direct inhibitory axons to the LC-NA pontine nucleus,³ we would expect that the latter might result in disinhibition from the C1 bridle, and thus LC-NA would reassume its central sympathetic regulatory role, during and after ₂ and/or imidazoline I₁ agonists administration. This does not occur because the LC-NA nucleus is also endowed with these types of inhibitory receptors.

In summary, both imidazoline I₁ and ₂ agonists, like those used in the experimental trial by Swedberg et al,¹ provoked not central but peripheral (adrenal glands) sympathetic inhibition. In short, CCHF patients present with peripheral but not central sympathetic hyperactivity. The latter, which is dependent upon the LC-NA neurons, is always abolished in these patients. Although they showed increased NA plasma levels, the NA/Ad ratio is <2. This low LC-NA sympathetic activity was further reduced by drugs administered, which resulted in worsening and death, because of absolute parasympathetic vs sympathetic predominance.

References

1. Swedberg K, Brislow M, Cohn JN, et al. Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure. Circulation. 2002; 105: 1797–1803.[Abstract/Free Full Text]
   
2. Lechin F, van der Dijs B, Orozco B, et al. Plasma neurotransmitters, blood pressure and heart rate during supine-resting, orthostasis and moderate exercise in severely ill patients: a model of failing to cope with stress. Psychother Psychosom. 1996; 65: 129–136.[Medline] [Order article via Infotrieve]
   
3. Lechin F, van der Dijs B, Lechin ME. Neurocircuitry and Neuroautonomic Disorders: Reviews and Therapeutic Strategies. Basel: Karger; 2002.
   
4. Moore RY, Bloom FE. Central catecholamine neuron system: anatomy and physiology of norepinephrine and epinephrine systems. Ann Rev Neurosci. 1979; 2: 113–168.[CrossRef][Medline] [Order article via Infotrieve]
   
5. Punnen S, Urbanski R, Krieger AJ, et al. Ventrolateral medullary pressor area: site of hypotensive action of clonidine. Brain Res. 1987; 422: 336–346.[CrossRef][Medline] [Order article via Infotrieve]
   

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Response

Karl Swedberg, MD

Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden

Michael R. Bristow, MD

Division of Cardiology, University Hospital, University of Colorado Health Sciences Center, Denver, Colo

Jay N. Cohn, MD

Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minn

Henry Dargie, MD

MRC Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow, UK

Matthias Straub, MD

Solvay Pharmaceuticals, Hanover, Germany

Curtis Wiltse, PhD; Theressa J. Wright, MD

Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Ind

We appreciate the further discussion of the regulation/dysregulation of sympathetic activity provided by Dr Lechin et al.

Regardless of whether moxonidine is acting centrally or peripherally to reduce sympathetic activity, the drug substantially lowers plasma norepinephrine in chronic heart failure. Thus, it is a suitable tool to test the hypothesis that this pharmacological effect would produce favorable clinical outcomes similar to that shown with ß-blocking agents. The lowering of cardiac norepinephrine output has been reported by Waagstein and co-workers to parallel total body spill-over.¹ This observation would contradict the observations by Lechin et al. As far as we understand, their observations were not made in patients with chronic heart failure, a situation very different from other forms of increased sympathetic activation. Furthermore, in contrast to the experience of Lechin et al, our experience indicates that the ratio of plasma norepinephrine/epinephrine is not attenuated in chronic heart failure. Our findings² that the clinical effects of moxonidine seem to differ from those of ß-blockers surprised us, and we would propose that much remains to be learned about the optimal way to correct sympathetic dysregulation in chronic heart failure.

References

1. Waagstein F, Mobini R, Andersson B, et al. Moxonidine attenuates transmyocardial norepinephrine concentration gradient and total body norepinephrine spillover in congestive heart failure. Eur Heart J. 1998; 19: 173.Abstract.
   
2. Swedberg K, Brislow M, Cohn JN, et al. Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure. Circulation. 2002; 105: 1797–1803.[Abstract/Free Full Text]
   

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lechin, F. Articles by Wright, T. J. Search for Related Content PubMed PubMed Citation Articles by Lechin, F. Articles by Wright, T. J. Related Collections Cardio-renal physiology/pathophysiology Other heart failure Congestive Heart failure - basic studies Autonomic, reflex, and neurohumoral control of circulation