Norepinephrine spillover to plasma during steady-state supine bicycle exercise. Comparison of patients with congestive heart failure and normal subjects.

Abstract

This study was performed to determine the relative contributions of plasma norepinephrine clearance and norepinephrine release to the increase in plasma norepinephrine concentration that occurs during exercise and to determine whether the high rates of cardiac norepinephrine release from the heart and kidney in patients with heart failure are associated with diminished reserve for regional sympathetic nervous stimulation. During supine steady-state bicycle exercise at 50% of maximum voluntary exercise capacity, the plasma norepinephrine concentration of six patients with congestive heart failure rose from 385±88 to 2,200±497 pg/ml, whereas that of nine normal subjects rose from 208±21 to 882±257 pg/ml. The change in plasma concentration in both groups was due to an increase in norepinephrine spillover to plasma without a change in plasma norepinephrine clearance. In patients with heart failure, cardiac spillover increased from 80 ± 26 to 528 ± 265 ng /min during exercise, and renal spillover rose from 146 ± 71 to 418 ± 69 ng/min. In the normal subjects, cardiac spillover rose from 5 ± 2 to 73 ± 23 ng/min, and renal spillover increased from 76 ± 27 to 275 ± 106 ng/min. There is no evidence of a reduced reserve for overall or regional sympathetic stimulation in patients with heart failure. Reduced reflex responses in these patients are more likely due to end-organ refractoriness than to inadequate stimulation. (Circulation 1988;78:516-521) E levated plasma norepinephrine concentration observed in patients with congestive heart failure is due to both reduced plasma norepinephrine clearance and increased spillover of norepinephrine to plasma. 1 Because reduced plasma clearance of norepinephrine is an important determinant of the baseline plasma concentration of norepinephrine, it might also be an important determinant of the increase in plasma norepinephrine that occurs during exercise. One would expect this effect to be more marked in patients with heart failure because of the intensity of splanchnic vasoconstriction during exercise in these patients.2There is also evidence of intense cardiorenal sympathetic nervous stimulation under resting conditions in patients with heart failure.' We hypothesized that the very high resting rates of norepinephrine spillover to plasma from the heart indicated maximal cardiac sympathetic stimulation. An inabil-

Direct measurement of cardiac sympathetic efferent nerve activity during dynamic exercise

“…tive in humans because baseline cardiac spillover of norepinephrine has been observed (9,12). To assess the effect of baseline cardiac sympathetic outflow on the cardiac pumping function, ␤-adrenergic blockade has been utilized.…”

“…During supine bicycle exercise at 50% of maximum voluntary exercise capacity, there was a 10-fold increase in cardiac norepinephrine spillover, which accounted for 9% of the total systemic norepinephrine spillover (12). This result suggests that sympathetic drive to the heart is considerably augmented during the moderate intensity of dynamic exercise.…”

“…On the other hand, measurements of cardiac spillover of norepinephrine from the coronary sinus in humans led to a different conclusion (9,12). During supine bicycle exercise at 50% of maximum voluntary exercise capacity, there was a 10-fold increase in cardiac norepinephrine spillover, which accounted for 9% of the total systemic norepinephrine spillover (12).…”

Selective enhancement of the cardiac sympathetic response to exercise by anginal chest pain in humans.

“…23 Arterial and coronary sinus catecholamine levels rise in response to upright bicycle exercise in humans,24 and isometric handgrip exercise causes a rise in arterial and coronary sinus NE concentration in patients with a variety of cardiovascular conditions.25 Supine bicycle exercise has previously been reported to increase arterial and coronary sinus NE concentrations, but the effect of angina was not assessed.26 Cardiac NE spillover has been assessed during dynamic exercise in small numbers of normal subjects and was reported to increase from 5 to 73 ng/min during maximal supine bicycle exercise. 27 The above study also purported to comment on the response of cardiac NE spillover to dynamic exercise in subjects with heart failure, but the numbers studied (three) were too small to allow meaningful comment. There is no previous information on cardiac NE spillover or coronary sinus NE concentrations during exertional angina.…”

Ajustes da atividade simpática periférica promovidos pelo treinamento aeróbio em normotensos e hipertensos: efeitos da remoção seletiva dos barorreceptores arteriais.

“…Dada a complexidade e a extensão da inervação simpática eferente (a circulação em todos os territórios encontra-se sob controle direto do simpático), a quantificação da atividade simpática não é uma tarefa fácil, tanto que várias técnicas têm sido utilizadas para a sua quantificação: dosagem de catecolaminas plasmáticas e/ou em vasos e tecidos por radioimunoensaio ou cromatografia líquida de alta performance (HPLC) (GOLDSTEIN, 1981;THOMPSON et al, 1995;GAROFALO et al, 1996), simpatectomia e/ou bloqueio ganglionar (JULIEN et al, 1990;SANTAJULIANA et al, 1996;CSIKY et al, 1997), 'spillover' de noradrenalina (HASKING et al,1988;GRASSI, ESLER, 1999); registro eletroneuronográfico da atividade simpática em diferentes leitos vasculares RICKSTEN et al, 1984;IRIGOYEN, KRIEGER, 1998, GUILD et al, 2005, análise espectral da variabilidade da PA e/ou freqüência cardíaca (AKSELROD et al, 1981;PAGANI et al, 1986;MALLIANI et al, 1994), análise de imagem associada a imuno-histoquimica (BURGI et al, 2011). Estas técnicas podem fornecer índices gerais da atividade simpática, sem particularizá-la aos diferentes territórios (dosagem de catecolaminas, bloqueio simpático, análise espectral) ou a registram diretamente, mas em apenas um território, em animais anestesiados (eletroneuronografia).…”