Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.

Abstract

The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In 12 patients with cardiac failure (left ventricular ejection fraction 10% to 39%), the mean arterial plasma norepinephrine concentration was 557 + 68 pg/ml (mean SE) compared with 211 + 21 pg/ml in 15 subjects without heart failure (p < .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 ± 9 vs 5 ± 1 ng/min; p < .002) and renal (202 ± 45 vs 66 ± 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was 181 + 38 pg/ml compared with 71 ± 12 pg/ml in control subjects (p < .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications. Circulation 73, No. 4, 615421, 1986. THE CONSENSUS that sympathetic nervous overactivity is important in the pathophysiology of congestive heart failure is based in part on observations that the sympathetic neurotransmitter norepinephrine is present in plasma at increased concentration.1 The plasma concentration of norepinephrine, however, is determined by the rates of both release of norepinephrine to plasma and removal of norepinephrine from plasma. Norepinephrine plasma clearance might be reduced, and the plasma concentration thereby increased, because of the reduced cardiac output and organ blood flows that accompany congestive heart failure. A second difficulty in the study of the role of the sympathetic nervous system in congestive heart failure has been the inability of clinical research methods to estimate sympathetic activity in internal organs. Microneurographic electrophysiologic methods are available for the clinical study of nerve firing rates in subcutaneous nerves supplying skin and skeletal muscle,2 but the nerves to internal organs are not accessible for such testing.Measurement of sympathetic transmitter release is an alternative technique for quantifying sympathetic nerve activity in internal organs. We have developed a method3 using infusions of tritiated norepinephrine to determine both the rate at which norepinephrine spills into plasma and its rate of clearance from plasma. The technique has recently been applied to determine the rates of norepinephrine spillover from individual organs.4Although only a small fraction of the norepinephrine

Arterial baroreflex function and cardiovascular variability: interactions and implications

“…In these patients, despite direct evidence of high levels of sympathetic activation (increased cardiac and total norepinephrine spillover and MSNA) (36,59), there is a blunting or absence of the LF component of R-R and SNA (83,116). The observed dissociation between sympathetic drive and LF power in the power spectra of cardiovascular variability implies that the traditional paradigm linking increased sympathetic drive to increased LF power in normal subjects cannot simply be extrapolated to include pathological conditions such as severe heart failure, where all homeostatic mechanisms are mobilized at close to maximum levels with little or no reserve to maintain variability.…”

Independent control of skin and muscle sympathetic nerve activity in patients with heart failure.

“…[3][4][5][6][12][13][14][15][16] These uniform findings of sympathetic activation directed to tissues governed by the baroreflexes have prompted the concept that impaired baroreflex restraint underlies sympathetic activation. It is unknown if increased sympathetic neural outflow in heart failure is limited to regions governed by the baroreflexes or is generalized to all tissues -a distinction with mechanistic implications.…”

Age-related regional differences in cardiac nerve growth factor expression

“…During chronic heart failure, myocytes are exposed to increasing wall stress, which has been shown to decrease the NGF expression in cardiomyocytes, sufficient to reduce sympathetic nerve growth ). In parallel, during chronic heart failure, there is an overflow of norepinephrine, which contributes to a downregulation of NGF in cardiomyocytes (Hasking et al 1986;Kimura et al 2010). Likewise NGF expression was shown to decrease in response to alpha-1 receptor stimulation ).…”