Plasma noradrenaline in cirrhosis: a study of kinetics and temporal relationship to ascites formation

Abstract

The kinetics of plasma noradrenaline (NA) were studied in 14 patients with cirrhosis and ascites and 13 normal subjects. [3H]noradrenaline ([3H] NA) was infused intravenously to steady state and the spillover of NA into plasma and its clearance from plasma calculated. The increase in plasma NA in the cirrhotic patients was due to an increase in NA spillover (14.5 vs 3.9 nmol min-1m-2; P less than 0.001). NA plasma clearance was also increased in the cirrhotic patients (3.5 vs 2.11 min-1m-2; P less than 0.01). Plasma NA and dihydroxyphenylglycol (DHPG), a metabolite of NA of which a portion is formed after re-uptake of NA into sympathetic nerve endings, were then measured in 23 patients with cirrhosis and ascites, 17 patients with cirrhosis who had never had ascites, and 34 normal subjects. Both plasma NA and DHPG were significantly increased in the patients with ascites (NA 4.7, DHPG 14.7 nmol l-1 and in the patients with cirrhosis but no ascites (NA 3.8, DHPG 12.0 nmol l-1) compared with normal subjects (NA 1.9, DHPG 8.8 nmol 1-1). Therefore, the increase in plasma NA in cirrhosis is due to increased activity of the sympathetic nervous system rather than interference with the metabolism of NA or impaired neuronal uptake of NA. This increase appears to precede the development of ascites.

Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: Impact of exogenous neuropeptide Y

“…This could represent the functional correlate for reported downregulation and regression of sympathetic innervation in the mesenteric arterial tree in cirrhosis [10,11]. Besides local SNS downregulation, other potential mechanisms could explain NPY deficiency: unquestionably, systemic NA levels are increased in cirrhosis [3,[6][7][8][9]. This might lead to enhanced a 2 -adrenergic presynaptic inhibition of NPY release [27,28].…”

“…Numerous investigations underline marked SNS activity in cirrhosis [3,[6][7][8][9]. However, recent reports suggest splanchnic sympathetic atrophy in portal hypertension.…”

“…Es gibt deutliche Evidenz dafür, dass bei portaler Hypertension die systemischen NA-Plasmakonzentrationen hauptsächlich von der mesenterialen NA-Produktion abhängen [5]. Aber anders als bei systemischen NAKonzentrationen sind Daten zu lokaler splanchnischer Neurotransmitter-Produktion und -Sekretion sehr spärlich vorhanden und zudem kontrovers [6][7][8][9][10][11][12].…”

“…In case of portal hypertension, systemic plasma NA levels could mainly depend on splanchnic NA production [5]. Besides systemic NA levels, data in terms of actual splanchnic synthesis/release of neurotransmitters are scarce and controversial [6][7][8][9][10][11][12]. Neuropeptide Y (NPY) is co-stored and co-released with NA from secretory vesicles of sympathetic nerve terminals, inducing potentiation of a 1 -adrenergic vasoconstriction via G-proteinassociated postsynaptic Y 1 receptors [13].…”

Challenges and Management of Liver Cirrhosis: Pathophysiology of Renal Dysfunction in Cirrhosis

“…Activation of the SNS is also present in patients with advanced cirrhosis as evidenced by increased plasma levels of norepinephrine [14]. Measurements of norepinephrine release and spillover in specific vascular beds have shown that the activity of the SNS is increased in many vascular territories, including the kidneys and splanchnic organs [15,16,17]. As occurs with RAAS, inhibition of the SNS in human and experimental cirrhosis results in marked arterial hypotension, suggesting that the SNS is also activated as a homeostatic response to maintain arterial blood pressure [18].…”