Role of atrial natriuretic peptide in adaptation of sodium excretion with reduced renal mass.

The kidney maintains constancy of body fluid volume by regulating urinary sodium (Na) excretion. In chronic renal failure, the reduction in glomerular filtration rate (GFR) is accompanied by an increase in Na excretion per nephron if dietary Na intake is not changed. Reduction in Na intake in proportion to reduced GFR obviates this adaptive increase in tubule Na excretion. To examine the potential role of endogenous atrial natriuretic peptide (ANP) in modulating the enhanced Na excretion per nephron in chronic renal failure, we studied rats subjected to 5/6 nephrectomy or sham operation on low, normal, and high Na intakes. Urinary Na excretion increased with increasing dietary Na in all groups, and Na excretion per nephron was increased in 5/6 nephrectomized rats as compared with sham-operated rats on the higher Na intakes. Plasma ANP levels were unaffected by dietary Na manipulations in sham-operated rats, but rose progressively in 5/6 nephrectomized rats with increasing Na intake. Despite extensive nephron reduction, however, plasma ANP levels failed to rise in uremic rats on low Na diets and in this group Na excretion per nephron also failed to rise. We conclude that enhanced ANP secretion may play an important role in promoting the adaptive increase in Na excretion per nephron in chronic renal failure. Restriction of dietary Na in the setting of reduced GFR obviates the stimulation of ANP secretion as well as the adaptive increase in Na excretion rate per nephron.     

Interactions of atrial natriuretic peptide with the sympathetic and endocrine systems in the pithed rat

We have found previously that atrial natriuretic peptides (ANPs) attenuate pressor response to alpha-2 adrenoceptor agonists but not to alpha-1 agonists in the pithed rat. We have now investigated the effects of ANP on other pressor agonists and on sympathetically mediated responses in rats. Bolus-injected ANP (0.1-10.0 nmol/kg) attenuated pressor responses to angiotensin II, vasopressin and alpha-2 adrenoceptor-mediated component of norepinephrine (NE)-induced responses (up to 17, 27 and 15%, respectively) in pithed rats. The threshold antipressor dose of ANP was the lowest for angiotensin II (comparable to normal levels of circulating ANP-immunoreactivity in rats) whereas it was higher for vasopressin and NE (comparable to plasma ANP-immunoreactivity stimulated by volume expansion). A 30-min infusion of ANP (0.15 nmol/kg/min) shifted the NE dose-pressor response curve 1.7-fold to the right. Conversely, neither that rate of ANP infusion nor the highest dose of bolus injected ANP altered pressor and plasma NE responses to sympathetic stimulation in demedullated pithed rats. However, at higher infusion rates, ANP reduced sympathetic stimulation-induced pressor responses (2.6-fold) and elevations of plasma NE levels (1.6-fold), without altering NE clearance. Similarly in conscious rats, ANP infusion prevented a reflex increase in plasma NE concentrations associated with hypotension. Thus, although the intrajunctional alpha-1 and presynaptic alpha-2 adrenoceptors are inaccessible to the short term bolus-induced elevation of circulating ANP during longer term increases in plasma ANP, it does reach the junction, reduces NE release and limits effects of receptor activation, possibly by diminishing Ca++ entry.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of atrial natriuretic peptide on vasopressin release

This study was designed to investigate the effects of intracerebroventricular or intravenous atrial natriuretic peptide (ANP) on plasma arginine-vasopressin (AVP) levels, plasma renin activity (PRA), blood pressure (BP) and heart rate (HR) in conscious rats. No changes were observed in plasma AVP levels and PRA after intracerebroventricular injection of ANP (0.3 nmol/kg). Also no changes were found in BP and HR after intracerebroventricular ANP injection in the dose range 0.01-0.3 nmol/kg. No significant changes were observed in plasma AVP levels after the intravenous administration of ANP at 2.5 nmol/kg to hydrated rats or at 0.1 nmol/kg and 2.5 nmol/kg to dehydrated rats, although the larger dose was sufficient to cause a small fall in BP. Even after 30 min intravenous infusion of ANP at 0.1 nmol min-1 kg-1, a dose sufficient to produce very high plasma ANP levels, no change in plasma AVP could be detected, although haemodynamic changes were observed. Intravenous ANP injection (2.5 nmol/kg) inhibited basal renin secretion in hydrated rats and also inhibited renin secretion which had been stimulated by prior dehydration. From these studies in hydrated and dehydrated rats, there was no evidence that either intracerebroventricular or intravenous ANP administration affected AVP release in vivo.     

Atrial content and plasma levels of atrial natriuretic peptides in rats with chronic renal failure

The possible role of atrial natriuretic peptides (ANP) for the adaptive changes in renal Na excretion during chronic renal failure was studied in 5/6 nephrectomized (NX) rats maintained on a normal (100 mmol/kg) and a high (800 mmol/kg) Na diet. Atrial content of natriuretic substances was determined by bioassay and plasma ANP by radioimmunoassay. Nephrectomized rats showed a twofold increase in plasma ANP irrespective of their Na intake. Atrial ANP content was increased by high Na diet but unchanged by NX. Nephrectomized rats maintained on high Na diet showed partial depletion of atrial ANP stores. There were no significant changes in the volume fraction of atrial granules determined. The results suggest that ANP is involved in the regulation of renal Na excretion during chronic renal failure and acute Na loading; other mechanisms are probably involved in the adaption to chronic Na loading.     

Atrial natriuretic peptide inhibits osmolality-induced arginine vasopressin release in man

1. Eight normal volunteers were infused with 5% saline (5 g of NaCl/100 ml) at a rate of 0.06 ml min-1 kg-1 for 120 min to increase plasma osmolality and plasma arginine vasopressin. Human atrial natriuretic peptide (alpha-hANP; 100 micrograms) or placebo was given in random order in a double-blind cross-over design for the last 20 min of the saline infusion. 2. Compared with the placebo infusion, atrial natriuretic peptide (ANP) produced a 43% greater sodium excretion and a 34% greater urinary volume in the subsequent hour. 3. Mean plasma immunoreactive ANP did not increase in response to changes in osmolality and rose to a peak of 118 pg/ml during the alpha-hANP infusion. alpha-hANP produced significant suppression of mean plasma arginine vasopressin over the 60 min after the infusions. 4. We conclude that ANP is not released in response to increased osmolality in vivo, and that it inhibits osmolality-induced arginine vasopressin release in man.     

Effects of captopril and NaCl loading on plasma atrial natriuretic peptide (ANP) in rat with chronic heart failure

In order to study long term changes in plasma atrial natriuretic peptide (ANP) in chronic heart failure, plasma ANP levels were determined in rats after myocardial infarction due to coronary artery ligation and in sham-operated controls. In addition, effects of oral captopril treatment and sodium loading on plasma ANP were studied. In accordance with earlier reports plasma ANP paralleled both infarct size and signs of cardiac dysfunction. The highest plasma ANP levels were found in rats having over 45% of their left ventricle infarcted while rats with mild-to-moderate-size infarcts had only slightly elevated plasma ANP levels as compared with controls. These differences in plasma ANP levels between experimental and control groups remained remarkably stable during the three-month observation period. Plasma renin activity (PRA) was elevated in infarcted rats but no differences could be found between rats with varying infarct sizes. Captopril treatment decreased the high plasma ANP levels in rats with the largest infarcts, probably by unloading the failing heart. During increased sodium intake, plasma ANP levels increased in sham-operated controls but not in rats with heart failure. Thus, sodium loading, as compared with cardiac insufficiency, appears to be a weak stimulus for ANP release in rats. I conclude that plasma ANP is a sensitive marker, better than PRA, in long term follow-up of cardiac dysfunction.     

Paradoxical inhibition of atrial natriuretic peptide release during pacing-induced hypotension

1. To determine the influence of loss of atrioventricular synchrony on release of atrial natriuretic peptide (ANP), plasma ANP concentrations were measured by radioreceptor assay in 16 patients during sequential and ventricular cardiac pacing at normal heart rates. 2. Ventricular pacing induced an increase in plasma ANP concentrations (means +/- SEM) from 44 +/- 3 to 104 +/- 4 pmol/l (P less than 0.01) in 11 patients in whom systemic blood pressure was maintained. 3. In contrast, when ventricular pacing was associated with a fall in blood pressure (five patients), ANP levels (means +/- SEM) fell from 68 +/- 6 to 14 +/- 4 pmol/l (n = 5, P less than 0.05) within 5 min, despite an increase in atrial pressure. Plasma catecholamines also rose significantly in these latter patients. 4. We conclude that when loss of atrioventricular synchrony is well tolerated haemodynamically, cardiac release of ANP is increased in keeping with elevation in atrial pressure. However, the fall in plasma ANP concentration observed when ventricular pacing produces a fall in blood pressure suggests that in addition to atrial pressure, ANP release may be influenced by negative feedback mechanisms, possibly involving the baroreflex and autonomic nervous system.     

Responses of atrial natriuretic peptide, vasopressin, aldosterone and renal function to intracerebroventricular infusion of angiotensin II in dogs.

To assess the mechanisms how angiotensin II (Ang II) given intracerebroventricularly (i.c.v.) induces natriuresis, the effects of Ang II (10 ng/kg/min, for 30 min) on the renin-angiotensin-aldosterone system, the release of vasopressin (AVP) and atrial natriuretic peptide (ANP) and on cardiovascular and renal functions were investigated in anesthetized dogs. In control dogs, vehicle alone (artificial cerebrospinal fluid) was infused at a rate of 10 microliters/min. Ang II given i.c.v. produced a gradual increase in urine flow, urinary sodium and potassium excretion and osmolar clearance, but had no effect on plasma ANP, aldosterone, arterial blood pressure, and renal blood flow. However, i.c.v. Ang II increased plasma AVP and decreased heart rate, plasma renin activity, inulin clearance and filtration fraction. In the cotrol group, vehicle treatment had no effect on these parameters except for decreases in inulin clearance and filtration fraction. These results suggest that circulating ANP and blood pressure may not play an important role in i.c.v. Ang II-induced natriuresis, but increased AVP release and decreased renal sympathetic nervous activity may contribute to the natriuresis.     

Effect of β1-adrenoceptor blockade on plasma levels of atrial natriuretic peptide during exercise in normal man

Summary. Increased plasma levels of atrial natriuretic peptide (ANP) during exercise have been reported. To investigate the role of tachycardia as a stimulus for release of ANP during exercise the following study was undertaken. Graded exercise was performed in six healthy volunteers before and after β₁-adrenoceptor blockade. Plasma levels of ANP were determined at different workloads in both cases. At rest and at all workloads during exercise plasma levels of ANP were higher after β₁-adrenoceptor blockade than without. Therefore, it is unlikely that tachycardia is a major stimulus for secretion of ANP during exercise. It is suggested that increased right atrial pressure and/or pulmonary arterial blood pressure and increased plasma levels of catecholamines are important secretory stimuli for ANP during exercise.     

Increased atrial natriuretic peptide in an early stage of chronic glomerulonephritis

Atrial natriuretic peptide (ANP), angiotensin II (AII), aldosterone (Aldo), arginine vasopressin (AVP) in plasma, urinary excretion of prostaglandin E2 (PGE2) and urinary sodium excretion rate (UNaV) were determined in 11 normotensive patients with chronic glomerulonephritis and a normal glomerular filtration rate (GFR) and in 14 healthy control subjects before, during and after intravenous infusion of a 2.5% sodium chloride solution. During basal conditions ANP was increased in patients compared with controls (9.8 pmol/l (median) versus 7.2 pmol/l, p less than 0.01). After sodium infusion ANP was unchanged in the patients but significantly increased in the controls. AII, Aldo, AVP in plasma and urinary PGE2 excretion were the same in patients and controls. The urinary sodium excretion rate was significantly increased in patients compared with controls during sodium infusion (p less than 0.05). No correlations were found between ANP and UNaV, AII or Aldo in either patients or controls. The relationship between serum osmolality (Sosm) and AVP was normal in the patients. It can be concluded that in normotensive patients with chronic glomerulonephritis and normal GFR, ANP is increased during basal conditions and the response to acute volume expansion may be blunted. The renin-angiotensin system, the osmoregulatory system and urinary PGE2 excretion are normal and respond in a normal way to volume expansion. It is suggested that the increased level of ANP can be viewed as a compensatory phenomenon to an abnormal sodium or volume homeostasis in the early stages of chronic glomerulonephritis.     

Effects of dextronatrin on blood pressure, hematocrit, urinary sodium excretion and sympathetic nerve activity of rats

The purpose of this investigation was to study in unanesthetized rats the blood pressure, renal and hematocrit responses to dextronatrin, a structural analogue of atrial natriuretic peptides (ANP). The peptide was infused intravenously for 20 min at doses of either 1 or 20 micrograms/min in binephrectomized rats as well as in rats with intact kidneys. The experiments were started 2 h after preparation of the rats under ether anesthesia. In binephrectomized rats, the small dose of dextronatrin lowered blood pressure and raised hematocrit. In those rats, the larger dose of the investigational peptide had no blood pressure lowering effect, but still increased hematocrit. Dextronatrin had no effect on heart rate, both in rats with and without kidneys. Dextronatrin given at the 1 microgram/min dose to normal rats caused a significant increase in urinary Na excretion. The large dose, however, did not modify this parameter. The effect of dextronatrin (1 microgram/min for 20 min) on splanchnic nerve activity was evaluated in other normal rats after a recovery period of 24 h from surgical procedure. Integrated nerve activity was found to significantly increase in parallel with heart rate while blood pressure was reduced. Taken together, these results show that a low dose of dextronatrin lowers blood pressure and induces an increase in urinary Na excretion and hematocrit. They also indicate that the blood pressure and renal effects of the peptide are abolished when a high dose is administered. In addition, it appears that the shift of fluid from the intra- to the extravascular compartment, reflected in binephrectomized rats by an increase in hematocrit, does not depend on the level of systemic blood pressure. Finally, the present observations suggest that the blood pressure lowering effect of dextronatrin is accompanied in the conscious rat by a stimulation of the sympathetic nervous system.     

Atrial natriuretic peptide regulation of noradrenaline release in the anterior hypothalamic area of spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHR), high NaCl diets increase arterial pressure and sympathetic nervous system activity by decreasing noradrenaline release in the anterior hypothalamic area (AHA), thereby reducing the activation of sympathoinhibitory neurons in AHA. Atrial natriuretic peptide (ANP) can inhibit the release of noradrenaline, and ANP concentration is elevated in the AHA of SHR. The present study tests the hypothesis that in SHR, local ANP inhibits noradrenaline release from nerve terminals in AHA. Male SHR fed a basal or high NaCl diet for 2 wk and normotensive Wistar Kyoto rats (WKY) fed a basal NaCl diet were studied. In SHR on the basal diet, microperfusion of exogenous ANP into the AHA elicited a dose-related decrease in the concentration of the major noradrenaline metabolite 3-methoxy-4-hydroxy-phenylglycol (MOPEG) in the AHA; this effect was attenuated in the other two groups. In a subsequent study, the ANP-C (clearance) receptor agonist c-ANP was microperfused into the AHA to increase extracellular concentration of endogenous ANP in AHA. c-ANP reduced AHA MOPEG concentration in SHR on the basal NaCl diet but not in the other two groups. These data support the hypothesis that local ANP inhibits noradrenaline release in the AHA and thereby contributes to NaCl-sensitive hypertension in SHR.     

Atrial natriuretic peptide release during sleep in patients with obstructive sleep apnoea before and during treatment with nasal continuous positive airway pressure

1. Plasma levels of atrial natriuretic peptide (ANP) were measured in seven patients with obstructive sleep apnoea (OSA) while they were awake, during repetitive apnoea and during treatment with nasal continuous positive airway pressure (CPAP). 2. ANP levels in both pulmonary artery and peripheral venous samples were elevated during apnoeic sleep and reduced when apnoea was prevented by nasal CPAP. Mean values of pulmonary artery ANP were 116.3 +/- 17.9 pg/ml during apnoea and 64.8 +/- 15.2 pg/ml (P less than 0.05) on nasal CPAP. 3. It is concluded that there is increased ANP release during sleep in patients with OSA and that CPAP treatment normalizes ANP secretion. These findings may explain previously identified urinary abnormalities in OSA.     

Effects of intracerebroventricular administration of adrenoceptor-agonists on the regulation of renal water and electrolytes handling through endocrine, renal and hemodynamic function

In order to assess the roles of central adrenoceptors in the release of atrial natriuretic peptide (ANP), aldosterone (ALD), vasopressin (AVP) and renin as well as in the regulation of renal and cardiovascular functions, either norepinephrine (NE; 0.07 microgram/kg/min), guanabenz (GB; alpha 2-agonist; 0.4 microgram/kg/min), methoxamine (MET; alpha 1-agonist; 0.4 microgram/kg/min), or isoproterenol (ISO; beta-agonist; 0.07 microgram/kg/min), dissolved in the artificial cerebrospinal fluid (ACSF), was intracerebroventricularly (i.c.v.) administered at a rate of 10 microliters/min for 30 min in anesthetized dogs. In the control study, the drugs were omitted. NE decreased mean arterial pressure (MAP), urinary osmolality (Uosm) and plasma ALD and AVP concentrations, and increased urine flow (UF). GB increased UF and urinary K excretion without any changes in urinary Na excretion, but decreased plasma ALD and AVP, heart rate, and Uosm without changes in MAP. ISO decreased MAP and plasma ALD, and increased Na and K output, renal plasma flow and UF with decreased Uosm. MET and ACSF failed to affect any of these parameters. Glomerular filtration rate, plasma ANP concentration and renin activity did not change in any of the studies. The present results suggest that central alpha 2- and beta-adrenoceptors may attenuate ALD and/or AVP release without changes in ANP and renin release, and decrease blood pressure, thereby causing a diuresis and natriuresis.     

Selective renal medullary damage and hypertension in the rat: the role of vasopressin

The induction of selective renal medullary damage by 2-bromoethylamine hydrobromide (BEA) results in polyuria and raised blood pressure. In view of the likely elevation of plasma vasopressin we have investigated the role of vasopressin (AVP) in the elevated blood pressure in this model. Plasma vasopressin levels in BEA pretreated rats were raised significantly (2 +/- 0.6 pg/ml vs 0.8 +/- 0.1 in normal rat, P less than 0.05) but not to pressor levels. In addition, pressor responsiveness was investigated in renal medullary damaged rats. There was a reduced response to vasopressin and noradrenaline but no alteration with angiotensin II. A specific V1, receptor AVP antagonist [d(CH2)5Tyr(Me)AVP] produced no fall in blood pressure but returned the noradrenaline dose-response curve to normal. This suggests an interaction between vasopressin and the sympathetic nervous system in this model. Thus there is no evidence that vasopressin contributes to the rise in blood pressure produced by chemical renal medullectomy and other mechanisms have to be sought.     

Atrial natriuretic peptide in human cerebrospinal fluid

We measured immunoreactive atrial natriuretic peptide (ANP) levels in cerebrospinal fluid (CSF) collected from patients with various neurologic disorders requiring diagnostic lumbar puncture. ANP was present in all of the CSF samples from 45 patients (1.7 +/- 0.6 pmol/L, mean +/- SD). CSF ANP levels were not related to the underlying central nervous diseases of the patients, to the presence or the absence of consciousness disturbance, or to CSF osmolalities in individual patients. In 35 patients, the mean ANP concentration in CSF corresponded to 27% of that in plasma, and there was no significant correlation between ANP concentrations in each paired sample. When ANP in pooled CSF was extracted by anti-ANP-agarose and analyzed by reverse-phase high performance liquid chromatography (HPLC), multiple peaks of ANP were found. One of the major ANP peaks was identified as ANP-(103-126) on the basis of its retention time on HPLC and the specificity of the antiserum used in the radioimmunoassay; however, none of other peaks coeluted with ANP-(99-126), ANP-(101-126), ANP-(102-126), ANP-(103-125), or ANP-(105-126). We conclude from these results that ANP is present in human CSF that is differently processed from ANP in the cardiac atrium.     

Dose-response study of atrial natriuretic peptide bolus injection in healthy man

Abstract. The effects of human atrial natriuretic peptide (ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by lithium clearance, and plasma levels of sodium and water homeostatic hormones were studied in a dose-response study with 50 healthy subjects. Placebo or ANP 0.5, 1.0, 1.5, or 2.0 μg kg^-1bwt was given as an intravenous bolus injection to five different groups. GFR rose after ANP, whereas no immediate change in RPF was observed. Significant increases with no distinct additional effect of ANP doses higher than 1.0 μg kg^-1were detected in filtration fraction, urinary flow rate and urinary excretion rate of sodium. Both proximal and distal fractional reabsorption of sodium was reduced and the effect seemed to flatten out at doses higher than 1 0 μ g kg ^-1. Dose-dependent increases in cyclic guano-sine monophosphate in urine and plasma were found after ANP bolus injection, and the rise in both was correlated with the increase in urinary sodium excretion. ANP caused a dose-dependent decrease in blood pressure and an increase in pulse rate. Plasma concentrations of angiotensin II and arginine vasopressin did not change after ANP.
In summary, we found that ANP bolus injection caused a natriuresis and diuresis in healthy man with a threshold at a dose of 1.0 μg kg^-1. No distinct further renal effects were observed with higher doses despite dose-dependent increases in urinary cGMP excretion and plasma cGMP. Inhibition of both proximal and distal tubular fractional sodium reabsorption by ANP contributed to the natriuretic effect. The correlation between the rise in cGMP and the increase in urinary sodium excretion is concordant with cGMP being a secondary messenger for ANP in man.     

Mechanisms of renal hyporesponsiveness to ANP in heart failure

The atrial natriuretic peptide (ANP) plays an important role in chronic heart failure (CHF), delaying the progression of the disease. However, despite high ANP levels, natriuresis falls when CHF progresses from a compensated to a decompensated state, suggesting emergence of renal resistance to ANP. Several mechanisms have been proposed to explain renal hyporesponsiveness, including decreased renal ANP availability, down-regulation of natriuretic peptide receptors and altered ANP intracellular transduction signal. It has been demonstrated that the activity of neutral endopeptidase (NEP) is increased in CHF, and that its inhibition enhances renal cGMP production and renal sodium excretion. In vitro as well as in vivo studies have provided strong evidence of an increased degradation of intracellular cGMP by phosphodiesterase in CHF. In experimental models, ANP-dependent natriuresis is improved by phosphodiesterase inhibitors, which may arise as new therapeutic agents in CHF. Sodium-retaining systems likely contribute to renal hyporesponsiveness to ANP through different mechanisms. Among these systems, the renin-angiotensin-aldosterone system has received particular attention, as angiotensin II and ANP have renal actions at the same sites and inhibition of angiotensin-converting enzyme and angiotensin-receptor blockade improve ANP hyporesponsiveness. Less is known about the interactions between the sympathetic nervous system, endothelin or vasopressin and ANP, which may also blunt ANP-induced natriuresis. To summarize, renal hyporesponsiveness to ANP is probably multifactorial. New treatments designed to restore renal ANP efficiency should limit sodium retention in CHF patients and thus delay the progression to overt heart failure.     

Urinary kallikrein excretion during potassium chloride infusion in potassium-adapted rats: effect of amiloride

1. Urinary kallikrein excretion in the anaesthetized rat was measured during intravenous KCl infusion in control and in K+-adapted rats. 2. The infusion of 0.1 mol/l KCl at 3.0 ml/h for 60 min in control rats resulted in a significant increase in urinary kallikrein excretion, associated with diuresis, natriuresis and kaliuresis. 3. When rats were offered 0.1 mol/l KCl to drink ad libitum for 14 days (K+-adaptation), the basal excretion of kallikrein was higher than in the control rats. In K+-adapted rats, intravenous infusion of 0.1 mol/l KCl resulted in significantly greater increase in urinary kallikrein excretion than in the control rats. 4. The Na+-channel blocker, amiloride (8.5 mg/kg body weight), significantly increased urinary kallikrein excretion immediately after injection in control and K+-adapted rats. However, in the subsequent 60 min, kallikrein excretion decreased markedly to values lower than those before injection of amiloride. 5. When amiloride was superimposed on a continuous 0.1 mol/l KCl infusion in K+-adapted rats, there was an immediate increase in kallikrein excretion. In the subsequent 20 min, kallikrein excretion decreased only to increase again in the next 40 min of KCl infusion. 6. Since amiloride injection reduces urinary kallikrein excretion in control and K+-adapted rats, the results suggest that urinary kallikrein excretion in the rat is through a mechanism(s) affected by amiloride. The high urinary kallikrein excretion and the greater response to KCl infusion in K+-adapted rats suggest that the K+-transport mechanism is more important than the mechanism affected by amiloride.     

Heart failure and neuroendocrine activation: diagnostic,prognostic and therapeutic perspectives

The important neuroendocrine systems involved in heart failure are reviewed with special emphasis on their possible role in pathophysiology and their relation to prognostic and diagnostic information. Plasma levels of noradrenaline (NA), renin, vasopressin, endothelin‐1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and tumour necrosis factor‐α (TNF‐α) are all elevated in heart failure. Activity of the sympathetic nervous system as reflected by NA is correlated to mortality and seems to possess independent prognostic information. Several studies have now documented the beneficial effect of β‐blockade in chronic heart failure (CHF). Renin seems to be a poor prognostic marker in CHF possibly because of the interference with diuretic treatment, angiotensin converting enzyme (ACE)‐inhibitors and angiotensin II antagonist, and probably also because of the significance of tissue renin‐angiotensin system (RAS), poorly reflected by plasma renin. On the other hand, several large‐scale trials with ACE‐inhibitors and angiotensin II antagonists have demonstrated reduced mortality and morbidity in CHF. Plasma vasopressin does not seem to possess prognostic information but testing of non‐peptide antagonists is ongoing. Endothelin‐1 seems to have independent prognostic information and endothelin receptor antagonists may represent a therapeutic possibility. The natriuretic peptides ANP and BNP are correlated to prognosis and possess independent information. Brain natriuretic peptide and N‐terminal ANP seem to increase early, i.e. in asymptomatic heart failure. Plasma BNP being more stable than ANP is therefore a promising measure of left ventricular dysfunction. Increase in ANP and BNP, potentially beneficial, may be achieved by administration of neutral endopeptidase inhibitors, at present an unsettled therapeutic possibility. Several cytokines are increased in heart failure and especially TNF‐α has drawn attention. Experimental studies suggest that TNF‐α is important in the pathophysiology of heart failure and preliminary studies indicate that inhibition of TNF‐α seems to be a possible therapeutic approach. Thus, neuroendocrine markers seem to (i) have a role in diagnosis and classification of heart failure, (ii) be useful in providing a ‘neuroendocrine profile’ which enlightens different aspects of heart failure, and therefore (iii) in the future probably will be valuable in the choice of medical treatment of the individual patient. In addition to β‐blockers, ACE‐inhibitors and angiotensin II antagonists several new drugs based on neuroendocrine modification are on their way and might become important in the future.