The clinical diagnosis of heart failure is predicted by neurohormonal and immune derangement

To characterize the complex picture of neurohormonal abnormalities in heart failure (HF), a comprehensive characterization was prospectively performed in 105 patients with cardiomyopathy at different clinical stages and compared to 47 sex/age-matched control healthy subjects. To assess the relationship between the diagnosis of HF and clinical and neurohumoral variables, multiple logistic regression with forward stepwise selection (Wald) was used. The diseased condition was predicted by creatinine level, gamma-glutamyl transpeptidase (GGT) activity, TNF-alpha, and plasma levels of several neurohormonal indices: (a) plasma renin activity; angiotensin II; aldosterone; (b) cortisol as a stress marker; (c) norepinephrine levels; (d) triiodothyronine; (e) ANP and BNP. Thus, renal and hepatic dysfunction, overexpression of cardiac natriuretic hormones, of adrenergic and renin–angiotensin–aldosterone system significantly augment the probability of HF, which was decreased by increasing values of thyroid hormone. In conclusion, a complex neurohormonal derangement associated with an overall predominance of vasoconstrictor systems is characteristic of HF syndrome.     

Studies on acute glucose-induced aldosterone suppression: Role of renin-angiotensin system

Summary Glucose loading is known to cause acute suppression of plasma aldosterone and stimulation of plasma renin activity. The relative contribution of variations in circulating angiotensin II to the regulation of aldosterone secretion following glucose loading was assessed in ten normal subjects. The effects of a standard oral glucose loading test (100 g) on plasma concentrations of glucose, insulin, potassium, aldosterone, renin activity and cortisol were studied (a) under basal conditions, and (b) after inhibition of angiotensin II with the converting enzyme inhibitor captopril (50 mg t.i.d. during 3 days). Under basal conditions the acute increase in plasma glucose and insulin after glucose loading was accompanied by a significant decrease (P<0.01) in plasma cortisol and aldosterone and by a significant increase in plasma renin activity (P<0.01); plasma potassium was decreased slightly but not significantly. Following captopril treatment preloading plasma renin activity was increased significantly, most probably reflecting an effective reduction of angiotensin II. Glucose loading caused a similar suppression of plasma aldosterone, as observed under basal conditions. This observation suggests that renin activation does not substantially contribute to the acute regulation of plasma aldosterone after an oral glucose load.     

Control of plasma aldosterone in a patient with Conn's Syndrome before and during spironolactone medication

Summary In a patient suffering from Conn's syndrome analysis of short-time fluctuations of plasma aldosterone, plasma cortisol and plasma renin activity were performed before and after a 9-months therapy period with spironolactone. Under the former conditions aldosterone was secreted episodically and a highly significant correlation was found between plasma aldosterone and plasma cortisol (r=0.817,p<0.001) while plasma renin activity was undetectable (<0.16 ng/ml/3 hr). Following a 9-months therapy with spironolactone episodic secretion of aldosterone and the significant correlation between aldosterone and cortisol persisted (r=0.819,p<0.001) in the presence of an abnormally high plasma renin activity. First, when the secretion of ACTH was suppressed by dexamethasone a weak correlation was found between renin activity and aldosterone (r=0.517,p<0.05). Our results show that both before and after a 9-months therapy with spironolactone episodic aldosterone release of an aldosterone producing adrenal adenoma was mediated through ACTH and that endogeneous angiotensin II had no or only little influence.     

Effects of estrogen replacement therapy on natriuretic peptides and blood pressure

OBJECTIVE: Estrogen replacement therapy (ERT) has been reported to affect blood pressure. Since natriuretic peptides have natriuretic and vasodilatory activity and also inhibit the renin-angiotensin-aldosterone system and lower blood pressure, it was hypothesized that the changes in blood pressure effected by ERT might be mediated via changes in natriuretic peptides. METHODS: Fifty-eight postmenopausal hysterectomized women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate 2 mg/day or transdermal estradiol gel containing 1 mg estradiol/day for 6 months. Blood pressure was measured by using an automatic, oscillometric device. Plasma atrial natriuretic peptide (ANP), N-terminal fragment of proANP (NT-proANP), B-type natriuretic peptide (BNP), aldosterone, and renin were determined by radioimmunoassay. RESULTS: The mean decrease in diastolic blood pressure was -6 mmHg both in the peroral group (n = 26) (P = 0.002) and in the gel group (n = 27) (P = 0.001), and the corresponding decreases in systolic blood pressure were -4 mmHg (P = 0.070) and -7 mmHg (P = 0.028) in the sitting position. Plasma NT-proANP rose from 212 to 264 pmol/l (P = 0.001) on peroral ERT and from 240 to 292 pmol/l (P = 0.008) on transdermal ERT. No significant changes were observed in the plasma ANP, BNP, aldosterone, and renin levels. CONCLUSIONS: Both peroral and transdermal ERT result in elevated plasma levels of NT-proANP, indicating an activation of the natriuretic peptide system. This could explain, at least in part, the lowering of blood pressure during ERT.     

Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure

Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations were measured in patients with dialysis-dependent chronic renal failure and in patients with coronary artery disease exhibiting normal or elevated left ventricular end-diastolic pressure (LVEDP) (n = 30 each). Blood samples were obtained from the arterial line of the arteriovenous shunt before, 2 h after the beginning of, and at the end of hemodialysis in patients with chronic renal failure. In patients with coronary artery disease arterial blood samples were collected during cardiac catheterization. BNP and ANP concentrations were determined by radioimmunoassay after Sep Pak C₁₈ extraction. BNP and ANP concentrations decreased significantly (P < 0.001) during hemodialysis (BNP: 192.1 ± 24.9, 178.6 ± 23.0, 167.2 ± 21.8 pg/ml; ANP: 240.2 ± 28.7, 166.7 ± 21.3, 133.0 ± 15.5 pg/ml). The decrease in BNP plasma concentrations, however, was less marked than that in ANP plasma levels (BNP 13.5 ± 1.8%, ANP 40.2 ± 3.5%; P < 0.001). Plasma BNP and ANP concentrations were 10.7 ± 1.0 and 60.3 ± 4. 0 pg/ml in patients with normal LVEDP and 31.7 ± 3.6 and 118.3 ± 9.4 pg/ml in patients with elevated LVEDP. These data demonstrate that BNP and ANP levels are strongly elevated in patients with dialysis-dependent chronic renal failure compared to patients with normal LVEDP (BNP 15.6-fold, ANP 2.2-fold, after hemodialysis; P < 0.001 or elevated LVEDP (BNP 6.1-fold, ANP 2.0-fold, before hemodialysis; P < 0.001), and that the elevation in BNP concentrations was more pronounced than that in ANP plasma concentrations. The present results provide support that other factors than volume overload, for example, decreased renal clearance, are also involved in the elevationin BNP and ANP plasma levels in chronic renal failure. The stronger elevation in BNP concentrations in patients with chronic renal failure and in patients with elevated LVEDP and the less pronounced decrease during hemodialysis suggest a different regulation of BNP and ANP plasma concentrations.[/ p]Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide - LVEDP left ventricular end-diastolic pressure Correspondence to: C. Haug     

Mechanisms of acute natriuresis in normal humans on low sodium diet

This study evaluates the relative importance of several mechanisms possibly involved in the natriuresis elicited by slow sodium loading, i.e. the renin-angiotensin-aldosterone system (RAAS), mean arterial blood pressure (MAP), glomerular filtration rate (GFR), atrial natriuretic peptide (ANP), oxytocin and nitric oxide (NO). Eight seated subjects on standardised sodium intake (30 mmol NaCl day⁻¹) received isotonic saline intravenously (NaLoading: 20 μmol Na⁺ kg⁻¹ min⁻¹ or ≈11 ml min⁻¹ for 240 min). NaLoading did not change MAP or GFR (by clearance of ⁵¹Cr-EDTA). Significant natriuresis occurred within 1 h (from 9 ± 3 to 13 ± 2 μmol min⁻¹). A 6-fold increase was found during the last hour of infusion as plasma renin activity, angiotensin II (ANGII) and aldosterone decreased markedly. Sodium excretion continued to increase after NaLoading. During NaLoading, plasma renin activity and ANGII were linearly related ( R = 0.997) as were ANGII and aldosterone ( R = 0.999). The slopes were 0.40 p m ANGII (mi.u. renin activity)⁻¹ and 22 p m aldosterone (p m ANGII)⁻¹. Plasma ANP and oxytocin remained unchanged, as did the urinary excretion rates of cGMP and NO metabolites (NO_x). In conclusion, sodium excretion may increase 7-fold without changes in MAP, GFR, plasma ANP, plasma oxytocin, and cGMP- and NO_x excretion, but concomitant with marked decreases in circulating RAAS components. The immediate renal response to sodium excess appears to be fading of ANGII-mediated tubular sodium reabsorption. Subsequently the decrease in aldosterone may become important.     

Control of plasma aldosterone in diabetic patients with hyporeninemic hypoaldosteronism

Summary In three patients with diabetes and hyporeninemic hypoaldosteronism changes in renin activity, plasma aldosterone and cortisol were examined under various conditions: orthostasis and intravenous furosemide, infusion of synthetic 1–24 ACTH on two consecutive days and diurnal variations in basal hormone fluctuations.Each patient showed unmeasurably low renin activity unresponsive to orthostasis and intravenous furosemide while plasma aldosterone was below normal range.Under ACTH-infusion only marked increases in aldosterone were observed in one patient whereas cortisol responded normally in all diabetics tested.Analysis of diurnal night day fluctuations (20.00–8.00) in plasma aldosterone and cortisol revealed a close and statistically significant relationship between both hormones in each of the three patients (p<0.05–<0.001). Variations in plasma aldosterone thus were mediated through changes in endogenous pituitary ACTH. Compared with normal controls however, diurnal aldosterone curves were set at a lower level.Our results demonstrate that a reduced sensitivity of the adrenal gland to ACTH is not responsible for the observed subnormal plasma aldosterone levels in these patients. Therefore, the lack of circulating angiotensin II seems to be the causative reason of hypoaldosteronism.The exact mechanism of undetectable renin activity in these patients remains unknown.     

Renin-angiotensin-aldosterone system in rats with neurogenic stress

In adult male rats moderate neurogenic stress was induced by crowding for periods of 1 and 7 days. The angiotensin I concentration and renin activity in the blood plasma and the aldosterone concentration in the peripheral blood and adrenal tissues were determined radioimmunologically. Crowding the rats for 1 day led to a considerably marked increase in the adrenal aldosterone concentration in the plasma. The aldosterone concentration in the blood and adrenals of the rats was lowered 7 days after the beginning of neurogenic stress but the renin activity and angiotensin I concentration in the peripheral blood plasma were raised. The causes of the dissociation observed in the renin-angiotensin-aldosterone system in response to neurogenic stress of varied duration are discussed.Laboratory of Pathophysiology, Research Institute of Pediatrics, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR P. D. Gorizontov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 10, pp. 1179–1181, October, 1976.     

Plasma Renin Aktivität und Aldosteronverhalten bei kritisch kranken Patienten

Summary To investigate the influence of critical illness on plasma renin activity and aldosterone levels and to examine potential inhibitory effects of dopamine therapy on aldosterone responsiveness, we measured plasma renin activity, and potassium and creatinine in serum, as well as the responses of aldosterone, cortisol and prolactin levels to TRH 200 µg i.v. + Synacthen 0.25 mg i.v. in 63 unselected, critically ill patients (32 females, 31 males, aged 18–84 years). Of the patients 19 received dopamine treatment (3–13 µg/kg/min i.v.); 21 of the patients died in the further course of their disease. Plasma renin activity was increased in 66.7% of the patients and aldosterone levels were elevated in 90.5% of the patients. There were correlations (P<0.05) of lethality with plasma renin activity and cortisol levels and correlations (P<0.01) of aldosterone concentrations with plasma renin activity and cortisol levels. Whereas dopamine treatment had no inhibitory effect on aldosterone levels before and after stimulation, prolactin stimulation was decreased in dopamine-treated patients.Thus, dopamine does not generally lose its potency of hormone inhibition in critically ill patients, but has no influence on the secondary aldosteronism developing regularly in the early phase of critical illness, which is apparently mainly due to the stimulatory effect of ACTH (or ACTH-related pituitary peptides) and is considered an epiphenomen of the stress mechanisms acting upon the patients in this condition.

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Abkürzungen ACTH Adrenocorticotropes Hormon - TRH Thyreotropin-Releasing Hormon - ZNS Zentrales Nervensystem     

Regional cardiac expression and concentration of natriuretic peptides in patients with severe chronic heart failure

The purpose of this study was to examine the regional cardiac mRNA expression and concentration of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in relation to the circulating peptide concentrations in patients with chronic heart failure (CHF). The myocardial mRNA levels and peptide concentrations of BNP and ANP were analysed in seven different regions of the heart from patients undergoing cardiac transplantation. Autopsy samples from individuals without known cardiovascular disease were used as controls. The plasma levels of natriuretic peptides and their N‐terminal propeptides, Nt‐proBNP and Nt‐proANP, were measured in the CHF patients and healthy volunteers. In the autopsy specimens, the atrial regions appeared to contain the highest peptide levels for BNP as well as ANP, the atrioventricular ratio being 12–262 and 72–637‐fold, respectively. In the CHF patients there was a relative shift towards the ventricle for BNP, reducing the atrioventricular ratio to 6–16‐fold. The circulating concentrations of BNP/Nt‐proBNP in the CHF patients correlated closely to the BNP mRNA expression in most myocardial regions including the left ventricle (r=0.72, P < 0.001). For circulating concentrations of ANP/Nt‐proANP, such correlation were limited to the left atrium free wall (r=0.66, P < 0.002). Thus, of the two natriuretic peptides, BNP/Nt‐proBNP may be a better reflector of left ventricular overload.     

Atrial natriuretic peptide, renin activity, aldosterone, urine volume and electrolytes during a 24-h sleep-wake cycle in man

To investigate the diurnal variation in the plasma atrial natriuretic peptide (ANP) concentrations and its relation to renin activity, aldosterone, urine volume and electrolytes, blood samples from six healthy male subjects were collected and blood pressure and heart rate recorded every 4 h during a 24-h sleep-wake period. Systolic blood pressure and heart rate were at the lowest during sleep. Plasma ANP, extracted on Sep-Pak cartridges and measured by radioimmunoassay, had the highest concentration at midnight and lowest at 04.00 h (27 +/- 18 vs 16 +/- 18 ng l-1, mean +/- SD, P less than 0.05 after normalization of the original values). Plasma renin activity and aldosterone were at the highest at 08.00 and 12.00 h, whereafter they both began to decrease (P less than 0.001, also normalized). Urinary volume, sodium, potassium and chloride showed highest values (P less than 0.05) between 08.00 and 16.00 h. Plasma ANP levels did not correlate with systolic blood pressure, heart rate, serum or urinary Na or plasma renin or aldosterone (r = 0.1-0.3, P greater than 0.05). Plasma renin activity correlated with aldosterone and aldosterone with urinary K (r = 0.66 and 0.58 respectively, P less than 0.001). These results suggest that the low plasma ANP levels found in our subjects at 04.00 h may be associated to diminished atrial distension accompanied by the inactivity of the sleep period. In addition, ANP does not appear to affect the secretion of renin and aldosterone in a normal sleep-wake cycle.     

Renin-angiotensin-aldosterone system of the normothermic marmot.

Adrenal steroid secretion rates and the renin-angiotensin-aldosterone (RAA) system were studied in the normothermic marmot. Adrenal secretion by the anesthetized, laparotomized marmot was (mean +/- SEM); aldosterone 1.2 +/- 0.3 ng/min, deoxycorticosterone 16.7 +/- 11.5 ng/min, corticosterone 15.2 +/- 7.8 ng/min, and cortisol 554 +/- 108 ng/min. Four forcings were investigated that affect feedback control at different sites: adrenocorticotropic hormone (ACTH) and angiotensin II (AII) infusion, sodium (Na) depletion, and Na loading. Plasma aldosterone, cortisol, Na, and potassium (K) concentrations as well as plasma renin activity (PRA) hematocrit (Hct), and in some studies, blood pressure were measured. ACTH infusion increased the plasma concentrations of aldosterone and cortisol. AII infusion increased aldosterone concentration, blood pressure, and Hct. Na depletion increased aldosterone, Hct, and PRA; plasma Na and K were decreased. Aldosterone concentration, Hct, and PRA decreased after salt loading. Normothermic, salt-depleted marmots demonstrated a pronounced fall in blood pressure following infusion of the AII analog, 1-sarcosine-8-alanine AII. The average plasma values for aldosterone, PRA, and cortisol found in 44 control animals were: aldosterone 3.8 +/- 0.3 ng/100 ml, PRA 1.9 +/- 0.2 ng AI-ml-1-h-1, and cortisol 54 +/- 4 ng/ml. It was concluded that normothermic marmots have a RAA system comparable to other mammalian species.     

Plasma levels of atrial natriuretic peptide are raised in essential hypertension during low and high sodium intake

Summary Plasma levels of -human atrial natriuretic peptide (hANP) were measured in 17 patients with primary hypertension (11 females, 6 males, aged 22–61; blood pressure systolic 154±7 mmHg, diastolic 92±4 mmHg) and in 9 normotensive controls (4 males, 5 females, aged 20–71; blood pressure systolic 117±4 mmHg, diastolic 76±2 mmHg) during unrestricted sodium diet, at the 4th day of a low sodium intake (40–60 mEq/day) and at the 6th day of sodium loading (280–320 mEq/day) both after an overnight rest and after 4 h of upright posture. In the controls, plasma levels of hANP at 8:00 a.m. were lowered from 73±11 to 49±7 pg/ml during low sodium diet and increased to 128±37 pg/ml after high salt intake. Plasma ANP levels were significantly lower after 4 h of upright posture during unrestricted, low and high sodium intake. In the hypertensive group, plasma ANP levels were elevated during unrestricted diet (203±43 pg/ml), during the low sodium period (139±31 pg/ml), and after high sodium intake (267±63 pg/ml) compared to the controls. All levels were lowered by upright posture. The absolute decrease was more pronounced compared to the normotensives, the relative decline was similar in both groups. In the hypertensives, plasma ANP levels significantly correlate with systolic and diastolic blood pressure (r=0.468,r=0.448,P<0.05) and with urinary aldosterone during unrestricted diet (r=0.536,P<0.05). There was an inverse correlation between plasma ANP levels and plasma renin concentration during low and high sodium intake (r=–0.469,r=–0.496,P<0.05).These studies demonstrate raised circulating plasma ANP levels in patients with essential hypertension. The modulation of ANP by different sodium intake and by upright posture is maintained similar to the changes in plasma ANP in normotensive controls. Raised ANP levels in the hypertensives are correlated with low renin secretion and high aldosterone excretion. High ANP levels, therefore, might indicate sodium retention in essential hypertension.Abbreviation ANP atrial natriuretic peptide Supported by a grant from Ministerium für Wissenschaft und Forschung, NRW     

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-alpha (TNF-alpha) 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 beta-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-alpha has drawn attention. Experimental studies suggest that TNF-alpha is important in the pathophysiology of heart failure and preliminary studies indicate that inhibition of TNF-alpha 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 beta-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.     

Serial measurements of plasma renin activity, aldosterone and cortisol during percutaneous transluminal angioplasty of the renal artery in man

Fifteen patients (eight men, seven women) with hypertension and renal artery stenosis underwent dilation of the stenosis by percutaneous transluminal renal angioplasty (PTRA). During and shortly after this treatment the effects on the renin-angiotensin-aldosterone system and blood pressure were studied. Plasma renin activity (PRA) was measured in peripheral blood and in renal venous blood during the PTRA. PRA increased in peripheral blood during PTRA as a result of an immediate significant rise in renal venous plasma renin activity by 132 +/- 134% (P less than 0.01) on the dilated side. PRA in the contralateral renal vein was close to that in peripheral blood. Within 10 min after PTRA there was a significant increase in serum aldosterone from 439 +/- 343 to 774 +/- 635 pmol 1-1 (P less than 0.025), while serum cortisol remained unchanged. The aldosterone increase was most probably mediated by angiotensin II. Systolic and diastolic blood pressures were unchanged during PTRA in spite of renin and aldosterone increases, suggesting that antihypertensive factors counteract the pressor effects of a physiologically relevant increase in PRA.     

Effects of the calcium antagonist felodipine on the sympathetic and renin-angiotensin-aldosterone systems in essential hypertension

Studies were performed in 10 male patients with untreated essential hypertension, WHO grade I-II, aged 25-62 years, to explore the acute (single dose) and long-term (8 weeks) effects of felodipine on sympathetic activity--evaluated by plasma and urinary catecholamines--as related to blood pressure, heart rate and the activity in the renin-angiotensin-aldosterone system. The patients were hospitalized for 8 (acute) and 6 (long-term) days and were maintained on a standardized daily intake of sodium (150 mmol), potassium (75 mmol) and water (2,500 ml). Acute felodipine administration (10 mg) significantly reduced blood pressure and increased heart rate. Plasma and urinary noradrenaline, plasma renin activity and angiotensin II increased, whereas plasma and urinary adrenaline, dopamine, aldosterone and plasma vasopressin were unaltered. Long-term felodipine treatment, 10 mg twice daily, reduced blood pressure to a similar extent as acute felodipine administration, but heart rate was not significantly changed. Plasma noradrenaline 3 and 12 hours after the last dose and urinary noradrenaline were increased, whereas plasma and urinary adrenaline and dopamine were unchanged. Plasma renin activity and angiotensin II were increased 3 hours, but unchanged 12 hours after the last dose. Plasma aldosterone was unchanged but urinary aldosterone increased. Plasma vasopressin was unchanged. The changes in plasma noradrenaline as related to blood pressure, heart rate, plasma renin activity and angiotensin II during long-term felodipine treatment may reflect decreased cardiac and renal beta-adrenoceptor-mediated responses. Increased renal clearance of aldosterone could partly explain the unaltered plasma aldosterone level in spite of increased plasma angiotensin II following long-term felodipine treatment.     

Brain natriuretic peptide and acute hypobaric hypoxia in humans

In animal models, the secretion of the cardiac hormone, brain natriuretic peptide (BNP), and its closely related peptide, atrial natriuretic peptide (ANP), are stimulated by acute hypoxia. There is extensive human evidence for a rise in ANP under acute hypoxic conditions but very little evidence regarding the BNP response to acute hypoxia in humans. We therefore subjected seven healthy subjects to an acute hypobaric hypoxic stimulus to examine if BNP secretion increases rapidly. Significant hypoxaemia (mean nadir oxygen saturation 62.3%) was induced but no significant rise in BNP occurred. This suggests that either such acute hypoxaemia is well tolerated by the healthy human heart or it is not a stimulus for BNP secretion.     

Dysregulation of pulsatility in aging IV. Pulsatile signaling and cardiovascular aging: functions and regulation of natriuretic peptide signaling

Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones connecting heart and kidney and playing a key role in hydromineral and hemodynamic homeostasis. In contrast with the renin-angiotensin-aldosterone system, circulating ANP and BNP are not temporally related with rapid eye movement (REM)-nonREM sleep cycles, autonomic activity, or blood pressure. Cardiac natriuretic peptides are secreted in a pulsatile manner, with short periods of 20-48 min, in normal as well as in pathological conditions. The frequency of pulses seems to be unchanged with aging, whereas the absolute amplitude of the oscillations seems to increase, most likely as a result of an increase in the plasma hormone levels observed in elderly. Enhanced cardiac secretion and decreased degradation partly explain the higher ANP and BNP concentrations observed in elderly. Despite higher levels, the natriuretic system seems to loose efficiency at the renal site in elderly. This more probably relies on reduced target organ responsivity and not on deeply altered hormone secretion. Here we review the impact of aging on the renal effects of the natriuretic peptides, and point out the lack of knowledge on the precise interactions between the ultradian rhythms of the systems involved in salt and water balance in elderly. Additional studies focusing on potential age-induced alterations of the intracellular signaling pathway are now needed.     

Influence and implications of the renin–angiotensin–aldosterone system in obstructive sleep apnea: An updated systematic review and meta-analysis

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension.     

Cardiac natriuretic peptide hormones during artificial cardiac pacemaker stimulation and left heart catheterization

Summary Brain natriuretic peptide (BNP) is synthesized and released predominantly in the ventricular myocardium whereas atrial natriuretic peptide (ANP) is produced mainly in the atria. This study evaluated whether artificial pacemaker stimulation or left heart catheterization results in specific changes in BNP and ANP plasma levels. Both BNP and ANP responded sensitively to changes in pacemaker stimulation (single-chamber pacemakers; pacing rates of 72 and 92/min) and during the left heart catheterization procedure. However, whereas higher pacing resulted in a more pronounced increase in plasma BNP levels, a stronger ANP release followed catheterization. This incongruous rise in ANP and BNP plasma concentrations points to at least partly independent mechanisms govering the release of BNP and ANP.Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide