Long-term elevations of dietary sodium produce parallel increases in the renal excretion of urodilatin and sodium

The effects of dietary sodium intake on the renal excretion of urodilatin and of sodium were examined in six healthy male subjects. The 24-day study period was divided into three phases of 8 days each. Subjects Ingested 2.8 mequiv sodium (kg body weight)^–1 day^–1 during the first phase, 5.6 mequiv (kg body weight)^–1 day^–1 during the second phase, and 8.4 mequiv (kg body weight)^–1 day^–1 during the third phase. The excretion of both sodium (P<0.002) and urodilatin (P<0.006) increased in response to the increasing dietary sodium, while urine flow did not change. Urinary urodilatin excretion correlated closely with renal sodium excretion (P<0.001). Serum aldosterone levels (P<0.01) as well as serum renin levels (P<0.05) significantly decreased with increasing sodium intake. Plasma [Arg]vasopressin levels increased significantly (P<0.05). Plasma atrial natriuretic factor and cGMP levels as well as urinary cGMP excretion rates were unaltered by the changes in sodium intake. We conclude from these results that the renal natriuretic peptide, urodilatin, but not the main cardiac member of the natriuretic peptide family may be involved in the regulation of day-to-day sodium balance.     

Reduced natriuresis during weightlessness

Summary The kidney response to weightlessness was measured in one volunteer during a 1-week space mission. Shortly after entering microgravity and later during the mission, consecutive urine sampling periods were monitored, covering in total about 50% of the inflight time. Preflight references were a sequence of ground-based experiments, which evaluated body fluid metabolism with different degrees of standardization. Additional variables, such as circadian rhythms and cortisol-associated stress, were also monitored. In contrast to current hypotheses, the volunteer showed a pronounced reduction in natriuresis and diuresis during the entire space flight, despite a considerable weight loss. For the first time, the urinary excretion of the renal natriuretic peptide urodilatin was also measured. Both, during the preflight experiments and during weightlessness, close correlations between urodilatin excretion and sodium excretion were observed. However, the correlation between natriuresis and urodilatin excretion was considerably altered during weightlessness. We conclude that the loss of body weight during space flight is not related to an increased renal fluid loss and that urodilatin might counteract the decrease in renal excretion observed in weightlessness.     

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     

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     

Natriuresis in conscious dogs caused by increased carotid [Na+] during angiotensin II and aldosterone blockade

The renal response to a selective increase in the Na⁺ concentration of the blood perfusing the central nervous system was investigated in conscious dogs treated with the converting enzyme inhibitor enalaprilat and the aldosterone antagonist canrenoate. In split-infusion experiments the plasma [Na⁺] of carotid blood was increased (approx. 6 mM) by bilateral infusion of hypertonic NaCl. Concomitantly distilled water was infused into the v. cava making the sum of the infusions isotonic. In control experiments isotonic saline was infused at identical rates into all three catheters. Na⁺ excretion increased markedly in both series, 103 ± 14 to 678± 84 μmol min^-1 during split-infusion and 90 ± 14 to 496 ± 74 μmol min^-1 during the isotonic volume expansion. Peak rate of excretion, peak fractional sodium excretion, and cumulative sodium excretion were all significantly higher (P < 0.05) during split-infusion than during control experiments. Plasma vasopressin increased only during split-infusion (0.68 ± 0.11 to 2.4 ± 0.8 pg ml^-1) while the increases in plasma atrial natriuretic peptide were similar in the two series. Urinary excretion of urodilatin (ANP95-126) increased significantly more during split-infusion (46 ±11 to 152 ±28 fmol min^-1) than during the isotonic volume expansion (45 ± 14 to 84 ± 16 fmol min^-1) (P < 0.05). It is concluded that the natriuretic mechanisms activated by a selective increase in the Na⁺ concentration of carotid blood and associated with increased excretion of urodilatin cannot be eliminated by blockade of the renin-angiotensin-aldosterone system.     

Atrial natriuretic peptide in human urine

Summary A highly sensitive radioimmunoassay to measure atrial natriuretic peptide (ANP) concentration in urine has been established, and its clinical usefulness is presented. ANP in urine was stable at 4° C for several days and was easily measured by our radioimmunoassay. The average ANP excretion in 65 healthy persons was 25.0±1.4 ng/day (mean ± SEM) and the fractional excretion of ANP was 0.7±0.05%. In 14 patients with congestive heart failure, the average ANP excretion was 119.2±29.4 ng/day, which decreased to 53.3±11.0 after successful treatment.Abbreviations ANP atrial natriuretic peptide - hANP human atrial natriuretic peptide - RIA radioimmunoasay - NSB non specific bound - FE_ANP the fractional excretion of atrial natriuretic peptide - FE_Na the fractional excretion of sodium - SIADH the syngrome of inappropriate secretion of antidiuretic hormone     

The goat mammary gland as a target organ for atrial natriuretic peptide

Milk secretion represents a major route for electrolyte and water excretion in the dairy goat. The aims of this study were to investigate whether the mammary gland is a target site for atrial natriuretic peptide (ANP) in the goat and whether ANP affects mammary sodium and water secretion. Receptor autoradiography using ¹²⁵I-ANP as radioligand revealed specific binding sites in the secretory tissue of the mammary gland. The radioligand was totally displaced by unlabelled ANP, but not by brain natriuretic peptide or the ANP fragment c-ANP_4–23, indicative of ANP-A receptor preference. To elucidate the role of ANP in milk secretion, ANP (30 ng kg^?1min^?1; 120 min) or 0.15 m NaCl (control) were administered in vivo. The ANP infusions caused haemoconcentration, but did not change milk flow or the concentrations of sodium, potassium, lactose, fat and protein in the milk. The results show that the mammary gland of the goat expresses ANP-specific binding sites, however, a physiological role of ANP in goat mammary gland function remains to be elucidated.     

Atrial natriuretic peptide attenuates pressor but enhances natriuretic responses to angiotensin II in pregnant conscious goats

This study was designed to examine the actions of ANP in acute, ANGII-mediated hypertension during pregnancy. Effects on blood pressure, blood volume, and renal Na and K excretion were evaluated in conscious goats (n= 6). ANP (2 μrg min^-1), ANGII (0.5 μg min^-1), or ANGII + ANP (doses the same as for each peptide alone) was infused intravenously for 60 min. The pressor response to ANGII was reduced in pregnant goats. This reduction was seen in systolic, but not in diastolic pressure. ANP decreased pressure by 5–10 mmHg both in pregnancy and in non-pregnancy. When ANGII + ANP was infused, blood pressure initially rose as with ANGII but then declined. ANP suppressed only the elevated systolic pressure. Plasma protein concentration and haematocrit was reduced by ANGII but increased by ANP alone or together with ANGII, thereby implying fluid shift into the vasculature by ANGII and opposite movement by ANP. ANGII increased renal Na excretion to 1500 μmol min^-1in non-pregnancy, but only to half of that in pregnancy. ANP alone caused small natriuresis, but enhanced ANGII-induced natriuresis to near 3000 μmol min^-1in both non-pregnant and pregnant goats. In summary, ANP further attenuated the blunted blood-pressure rise due to ANGII in pregnant goats, and reduced plasma volume, but enhanced renal Na excretion as in non-pregnant goats. This implies that with the present combination ANP and ANGII caused a near maximal natriuretic response that was not modified by the systemic cardiovascular changes occurring in pregnant goats.     

Changes of molecular forms of atrial natriuretic peptide after treatment for congestive heart failure

Summary In the present study, an attempt was made to clarify whether ANP molecular forms in the plasma of severe congestive heart failure patients differ from those in healthy persons and whether ANP molecular forms in the plasma of the patients were changed by successful treatment of cardiac disease.Twenty patients with congestive heart failure were treated at Kitasato University Hospital. They were classified as class III or IV by New York Heart Association criteria at the time of admission. Plasma ANP concentrations decreased after treatment from 356 ± 58.2 to 72.3 ± 14.8 pg/ml. The gel permeation chromatograms from the plasma of healthy persons showed low, or low and high molecular weight ANP peaks which correspond to the elution positions of authentic -ANP or ribonuclease A (mol.wt., 13.7 kdalton). In patients with severe congestive heart failure at a severe stage, middle molecular weight ANP consisted with the elution position of authentic-ANP was particularly noted in addition of low and high molecular weight ANP peaks. This middle molecular weight peak disappears in most of cases by successful treatment. Molecular forms in the plasma obtained from the coronary sinus and the inferior or superior vena cava were essentially the same.These results indicate that the middle molecular weight ANP supposed as-ANP may particularly be secreted in severe congestive heart failure patients.Abbreviations ANP atrial natriuretic peptide - NYHA criteria New York Heart Association criteria - SIADH Syndrome of inappropriate secretion of ADH     

Concomitant increase in plasma atrial natriuretic peptide and cyclic GMP during volume loading

Summary To investigate the effects of fluid expansion on endogenous atrial natriuretic peptide (ANP) and cyclic 3,5-guanosine monophosphate (cGMP), four male volunteers were studied before, during and after intravasal volume loading. Volume expansion was performed by intravenous infusion of 2,000 ml isotonic saline solution within 30 min. Mean plasma ANP levels increased 2.5-fold from 31.2 pg/ml to 81.7 pg/ml 40 min after the start of infusion. Plasma cGMP levels paralleled the rise in ANP, shwoing a mean cGMP increment from 2.7 pmol/ml to a maximum of 8.2 pmol/ml. Both ANP and cGMP levels were back to basal levels 120 min after termination of the infusion. Stimulation of endogenous ANP release by volume loading suggests that ANP is involved in the regulation of fluid homeostasis in man. The parallel rise in plasma cGMP levels supports the idea that cGMP is a mediator for the effects of ANP.Abbreviations ANP atrial natriuretic peptid - cGMP cyclic 3,5-guanosine monophosphate - PRA plasma renin activity     

Natriuretic peptides increase a K+ conductance in rat mesangial cells

Mesangial cells (MC) are a main target of natriuretic peptides in the kidney and are thought to play a role in regulating glomerular filtration rate. We examined the influence of cGMP-generating (i.e. guanosine 3,5-cyclicmonophosphate) peptides on membrane voltages (V_m) of rat MC by using the fast whole-cell patch-clamp technique. The cGMP-generating peptides were tested at maximal concentrations ranging from 140 to 300 nmol/1. Whereas human CNP (C natriuretic peptide), rat guanylin and human uroguanylin had no significant effect on V_m of these cells, human BNP (brain natriuretic peptide), rat CDD/ANP-99-126 (cardiodilatin/atrial natriuretic peptide) and rat CDD/ANP-95-126 (urodilatin) hyperpolarized V_m significantly by 1.6 ± 0.4 mV (BNP,n = 8), 3.7 ± 0.3 mV (CDD/ANP-99-126,n = 25) and 2.8 ± 0.4 mV (urodilatin,n = 9), respectively. The half-maximally effective concentration (EC₅₀) for the latter two was around 400 pmol/l each. This hyperpolarization could be mimicked with 0.5 mmol/1 8-bromo-guanosine 3,5-cyclic monophosphate (8-Br-cGMP) and was blocked by 5 mmol/1 Ba²⁺. The K⁺ channel blocker 293 B (1O)) mol/l) depolarized basal V_m by 4.3 ± 0.4 mV (n = 8), but failed to inhibit the hyperpolarization induced by CDD/ANP-99-126 (160 nmol/1) (n = 8). The K⁺ channel opener cromakalim (10 mol/1) neither influenced basal V_m nor altered the hyperpolarization induced by 160 nmol/1 CDD/ANP-99-126 (n = 8). Adenosine (100 mol/1) hyperpolarized V_m by 13.4 ± 1.3 mV (n = 16). At 100 mol/1, 293 B did not inhibit the adenosine-induced hyperpolarization (n = 6). At 160 nmol/l, CDD/ANP-99-126 enhanced the adenosine-induced hyperpolarization significantly by 1.5 ± 0.6 mV (n = 10). CDD/ANP-99-126 (160 nmol/1) failed to modulate the value to which V_m depolarized in the presence of 1 nmol/l angiotensin II (n = 10), but accelerated the repolarization to basal V_m, by 49 ± 20% (n = 8). These results indicate that the natriuretic peptides CDD/ANP-99-126, CDD/ANP-95-126 and BNP hyperpolarize rat MC probably due to an increase of a K⁺ conductance. This effect modulates the voltage response induced by angiotensin II. The natriuretic-peptide-activated conductance can be blocked by Ba²⁺, but not by 293 B and cannot be activated by cromakalim. This increase in the K⁺ conductance seems to be additive to that inducable by adenosine, indicating that different K⁺ channels are activated by these hormones.     

Urodilatin: a new peptide with beneficial effects in the postoperative therapy of cardiac transplant recipients

Summary Renal failure after heart transplantation (HTx) still remains a serious problem, especially when cyclosporin A is used for immunosuppression in the early postoperative therapy. To preserve good renal function without reducing immunosuppressive cyclosporin A treatment, we administered urodilatin (CDD/ANP-95-126) in a long-term, low-dose infusion in addition to the usual medication after heart transplantation. From November 1990 to June 1991, 51 patients (46 male and 5 female; mean age 48 years) were treated with a 620 ng/kg bw·min infusion for 96 h after HTx. The renal function and hemodynamic parameters of these urodilatin-treated patients were compared in this sequential study with 40 patients (33 male and 7 female; mean age 49 years) who had undergone HTx previously from May to November, 1990, as controls. In this phase IIa study, both groups did not differ significantly with respect to age, sex, indication for HTx, and preoperative renal function. In comparison with controls patients treated with urodilatin had a significantly better renal function: a reduction in the peak plasma creatinine (PC values day 4 : 1.5 ± 0.11 vs. 2.19 ± 0.19 mg/dl; P = 0.002), a lower peak serum urea (SU values day 4 : 109 ± 8 vs. 154.7 ± 8.94 mg/dl ; P = 0.0036), and a lower incidence of hemodialysis (6% vs. 10%) were observed. Adequate diuresis was maintained in spite of the reduction of furosemide by more than 60% (P = 0.005) on each day of urodilatin infusion in comparison with controls. The mean central venous pressure was significantly lower by about 50% (P = 0.02) during the administration of urodilatin in spite of reduced vasodilator medication with nitroglycerin. From this phase IIa study, we may conclude that urodilatin could be an important drug in intensive care treatment. For patients undergoing HTx, this peptide seems to be indicated for the improvement of renal function and cardiovascular status, especially in postoperative therapy using high-dose cyclosporin A treatment.Abbreviations ACE angiotensin converting enzyme - ANP atrial natriuretic polypeptide - ATG antithymocyte globulin - bpm beats per minute - bw body weight - CDD cardiodilatin - CDD/ANP-99-126 circulating form of vasorelaxant cardiac peptide - CHD coronary heart disease - CyA cyclosporin A - DCM dilated cardiomyopathy - GLM general linear model - hANP human atrial natriuretic polypeptide - HTx heart transplantation - NTG nitroglycerine - PC plasma creatinine - SU serum urea - SAS statistical analysing system     

Characterization of the 5′-flanking region and chromosomal assignment of the human brain natriuretic peptide gene

Brain natriuretic peptide (BNP) is a cardiac hormone that occurs predominantly in the ventricle, and synthesis and secretion of BNP are greatly augmented in patients with congestive heart failure and in animal models of ventricular hypertrophy. In order to elucidate the molecular mechanisms underlying the human BNP gene expression in the heart, the human BNP gene was isolated from a size-selected genomic minilibrary. The 1.9-kb human BNP 5-flanking region (–1813 to +110) contained an array of putative cis-acting regulatory elements. Various lengths of the cloned 5-flanking sequences were linked upstream to the bacterial chloramphenicol acetyltransferase (CAT) gene, and their promoter activities were assayed. The 1.9-kb promoter region showed a high-level CAT activity in cultured neonatal rat ventricular cardiocytes. When the CT-rich sequences (–1288 to –1095) were deleted, the high-level activity was reduced to approximately 30%. The 399-bp BNP 5 flanking region (–289 to +110) showed approximately 10% activity of the 1.9-kb region. Furthermore, using human-rodent somatic hybrid cell lines, the BNP gene was assigned to human chromosome 1, on which the atrial natriuretic peptide gene is localized. The present study leads to a better understanding of the molecular mechanisms for the human BNP gene expression in the heart.Abbreviations ANP Atrial natriuretic peptide - AP-1 Activator protein-1 - BNP Brain natriuretic peptide - CAT Chloramphenicol acetyltransferase     

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.     

Localization of the bronchodilator effect induced by type A natriuretic peptide in asthmatic subjects

Type A natriuretic peptide (CDD/ANP99-126) in its circulating form was analyzed with respect to the localization of its bronchodilating effects in asthmatic subjects in vivo. The intravenous infusion of 5.7, 11.4, and 17.1 pmol kg^–1 min^– CDD/ANP-99-126 caused a significant bronchodilation of both central and peripheral airways. While the localization of the bronchodilating effects was similar to ₂-agonists, an improvement in lung function parameters comparable to these substances was not observed. But other members of the natriuretic peptide family may reveal a stronger bronchodilating potency.Abbreviations FEV forced expiratory volume in 1 s - FVC forced vital capacity - PEF peak expiratory flow - MEF₇₅, MEF₅₀, MEF₂₅ maximal expiratory flow at 75%, 50%, 25% of forced vital capacity Correspondence to: T. Edge     

Atrial natriuretic peptide has no direct effect on proximal tubule sodium and water reabsorption

Infusion of ANP has been shown to increase the urinary excretion of sodium and water. However it is still controversial in which tubular segment sodium reabsorption is inhibited. To clarify this problem we have performed in vivo and in vitro studies to examine the direct effect of ANP on rat proximal tubules. The in vivo effect of ANP has been tested by using the micropuncture technique and in particular the shrinking droplet method that allows each investigated tubule to serve as its own control. Addition of either low (10^–9 M) or high (2×10^–6 M) concentrations of ANP to the luminal perfusate resulted in no significant change in isotonic fluid reabsorption (J _v). The same holds when the proximal tubules were perfused on both the tubular and peritubular side, with modified Ringer solution containing 10^–9 M ANP. To examine possible in vitro effects of ANP we prepared highly purified proximal tubule suspension derived from rat renal cortex and monitored oxygen consumption (QO₂) that is tightly coupled to sodium transport in this segment. Synthetic ANP, either at low (10^–9 M) or at high (10^–6 M) concentrations, did not affect basal rate of tubular respiration. Moreover the peptide hormone (10^–9 M) did not inhibit nystatin stimulated and ouabain sensitive QO₂. These results indicate that the enhancement of renal sodium excretion induced by ANP is not related to a direct inhibition of sodium transport in the proximal tubule.     

黄芪水提物对阿霉素肾病大鼠ANP抵抗的改善作用及其机制研究

目的：研究黄芪水提物(ARE)对阿霉素肾病大鼠心房利钠肽(ANP)抵抗的影响，并探讨其机制。方法:雄性SD大鼠随机分为正常对照组、阿霉素肾病模型组(ADR)、ADR＋黄芪水提物(2.5 g·kg^-1·d^-1)组及ADR＋苯那普利(10 mg·kg^-1·d^-1)组。用药6周后观察大鼠在2%体重生理盐水扩容情况下的利钠反应、血浆ANP的浓度、尿环鸟苷酸(cGMP)排泄量(U_cGMPV)、肾内髓组织磷酸二酯酶5(PDE5)活性及蛋白表达水平。结果:ADR大鼠扩容后，尽管血浆ANP水平较正常大鼠明显增加，其利钠反应和U_cGMPV却显著降低(P<0.01)。ARE能部分恢复大鼠扩容利钠反应，显著增加尿钠排泄量(U_NaV)及U_cGMPV (P<0.01)。ARE明显抑制肾内髓组织PDE5活性［(6.8±0.8）nmol·g^-1·min^-1 vs (9.9± 1.1）nmol·g^-1·min^-1，P<0.01］及蛋白表达 (1.0±0.1 vs 1.4±0.2, P<0.01)。结论:ARE能显著改善阿霉素肾病大鼠ANP抵抗，其机制可能与其抑制PDE5活性及蛋白表达有关。     

Presence of immunoreactive atrial natriuretic peptide in nerve fibres and conduction cells in the conduction system of the bovine heart

Previous findings of atrial (A-type) natriuretic peptide (ANP) in nervous tissue, such as the brain and the superior cervical ganglia, led us to investigate the possible occurrence of ANP in nervous tissue in the heart. The distribution of ANP in the bovine heart, particularly its conduction system, was examined by the use of immunohistochemical methods and an antiserum against -hANP. ANP immunoreactivity was frequently detected in atrial myocytes and in the Purkinje fibres of the AV-bundle, and was sometimes seen in the Purkinje fibres of the bundle branches and their ramifications. On the other hand, ANP immunoreactivity was never seen in the conduction cells of SA- and AV-nodes. ANP immunoreactivity was also detected in small nerve-fibre varicosities, mainly in the AV-node and AV-bundle. Most of these varicosities were located in the proximity of the conduction cells, but some occurred close to fine blood vessels or in the walls of arterioles. These observations show for the first time that ANP immunoreactivity is present not only in atrial myocytes and conduction cells but also in nerve-fibre varicosities in the conduction system. The observations suggest that ANP may act as a neuromodulator and/or neurotransmitter in the conduction system.     

Erhöhtes atriales natriuretisches Peptid (ANP) bei essentieller Hypertonie — Abhängigkeit vom rechtsatrialen Druckverhalten

Summary The role of atrial natriuretic peptide (ANP) in the pathogenesis of essential hypertension has not yet entirely been clarified. We investigated whether the increase of ANP in essential hypertension may be explained by elevated right atrial pressures and/or a different relationship between right atrial pressures and ANP secretion. Patients with stable essential hypertension undergoing right and left heart catheterization because of suspected coronary heart disease had significantly higher ANP levels than normotensives: 58.7±6.7 pg/ml in hypertensives versus 42.0±4.1 pg/ml in normotensives (p<0,01). Matching hypertensives with normotensives at identical levels of left ventricular enddiastolic pressure revealed significantly higher mean pulmonary artery pressures in hypertensives. Right atrial diastolic pressure (v-wave) after matching for LVEDP was 4.8±0.5 mm Hg in hypertensives and 3.1±0.2 mm Hg in normotensives (p<0.05). In addition, at any given mean right atrial pressure hypertensives showed higher ANP levels than normotensives. These results demonstrate that hypertensives exhibit raised pressures in the pulmonary artery independent of left ventricular pressure load. The elevation in right atrial pressures and the steeper relationship between these pressures and ANP are a suitable explanation for raised ANP levels in hypertension. ANP in essential hypertension may represent a counterregulation against elevated pulmonary resistance.

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Abkürzungsverzeichnis ANP Atriales natriuretisches Peptid - LVEDP Left ventricular enddiastolic pressure (Linksventrikulärer enddiastolischer Druck) - RAO Right anterior oblique (Aufnahmetechnik von rechter schräger Bildröhrenposition aus) - SEM Standard estimate of the mean (Standardabweichung dividiert durch die Wurzel aus der Fallzahl) - HT Hypertoniker - NT Normotoniker Mit Unterstützung der Deutschen Forschungsgemeinschaft     

The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure

The nocturnal secretion profile of the newly identified natriuretic peptide (NP), brain natriuretic peptide (BNP), was studied in 14 patients with obstructive sleep apnoea syndrome (OSAS) (apnoea hypopnoea index: 60.5±3.4, mean±SE) during two separate nights before and during nasal continuous positive airway pressure (NCPAP) therapy. Plasma levels of NPs (atrial natriuretic peptides; ANP and BNP) were measured at 2-h intervals during sleep. Simultaneously, blood pressure was measured by a non-invasive method (Finapres^®, Ohmeda, Englewood, CO, USA) and urine was collected for determing volume and catecholamine levels. Urinary and serum sodium concentration were determined before and after the study. Eight non-snoring subjects were also studied for the investigation of normal nocturnal profiles of BNP levels. To understand the discrete secretion profiles of the two NPs during sleep, blood was sampled from an additional seven patients every 5 min over a 30-min period around 00.00 and 04.00 hours before NCPAP. In patients with OSAS, plasma BNP levels increased from the beginning of sleep (22:00 h) to the morning (06:00 h) before NCPAP therapy (P< 0.01, anova ). Baseline BNP levels were not significantly correlated with patient's clinical and poly- somnographic parameters. However, in the latter half of the sleep period (02:00–06:00 h), increases in BNP levels during the night before NCPAP therapy were significantly correlated with blood pressure elevations (systolic: r=0.784 P< 0.01, diastolic: r=0.587 P< 0.01) and with apnoea duration (r=0.582 P< 0.01). In normal subjects BP and BNP levels were not changed significantly during sleep. Plasma BNP levels were well correlated with concomitant ANP levels (P< 0.001). NCPAP therapy reduced ANP and BNP levels during sleep and in the morning (P< 0.01). Plasma levels of BNP at 5 min intervals before NCPAP therapy revealed few variations. On the other hand, ANP levels fluctuated over the 30-min period. Changes in BNP levels during sleep in the patients with OSAS may be related to blood pressure variations, but may be too small to play a significant physiological role in regulating diuresis in OSAS. Further work is required to determine the precise role of dual natriuretic system in cardiovascular load and natriuresis in OSAS.