Differential haemodynamic effects of atrial natriuretic peptide (ANP) in normotensive and spontaneously hypertensive rats

Central haemodynamic parameters and cardiac performance were measured in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) control rats after a 10-min infusion of rat ANP (103-125), 1 micrograms kg-1 min-1. Mean Arterial blood pressure (MAP) decreased by approximately 10% in both groups of rats. Heart rate (HR) increased slightly in both strains during the infusion. In the normotensive group the fall in MAP was due to a reduction in cardiac output (CO) while in the SHR there was a decrease in CO as well as in total peripheral resistance (TPR). The ANP infusion also reduced central blood volume (CBV) and stroke volume (SV) in both groups of rats. The reduction in CBV and CO was significantly more pronounced in the WKY strain. Left ventricular end diastolic pressure (LVEDP) and cardiac contractility (dP/dt) did not change while central venous pressure (CVP) was slightly decreased in the WKY group as a result of the ANP infusion. We conclude that ANP reduces MAP in normotensive animals by a reduction in CO. In the SHR a reduction in TPR also contributes to the fall in MAP. Atrial natriuretic peptide did not exert any negative inotropic effects, but the reduction of CO was due to an increased venous compliance.     

Haemodynamics and plasma ANP (atrial natriuretic peptide) after acute blood volume expansion in normotensive and spontaneously hypertensive rats

Atrial natriuretic peptide (ANP) was measured in plasma during acute volume load in conscious, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. During basal conditions immunoreactive ANP were similar in the SHR (630 +/- 56 pmoles l-1) and the WKY (657 +/- 114 pmoles l-1) groups. An acute 10% and 20% whole blood volume expansion resulted in a linear increase in immunoreactive plasma ANP in the WKY. In the SHR the increase in plasma ANP was attenuated during the 20% volume load. During the 10% and 20% volume load central venous pressure (CVP), central blood volume (CBV) and cardiac output increased relatively more in the SHR compared with the WKY group. In contrast, the increase in peripheral blood volume (PBV) and decrease in heart rate (HR) was attenuated in the SH rats. In the SHR group there was a shift of the ANP vs. CVP and ANP vs. CBV curves to the right compared with the WKY. We conclude that acute volume loading is a potent stimulus for ANP release in WKY as well as SHR. However, in the SHR, ANP release was blunted in spite of the increased centralization of the volume load in this rat strain. Thus, the decreased responsiveness of the ANP hormonal system may contribute to the development and maintenance of hypertension in this genetic form of hypertension.     

Renal and cardiovascular effects of atrial natriuretic peptide in Wistar-Kyoto and spontaneously hypertensive rats during a chronic salt loading

Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were maintained on tap water or 1.5% NaCl for 3 weeks. During the high sodium regime 24-h urinary sodium excretion increased 10-fold and the basal blood pressure increased in the SHR. After 3 weeks the rats received arterial (carotid artery), venous and bladder catheters (suprapubic). Saline was infused continuously and in conscious rats atrial natriuretic peptide (alpha-hANP) was administered as bolus injections (8 and 16 nmol kg-1) and the blood pressure and heart rate and the urinary excretions of sodium, potassium (flame photometry), noradrenaline and dopamine (HPLC) were followed at 5-min intervals. The administration of ANP caused a short-lasting blood pressure reduction, tachycardia, diuresis and increased urinary excretions of sodium, potassium, noradrenaline and dopamine. The blood pressure responses to ANP did not differ between the rat strains, irrespective of the diet. The natriuresis and diuresis to ANP was reduced in animals on a high sodium diet, especially in the SHR. This may be interpreted as a down-regulation of target organ responsiveness to ANP during a high sodium diet and the inappropriately large decrease in the responsiveness that was observed in the SHR may be related to increase in blood pressure during the high sodium diet.     

Effects of atrial natriuretic peptide (ANP) on jejunal net fluid absorption in the rat

The role of atrial natriuretic peptide (ANP) on jejunal net fluid transport was studied in intact rats as well as in rats subjected to a perivascular denervation of the intestinal segment. In rats with intact nerves, an acute volume expansion with 5% albumin (10% of estimated blood volume) decreased jejunal net fluid absorption by approximately 70% compared to control animals not subjected to volume expansion. After a perivascular denervation of the intestinal segment, the acute volume expansion reversed net fluid absorption into a net fluid secretion. In order to reduce the volume expansion-induced endogenous release of ANP, one group of rats was subjected to a right atrial appendectomy 7 days prior to the experiments. In these animals, the intestinal response to the same 10% volume load was blunted compared to controls. Administration of rat alpha-ANP (99-126; 5 micrograms kg-1 i.v.) induced effects similar to those of volume expansion both in rats with intact perivascular nerves as well as in denervated animals. Volume expansion increased mean arterial pressure (MAP) as well as central venous pressure and decreased heart rate (HR) in all groups. When exogenous ANP was administered, a fall in MAP was seen, while HR remained unchanged. In conclusion, these data strongly indicate a physiological role for ANP in jejunal fluid transfer in response to acute volume expansion.     

Effects of atrial natriuretic peptide (ANP) during converting enzyme inhibition

Studies were performed on anesthetized adult Münich-Wistar rats to investigate the role of angiotensin II in the natriuretic response to synthetic atrial natriuretic peptide (ANP, 28 amino acids). For this purpose the whole kidney glomerular filtration rate (GFR) and urinary excretion of electrolytes were measured in groups of animals pretreated with the converting enzyme inhibitor captopril (3 mg h-1 kg-1 body wt) or vehicle and then given a continuous intravenous infusion of ANP at 10 micrograms h-1 kg-1 body wt. In the vehicle-pretreated animals, 45 min of ANP infusion did not change GFR (control value 1.17 +/- 0.11, experimental value 1.17 +/- 0.06 ml min-1 g-1 kidney wt). Sodium excretion (UNaV) increased more than three-fold from 0.036 +/- 0.010 to 0.134 +/- 0.058 mumol min-1 g-1 kidney wt (p less than 0.05) and potassium excretion (UKV) increased from 0.481 +/- 0.055 to 0.946 +/- 0.068 mumol min-1 g-1 kidney wt (P less than 0.05). Urine osmolality (UOsm) remained unchanged, while the blood pressure (BP) decreased by 15%. In animals pretreated with captopril, ANP infusion led to a decrease in GFR from 1.27 +/- 0.11 to 1.05 +/- 0.09 ml min-1 g-1 kidney wt (P less than 0.05). Despite this effect, UNaV increased more than two-fold from 0.076 +/- 0.020 to 0.193 +/- 0.087 mumol min-1 g-1 kidney wt (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of calcium supplementation and deoxycorticosterone on plasma atrial natriuretic peptide and electrolyte excretion in spontaneously hypertensive rats

The effects of calcium and the mineralocorticoid deoxycorticosterone (DOC) on blood pressure were studied in four groups of spontaneously hypertensive rats (SHR): (1) control; (2) calcium; (3) deoxycorticosterone and; (4) deoxycorticosterone + calcium. Calcium was given as 1.5% calcium chloride in drinking fluid and deoxycorticosterone by weekly subcutaneous injections (25 mg kg^-1). During the nine weeks of treatment the increase in systolic blood pressure was enhanced in the deoxycorticosterone and attenuated in the calcium group, whereas the deoxycorticosterone + calcium group did not deviate from control. Total plasma calcium was elevated in the calcium group. Plasma concentrations of sodium and atrial natriuretic peptide (ANP) were increased by deoxycorticosterone while neither of the calcium-treated groups differed from control in these respects. Urinary excretions of calcium and sodium were increased in both groups receiving calcium, and also the deoxycorticosterone group excreted more calcium into urine than the control. Adrenergic nerve density in a section of the mesenteric artery and the urinary excretion of noradrenaline and adrenaline were similar in all study groups. The results indicate that calcium supplementation can attenuate the development of hypertension and prevent the deoxycorticosterone-induced blood pressure rise in SHR, possibly by influencing sodium metabolism as seen in increased natriuresis, and by preventing the actions of deoxycorticosterone on sodium balance.     

Effects of calcium supplementation and deoxycorticosterone on plasma atrial natriuretic peptide and electrolyte excretion in spontaneously hypertensive rats.

The effects of calcium and the mineralocorticoid deoxycorticosterone (DOC) on blood pressure were studied in four groups of spontaneously hypertensive rats (SHR): (1) control; (2) calcium; (3) deoxycorticosterone and; (4) deoxycorticosterone + calcium. Calcium was given as 1.5% calcium chloride in drinking fluid and deoxycorticosterone by weekly subcutaneous injections (25 mg kg-1). During the nine weeks of treatment the increase in systolic blood pressure was enhanced in the deoxycorticosterone and attenuated in the calcium group, whereas the deoxycorticosterone + calcium group did not deviate from control. Total plasma calcium was elevated in the calcium group. Plasma concentrations of sodium and atrial natriuretic peptide (ANP) were increased by deoxycorticosterone while neither of the calcium-treated groups differed from control in these respects. Urinary excretions of calcium and sodium were increased in both groups receiving calcium, and also the deoxycorticosterone group excreted more calcium into urine than the control. Adrenergic nerve density in a section of the mesenteric artery and the urinary excretion of noradrenaline and adrenaline were similar in all study groups. The results indicate that calcium supplementation can attenuate the development of hypertension and prevent the deoxycorticosterone-induced blood pressure rise in SHR, possibly by influencing sodium metabolism as seen in increased natriuresis, and by preventing the actions of deoxycorticosterone on sodium balance.     

Increased plasma levels of atrial natriuretic peptide (ANP) in patients with paroxysmal supraventricular tachyarrhythmias

Atrial natriuretic peptide (ANP) is a cardiac hormone originating from atrial cardiocytes. It seems to be involved in the regulatory control of circulating volume and vascular tone. Plasma immunoreactive atrial natriuretic peptide (IrANP) was investigated in 22 patients with paroxysmal supraventricular tachyarrhythmia (16 with atrial fibrillation, 4 with atrial flutter, one with a Wolf-Parkinson-White syndrome (WPW) and one with atrial tachycardia). During the aute attack, IrANP was significantly increased (125.3 +/- 11.4 pmol/l) compared to samples obtained during convalescence (55.9 +/- 4.7 pmol/l). Heart rate (HR) was 144 +/- 4.3 beats/min during the arrhythmia and 75 +/- 2.6 during convalescence. The reduction of IrANP in plasma from the acute attack of tachycardia to follow-up was significantly related to the reduction of HR (p less than 0.05). Irrespective of type of paroxysmal supraventricular tachyarrhythmia, 50% of the patients experienced polyuria during the attack. This symptom was more frequent in younger patients with a shorter duration of tachycardia. Polyuria patients had a higher HR during the attack of supraventricular tachycardia. Even though polyuria was not always found in the patients with the highest IrANP values, the symptom was associated with significantly higher concentrations of IrANP in plasma compared to the non-polyuria group. We conclude that IrANP is increased in plasma during acute attacks of paroxysmal supraventricular tachycardia. Furthermore, the polyuria frequently associated with this condition may partly be due to excess release of ANP from cardiac myocytes.     

Basal and stimulated plasma atrial natriuretic peptide (ANP) concentrations and cardiac ANP contents in old and young rats.

To investigate the ability of the ageing heart to release atrial natriuretic peptide (ANP) we compared the response of awake, trained, chronically catheterized old (20-21 months) and young (4 months) rats to an acute, hypertonic saline challenge. There were no differences between young and old rats in basal plasma concentration of sodium (PNa; old: 141 +/- 3 meq/l; young: 143 +/- 3 meq/l) or ANP (old: 61 +/- 5 pg/ml; young: 67 +/- 12 pg/ml). Five minutes after acute saline challenge, PNa rose in both groups (old: 146 +/- 2 meq/l; young 149 +/- 1 meq/l) and approximately 3-fold increases in plasma ANP levels (182 +/- 24 pg/ml; young: 179 +/- 42 pg/ml). Hearts of old and young rats were assayed for atrial and ventricular ANP content. Atrial ANP levels were similar in old and young rats (13.5 +/- 3.6 vs. 24.9 +/- 8.7 micrograms/g atrial tissue), whereas ventricular ANP content was approximately 4-fold higher in old vs. young rats (153.7 +/- 39.3 vs. 47.5 +/- 6.4 ng/g ventricular tissue). Thus, the ageing rat heart responds equally as well as the young rat to an acute NaCl challenge.     

Relationship between renal sympathetic activity and diuretic effects of atrial natriuretic peptide (ANP) in the rat

The effects of various adrenergic agonists and antagonists on the diuretic/natriuretic effects of rANP (103-125) were investigated in conscious and anaesthetized normotensive rats. Pharmacological sympathetic inhibition by reserpine completely inhibited the diuretic/natriuretic effects of ANP. However, surgical renal nerve denervation did not influence the renal response to ANP. Further studies using various pharmacological agents which interfere with adrenergic activity revealed that the diuretic mechanism of action differed between conscious and anaesthetized animals. In the anaesthetized group only, dopamine (D1) blockade reduced ANP-induced diuresis. In the conscious as well as anaesthetized rats, however, pre-synaptic dopamine (D2) stimulation and alpha 2-adrenergic receptor blockade effectively inhibited the renal response to ANP. The results of this study are compatible with the notion that ANP acts indirectly within the kidney via interaction with dopamine-containing neuronal or non-neuronal structures in the kidney.     

Demonstration of atrial natriuretic peptide/cardiodilatin (ANP/CDD)-immunoreactivity in the salt gland of the pekin duck

Summary A novel peptide hormone, atrial natriuretic factor/cardiodilatin (ANP/CDD), was recently isolated and characterized from mammalian heart. Its presence has been demonstrated in several organs that contribute to water and sodium homeostasis, such as salivary glands. This study demonstrates the presence of ANP/CDD immunoreactivity in the salt gland of Pekin ducks by high performance liquid chromatography, radioimmunoassay and immunocytochemistry, using a specific antibody against atriopeptide I. A small number of distinct, ovoid or cuboid shaped ANP/CDD-immunoreactive cells were localized in the connective tissue surrounding and separating the central secretory tubules, whereas no immunostaining was observed in the peripheral tubules. Salt glands of ducks that were adapted to salt water revealed a significant hypertrophy of their secretory lobules. However, no differences were found between the number or localization of immunoreactive cells in the salt gland of salt water-acclimatized ducks and non-stimulated glands of ducks that were housed with ad libitum access to fresh water. Our results indicate that ANP/CDD may play a role in the regulation of sodium secretion in the salt gland of aquatic birds.Supported by the Walter-Schulz-Stiftung and Deutsche Forschungsgemeinschaft DFG, We 608/8-2Dedicated to Prof. Dr. med. Dr. phil. h.c. D. Starck on the occasion of his 80th birthday     

Localization of 125I-atrial natriuretic peptide (ANP) in the rat fetus.

Summary In this in vitro autoradiographic study of ANP-binding sites in fetal rats, ¹²⁵I-ANP bound to receptors in certain developing neural crest derivatives, including the boundary caps, dorsal root ganglia, and Schwann cells of peripheral nerves. Within the spinal cord, ANP receptors were localized in the roof plate and floor plate. The developing meningeal layer of the CNS, blood vessels, lung, liver, and wall of the herniated gut were also labeled. The topographical and temporal correlation of the appearance of ANP receptors with the developmental processes of the targets suggests that ANP in the fetus is multifunctional, and may be involved in diverse events such as gliogenesis, formation of axonal pathways or surfactant production.     

The existence of low concentrations of atrial natriuretic peptide (ANP) in canine cerebrospinal fluid which does not correlate with plasma ANP levels

Atrial natriuretic peptide (ANP) concentrations in the cerebrospinal fluid (CSF) and plasma of canine were 2.1 +/- 1.1 pg/ml (mean +/- S.D.) and 53.1 +/- 21.1 (n = 20), respectively. The regression coefficient between these concentrations was -0.0045 (P = n.s.). The ANP concentration in the CSF did not change even after the plasma ANP concentration was altered following the change of left atrial pressure, as in 4 cases of an experimental aortic regurgitation. Thus, ANP concentration in the CSF is not influenced by ANP concentrations in the plasma at least under our condition. Gel permeation chromatography revealed a single form of ANP in the position of authentic alpha-ANP in canine CSF, while a high molecular weight ANP peak was observed as well as alpha-ANP in the plasma.     

Effect of extracellular fluid volume contraction and expansion on plasma atrial natriuretic peptide (ANP) concentration in patients with acromegaly

Atrial natriuretic peptide (ANP) is a hormone release into the circulation by atrial cardiocytes (Gutkowska et al. 1984). Extracellular fluid volume expansion acts as a powerful stimulus for ANP secretion and results in the augmentation of its plasma concentration (Lang et al. 1985). Patients with active acromegaly demonstrate the increased extracellular fluid volume (Falkheden et al. 1964), while a successful treatment of the disease results in the disappearance of hypervolemia (Strauch et al. 1977). We have recently demonstrated that in patients with active acromegaly the increased total body plasma volumes are accompanied by the elevated plasma ANP concentrations, whereas, in the successfully treated patients, both: total plasma volumes and plasma ANP levels do not differ significantly from these in healthy subjects (Czekalski et al. 1988b).     

Development of immunoreactive atrial natriuretic peptide in fetal hearts of spontaneously hypertensive and Wistar-Kyoto rats

Summary The development of immunoreactive atrial natriuretic peptide (ANP) was studied in fetal hearts of spontaneously hypertensive (SHR) and compared to normotensive Wistar-Kyoto (WKY) rats. While SHR fetal hearts were noticeably less developed than those of WKY at 10 and 11 days gestation, both strains showed ANP immunoreactive cells in some but not all primitive heart tubes. At 12 days additional ANP immunoreactive cells appeared in formative trabeculae of the ventricle and atrium. ANP cells were also observed in the myogenic layer of the truncus and bulbus arteriosus and their derivatives from 11 through 16 days, but not at 18 days. In both strains, there were more ANP cells in the left ventricle than in right beginning at day 13. There were no obvious strain differences in the developmental pattern and timing of ANP producing cells. However, on the day of birth, staining was reduced in hearts from some WKY newborn pups compared with hearts from SHR newborns and ventricular staining was reduced in both strains when compared to fetal hearts. These observations indicate that ANP is one of the earliest peptide hormones produced and that the predisposition to genetic hypertension does not appear to influence the development of ANP.     

Postural changes in atrial natriuretic peptide (ANP) and fluid balance in conscious goats.

To gain insight into how weak physiological stimuli suffice to release ANP, the effects of 15 degrees head-up and head-down tilt, 90 min each in succession, on plasma atrial natriuretic peptide (ANP), plasma cortisol, plasma and urinary Na, K and osmolality, plasma proteins and haematocrit were studied in five conscious goats before and after 2 wk daily training for the tilting procedure. In the trained goats the 15 degrees tilt did not affect the plasma ANP, cortisol or the urine excretion significantly. Total plasma proteins decreased significantly. In the untrained goats, on the other hand, an increasing trend was observed in the plasma ANP and cortisol as well as in the urine Na excretion during the head-up tilt. During the head-down tilt, the levels of ANP and Na excretion remained elevated. The plasma ANP was significantly increased after 40 min, by 28% as compared to the pre-tilting level. The plasma cortisol was first elevated, but then returned to the starting level. The results suggest that in the trained goats the responses to tilting were unmasked. Despite minor effects of the 15 degrees tilt in itself, increased plasma ANP seemed to be associated with increased natriuresis.     

Organ extraction of atrial natriuretic peptide (ANP) in man. Significance of sampling site

Arterial plasma immunoreactivity of endogenous human alpha-atrial natriuretic peptide (ANP) underwent mean 54%, 28% and 40% extraction during one passage through the circulation in the kidney (n = 12), liver-intestine (n = 14) and lower limb (n = 8), respectively, in supine fasting subjects with no detectable disease or subjects with cardiovascular or hepatic disorders of minor degree undergoing a haemodynamic investigation. No extraction was identified across the lungs as evaluated by the same concentration of ANP in pulmonary and femoral arteries (n = 7). The concentration of ANP in a superficial arm vein relative to the femoral artery varied considerably and extractions from 0% up to 58% were identified (mean 18%). The results suggest a high degree of, but only to some extent selective, extraction of ANP, which may account for its proposed short plasma half-life. Due to the different concentrations of ANP in various vascular beds, sampling site should be thoroughly specified.