NO EFFECT OF ATRIAL NATRIURETIC FACTOR ON CARDIAC RATE, FORCE AND TRANSMITTER RELEASE

1. The effects of atrial natriuretic factor (ANF, 1-300 nmol/l) on cardiac rate, force and neurotransmitter release were examined in guinea-pig isolated heart preparations. 2. Synthetic ANF had little effect on the contractile force of electrically driven papillary muscle regardless of the presence or absence of isoprenaline. 3. The pulse period of spontaneously beating right atria was not affected by ANF. Neither the positive nor negative chronotropic effect of isoprenaline or bethanechol respectively were changed in the presence of ANF. 4. ANF did not affect the release of neurotransmitter from the nerve endings in the isolated atrium. 5. ANF was confirmed to relax isolated aortic rings precontracted with either noradrenaline (ANF, IC₅₀= 3 nmol/l, s.e.m. = 0.2, n= 5) or potassium (ANF, IC₅₀= 24 nmol/l, s.e.m. = 0.2, n= 5). 6. These results demonstrate that ANF within doses effective for vasorelaxation has no appreciable effect on myocardial function or neutrotransmitter release in the heart.     

PLASMA ATRIAL NATRIURETIC PEPTIDE IS INCREASED DURING ATRIAL PACING IN CONSCIOUS RABBITS

The effect of increases in heart rate on plasma atrial natriuretic peptide (ANP) concentrations was investigated in conscious rabbits. Plasma ANP concentrations were significantly increased following abrupt increases in heart rate produced by atrial pacing at 400 beats/min. Pacing at 300 beats/min resulted in smaller increases in plasma ANP concentration. Stepwise increases in heart rate produced by atrial pacing at 250, 300, 350 and 400 beats/min resulted in increases in plasma ANP concentrations at 400 beats/min only. The increase in plasma ANP concentration during atrial pacing correlated significantly with the increase in heart rate achieved.     

ATRIAL NATRIURETIC HORMONES ORIGINATING FROM THE N-TERMINUS OF THE ATRIAL NATRIURETIC FACTOR PROHORMONE

1. Four peptide hormones consisting of amino acids 1–30 (Long Acting Sodium Stimulator), 31–67 (Vessel Dilator), 79–98 (Kaliuretic Stimulator) and 99–126 (Atrial Natriuretic Factor [ANF]) originate from the same 126 amino acid ANF prohormone. 2. Each of these four peptide hormones circulates as a distinct peptide with vessel dilator and long acting sodium stimulator circulating at 10- to 24-fold higher concentrations than ANF while kaliuretic stimulator circulates at a three-fold higher concentration than ANF. 3. Each of these peptide hormones is released with an increase in central volume causing stretch of the atrium of the heart and with rapid heart beats greater than 125 beats/min. 4. Each of these peptide hormones lowers blood pressure, causes a diuresis and enhances sodium and/or potassium excretion. 5. In disease states which retain sodium and water such as congestive heart failure (CHF), each of these atrial peptides increases in the circulation proportionately to the severity of sodium retention, but of the radioimmunoassays to each of these hormones only the vessel dilator radioimmunoassay differentiates between mild (class I) CHF and healthy individuals.     

BLUNTED NATRIURETIC RESPONSE TO ENDOGENOUS ATRIAL NATRIURETIC PEPTIDE DURING RAPID CARDIAC PACING IN ANAESTHETIZED DOGS

1. We investigated whether diuresis and natriuresis induced by endogenous atrial natriuretic peptide (ANP) were blunted during rapid cardiac pacing. 2. Changes in plasma ANP, renal function and haemody-namics during rapid cardiac pacing were studied in anaesthetized closed-chest dogs. Dogs were paced via the right ventricle at a rate of 200 b.p.m. (moderate pacing) or 250 b.p.m. (severe pacing) for 180 min. 3. The maximal increases in plasma ANP and urinary excretion of cGMP during severe pacing were four- and three-fold higher, respectively, than those during moderate pacing. Despite the higher concentration of plasma ANP, the maximal increases in urine volume, urinary excretion of sodium and fractional excretion of sodium during severe pacing were similar to those during moderate pacing. Mean arterial pressure and renal vascular resistance were decreased only by severe pacing. The increase in total peripheral resistance during severe pacing was significantly smaller than that during moderate pacing. However, the glomerular filtration rate was kept at basal levels by both moderate and severe pacing. 4. These results suggest that there are certain mechanisms that counteract renal tubular sodium reabsorption induced by endogenous ANP under conditions of severe pacing. The suppression occurs at tubular sites but not at glomerular sites. One of the possibilities for the suppression is the decrease in renal perfusion pressure accompanied by decreases in peritubular capillary hydrostatic pressure.     

CHF患者cAMP cGMP和NE ANF的变化及临床意义

通过放免法和高压液相色谱－电化学法，测定了９２例充血性心力衰竭（ＣＨＦ）患者血浆环核苷酸（ｃＡＭＰ、ｃＧＭＰ）、心钠素（ＡＮＦ）和去甲肾上腺素（ＮＥ）水平。结果表明：血浆ｃＡＭＰ、ｃＧＭＰ和ＡＮＦ、ＮＥ浓度随着心衰程度加重而显著增加，ｃＡＭＰ／ｃＧＭＰ比值下降，与病因无关；心衰纠正后，上述指标明显恢复。血浆ｃＡＭＰ、ｃＧＭＰ与ＮＥ、ＡＮＦ水平显著相关。提示：血浆环核苷酸浓度同ＮＥ、ＡＮＦ一样，可作为评价ＣＨＦ患者心功能和观察疗效的一种生化指标。     

PLASMA NEUROPEPTIDE Y AND ATRIAL NATRIURETIC PEPTIDE CONCENTRATIONS IN MAN

1. In order to examine the concentration of neuropeptide Y-like immunoreactivity (NPY-LI) and atrial natriuretic peptide (ANP) in the circulation in man, blood was sampled from the iliac vein, the inferior vena cava, the superior vena cava, the pulmonary artery and the femoral artery in 13 patients undergoing cardiac catheterization. 2. Plasma NPY-LI levels were similar at all points sampled and no arteriovenous differences were found. Plasma ANP concentration in the pulmonary artery was greater than in peripheral venous blood but there was a strong correlation between the two. 3. The concentration of NPY-LI and ANP in peripheral venous blood reflects central venous and arterial concentrations.     

AFFERENT CONTROL OF VASOPRESSIN AND RENIN RELEASE DURING HAEMORRHAGE IN NORMAL AND AUTONOMICALLY BLOCKED RABBITS

1. The role of the arterial and cardiac baroreceptors on the arginine vasopressin (AVP) and plasma renin activity (PRA) responses to haemorrhage was studied in conscious rabbits. They were bled at a rate of approximately 3% of their blood volume (BV)/min, both when the autonomic nervous system (ANS) was intact and during ANS blockade, which markedly enhances the AVP response due to the much greater haemodynamic disturbance. Under each condition of ANS function 2 x 2 factorial analysis was performed, each with four groups of rabbits, including animals with both sets of baroreceptors working, one or other set working and neither set working. 2. With intact ANS, haemorrhage had to be terminated at different times in the four groups. This presents problems for factorial analysis due to differences in the relationship between plasma AVP (or PRA) and release rate. A method for overcoming this was developed by extrapolating the BV-log AVP curves to a common time from the start of bleeding. 3. Under both conditions of ANS function the arterial and cardiac baroreceptors together accounted for 90-95% of the rise in AVP during haemorrhage. With normal ANS function, the rise in AVP was about 70% through cardiac (probably ventricular) baroreceptors (P = 0.01) and about 30% through arterial baroreceptors (P = 0.08). This compares with an earlier study at a rate of bleeding of 1.8% BV/min, where the entire drive came from the cardiac receptors. During ANS blockade, plasma AVP was enhanced approximately five-fold, which was mostly mediated through the arterial baroreceptors, but the cardiac baroreceptor component was also greater; arterial/cardiac baroreceptor drive was 2/1. 4. Baroreflexes played no role in renin release during haemorrhage, but the experiments with ANS blockade suggest that a hormonal factor, which was related to the cardiac innervation, may limit the rise in PRA in the latter part of haemorrhage.     

EFFECTS OF VOLUME EXPANSION AND CONTRACTION ON PLASMA LEVELS OF ATRIAL NATRIURETIC PEPTIDE IN MAN

1. Effects of saline infusion and blood removal on atrial natriuretic peptide (ANP) in normal subjects were examined in order to better define the magnitude of acute central volume regulatory influences on ANP. 2. Plasma ANP levels increased progressively during volume expansion with saline infusion, increasing by 18% after 30 min and by 93% after 120 min, and did not change during recumbency alone. 3. Plasma ANP levels immediately after a standard blood donation performed semirecumbent were significantly lower than before blood donation; they fell by 18%. 4. The magnitude of the fall in ANP induced by blood donation correlated significantly with basal plasma ANP. 5. In man, ANP responds to both increases and decreases in central blood volume, consistent with a role for ANP in blood volume homeostasis.     

EFFECTS OF RENAL DENERVATION AND ATRIAL NATRIURETIC FACTOR ON TUBULAR REABSORPTION IN ANAESTHETIZED RATS

1. The effects of acute unilateral renal denervation were examined in 17 anaesthetized rats. Renal haemodynamic changes were monitored using standard clearance techniques. Lithium clearance was used to assess fractional proximal sodium and water reabsorption. 2. Denervation resulted in ipsilateral renal vasodilatation with marked natriuresis and diuresis, a small increase (15%, P less than 0.05) in glomerular filtration rate (GFR) and a consequent reduction in filtration fraction. Fractional lithium reabsorption decreased (67.3 +/- 2.9% to 54.5 +/- 4.0%, P less than 0.01) and absolute proximal reabsorption did not change, indicating impairment of proximal glomerulotubular balance (GTB). No similar changes in haemodynamic or transport parameters were observed in the contralateral, innervated kidney, although vascular resistance increased. 3. In 9 experiments following denervation of the left kidney, systemic low dose infusion (10 ng/min) of atrial natriuretic factor (ANF) resulted in a fall in mean arterial blood pressure from 116 +/- 3 mmHg to 107 +/- 3 mmHg (P less than 0.05). In the denervated kidney ANF increased urine flow rate and sodium excretion to rates above those established following denervation alone. However, in the right kidney, despite the increased filtered load (35%, P less than 0.01), the natriuretic and diuretic responses to ANF were abolished. 4. In the denervated kidney, ANF further reduced the fractional reabsorption of lithium from 53.6 +/- 2.3% to 45.6 +/- 3.8% (P less than 0.05). GFR increased by 32% (a total of 49% higher than during pretreatment) but absolute proximal reabsorption (APR) did not change. However, in the right, innervated kidney ANF infusion produced a 35% increase in GFR accompanied by a 53% rise in APR. 5. It is concluded that the natriuresis induced by unilateral denervation is due predominantly to impaired proximal GTB. The natriuretic action of ANF was associated with further impairment of proximal GTB, not dependent upon decreasing activity of renal sympathetic nerves, but was abolished when filtration fraction and renal sympathetic tone were elevated.     

INTERRELATIONSHIP BETWEEN CORTISOL AND ATRIAL NATRIURETIC FACTOR IN THE IMMATURE OVINE FETUS

1. In chronically cannulated ovine fetuses (100-130 days of gestation) the infusion of cortisol (86.7 +/- 15 micrograms/h for 4 h) or human atrial natriuretic factor (ANF; 4.4 micrograms for 2 h) resulted in highly significant increases in the excretion of sodium, chloride, potassium and water. 2. Cortisol had no significant effect on fetal plasma ANF concentrations. All values are mean and s.e.m. Plasma immunoreactive ANF was 53 +/- 5 and 67.3 +/- 13 pmol/L in the 4 h saline infused fetuses, and 51.3 +/- 14.3 and 74 +/- 13.3 pmol/L in cortisol-infused fetuses (n = 7). A separate group of fetuses received 2 h infusions of saline or hANF (4.4 micrograms/h), and plasma IR-ANF values were measured (n = 3). The values, at 0, 60, 90 and 120 min were, respectively, 19.7 +/- 3, 17.3 +/- 0.7, 18.7 +/- 3.7 and 20.7 +/- 3.7 pmol/L in the saline infused group, and 25.3 +/- 5.3, 80.7 +/- 32.3, 123.3 +/- 4.3 and 100 +/- 15 pmol/L in the ANF-infused fetuses. 3. Blood cortisol concentrations, in fetuses infused for 4 h with 0.9% NaCl, were 3.1 +/- 0.8 nmol/L (n = 7); in fetuses infused with 0.9% NaCl for 2 h were 3.6 +/- 1 nmol/L (n = 3); in fetuses infused for 4 h with cortisol were 19.9 +/- 1.9 nmol/L (n = 7); and in fetuses infused with hANF for 2 h were 6.0 +/- 3.0 nmol/L (n = 5). 4. There was no effect of fetal hANF infusion on maternal or fetal blood aldosterone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

COMPLEMENTARY CHANGES IN PLASMA ATRIAL NATRIURETIC PEPTIDE AND ANTIDIURETIC HORMONE CONCENTRATIONS IN RESPONSE TO VOLUME EXPANSION AND HAEMORRHAGE: STUDIES IN CONSCIOUS NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS

1. Plasma concentrations of atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) were measured in conscious stroke-prone spontaneously hypertensive (SPR), spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats before and after acute volume expansion or haemorrhage. 2. Plasma ANP concentration was reduced to one-third of resting values 30 min after a 1.5% haemorrhage (1.5 ml of blood per 100 g bodyweight). Plasma ADH concentration rose immediately 50-fold on haemorrhage and remained elevated at 30 min. 3. Plasma ANP concentration increased 2.5-fold relative to resting values 1 min after infusion of 2.0 ml per 100 g 5% dextrose; after 10 min plasma ANP remained elevated. Plasma ADH concentration tended to fall on volume expansion although no significant decrease was observed. 4. There was no difference in the basal levels of ANP and ADH, or in the changes produced by alterations in blood volume, in hypertensive SPR and SHR compared with normotensive WKY. 5. Thus, plasma ANP concentrations moved in opposite directions in response to two physiological stimuli: volume expansion and haemorrhage. Reciprocal changes were observed in plasma ADH.     

ATRIAL NATRIURETIC FACTOR IN CHRONIC RENAL FAILURE: STUDIES IN MAN AND THE RAT

1. Plasma concentration and atrial content of atrial natriuretic factor (ANF) were measured in rats with chronic renal failure induced by subtotal nephrectomy. 2. Plasma ANF was higher, and atrial ANF content lower in rats with renal failure when compared with sham-operated controls. 3. Plasma renin activity (PRA) and ANF were elevated at 1 week following subtotal nephrectomy. After 1 month plasma ANF had risen further, but PRA was suppressed to below control values. 4. Plasma ANF was also measured in six patients with chronic renal failure undergoing routine haemodialysis. 5. Elevated plasma ANF levels in patients with renal failure were lowered by haemodialysis, although extraction of ANF across the dialysis membrane was negligible. 6. Secretion of ANF is increased in chronic renal failure in man and the rat, possibly mediated by increased intravascular volume.     

ATRIAL NATRIURETIC PEPTIDE RELEASE IN THE RABBIT IS INDEPENDENT OF CARDIAC NERVE ACTIVITY

1. Changes in plasma atrial natriuretic peptide (ANP) were examined in conscious rabbits in response to a 33% blood volume expansion in intact animals and after blockade of cardiac nerve activity. 2. Blood volume expansion by one-third markedly increased right atrial pressure and resulted in a four-fold increase in plasma ANP. 3. Cardiac nerve blockade with intrapericardial procaine had no effect on resting plasma ANP levels. The ANP responses to volume expansion in the presence of cardiac nerve blockade were similar to those seen in intact animals. 4. Release of ANP from its cardiac stores in response to volume expansion is not influenced by cardiac nerve activity.     

EFFECT OF OPIATE, GENERAL ANAESTHESIA AND SURGERY ON PLASMA ATRIAL NATRIURETIC PEPTIDE LEVELS IN MAN

1. Animal data suggest that opiates, halothane anaesthesia and activation of the sympathetic system stimulates release of atrial natriuretic peptide (ANP). To examine whether this is so in man, venous ANP levels were measured in five patients undergoing elective cholecystectomy. 2. Plasma levels of cortisol, aldosterone, norepinephrine and epinephrine increased 3-6 fold during the study. Cortisol-aldosterone relationships were close in all patients (r = 0.73-0.97), whereas plasma renin activity and aldosterone correlations were strong in only two subjects. 3. Baseline plasma ANP concentrations were within the normal range and were not altered by opiate injection, anaesthesia, or surgery. 4. Unlike experimental animals, man exhibits little or no ANP response to opiates, halothane, or surgical stimulation of the sympathetic nervous system.     

THE PATTERN OF ATRIAL NATRIURETIC PEPTIDE RELEASE DURING VENTRICULAR TACHYCARDIA IN MAN

1. Plasma levels of atrial natriuretic peptide (ANP) are high in many patients with tachycardia, but patterns of release with onset and termination of tachycardia and relationships to haemodynamic recordings are not clear. Blood for ANP measurements was therefore drawn from the coronary sinus, femoral artery and femoral vein, and simultaneous haemodynamic recordings were made in five patients before, during and after induction of stable ventricular tachycardia for 30 min. 2. Tachycardia induced increases in ANP to peak levels, 2.6 to 5.7 times higher than baseline values at 20 min or later, whereas maximum haemodynamic changes, including a rise in pulmonary artery diastolic pressure, were achieved within 4 min. 3. Reversion to sinus rhythm resulted in immediate changes in haemodynamic recordings, whereas ANP levels in arterial and venous plasma fell sluggishly with an apparent half-life of 9.6 and 7 min, respectively. 4. The results support a central role for atrial pressure in determining ANP secretion, but demonstrate a temporal delay between changes in atrial pressure and ANP secretion.     

PLASMA ATRIAL NATRIURETIC PEPTIDE: CONCENTRATIONS AND CIRCULATING FORMS IN NORMAL MAN AND PATIENTS WITH CHRONIC RENAL FAILURE

A specific and sensitive radioimmunoassay has been developed and used to measure circulating atrial natriuretic peptide (ANP) in normal man and in patients with chronic renal failure. Circulating ANP levels rose with head-down tilt and exercise, and were raised in patients with chronic renal failure in proportion to volume status. This suggests that ANP release is mediated via increased atrial stretch, although other release mechanisms cannot be excluded. Extracts of normal human plasma subjected to reverse phase HPLC showed one major peak of immunoreactivity co-migrating with alpha-human ANP. However, when plasma extracts from patients with renal failure were chromatographed on a similar system, a second later eluting peak of ANP immunoreactivity was observed. This may represent circulating ANP precursors or degradation molecules. Significant arteriovenous differences in plasma ANP concentration were observed in patients with chronic renal failure. Arterial and venous plasma ANP levels decreased slightly after haemodialysis. Plasma ANP concentrations were inversely correlated with haematocrit in these patients.     

INTERACTION BETWEEN ATRIAL NATRIURETIC FACTOR AND OUABAIN: VASCULAR REACTIVITY TO NORADRENALINE IN PENTOBARBITAL ANAESTHETIZED DOGS

1. The influence of intra-arterial infusion of rat atrial natriuretic factor (ANF 8-33) and/or ouabain on the vascular responses to noradrenaline was investigated in the denervated and flow-controlled hindlimb preparations in pentobarbital anaesthetized dogs. 2. During the continuous infusions of ANF (30-40 min) vascular responses to noradrenaline were significantly depressed. Subsequent infusion of ouabain together with ANF (50-60 min) reversed and restored the vascular reactivity to the control levels. Hypotension produced by ANF infusion was partially reversed during the simultaneous infusions of both the agents. 3. In a separate series of experiments, in which ouabain was first infused (50-60 min) vascular responses to noradrenaline were significantly enhanced. Subsequent infusions of ANF (plus ouabain) even up to 60 min or longer failed to alter the enhanced vascular responsiveness facilitated by ouabain. 4. The present studies demonstrate a physiological antagonism between ANF and ouabain and such a phenomenon could account for the previous observation that vascular reactivity to noradrenaline was progressively enhanced after acute blood volume expansion. Whereas plasma levels of both ANF and ouabain-like inhibitor(s) of the sodium pump are elevated after volume expansion, inhibitory effects of ANF on the vascular smooth muscle may be compromised in the presence of an Na+ pump inhibitor(s).     

VASOPRESSIN RESPONSE TO HAEMORRHAGE IN RATS: EFFECT OF HYPOXIA AND WATER RESTRICTION

1. The aim of the present study was to determine the effect of water restriction and/or hypoxia on the vasopressin response to haemorrhage in conscious rats. 2. Male, Long-Evans rats (n = 39) were prepared with chronically indwelling femoral artery and vein catheters and exposed to 24 h of one of the following: normoxia with ad lib drinking water (N + W); normoxia with water restriction (N - W); hypoxia with ad lib drinking water (H + W); and hypoxia with water restriction (H - W). At the end of 24 h, a 15 mL/kg arterial haemorrhage was performed. 3. Water restricted rats had elevated pre-haemorrhage vasopressin levels. Haemorrhage induced an increase in vasopressin in all groups. Water restriction (N - W) or hypoxia (H + W) each augmented the vasopressin response to haemorrhage. However, the combination of hypoxia and water restriction (H - W) failed to augment the vasopressin response to haemorrhage as compared to normoxic, water replete (N + W) rats. 4. Hypoxia or water restriction per se augment the vasopressin response to haemorrhage. This augmented vasopressin response to haemorrhage is not maintained when hypoxia and water restriction are combined.     

RENAL DENERVATION POTENTIATES THE NATRIURETIC AND DIURETIC EFFECTS OF ATRIAL NATRIURETIC PEPTIDE IN ANAESTHETIZED RABBITS

1. The role of the renal nerves in modulating the action of atrial natriuretic peptide (ANP) in the kidney was studied by comparing the responses to ANP in innervated and surgically denervated kidneys in anaesthetized rabbits. 2. A low dose of ANP (0.05 μg/kg per min, i.v.) was used to minimize the confounding effects of systemic hypotension. 3. The natriuretic and diuretic responses to ANP were significantly greater in denervated kidneys than in kidneys with intact innervation. Sodium excretion from denervated kidneys rose by 7.49 ± 3.11 μmol/min in response to ANP (-55%, P<0.05) compared to 0.84 ± 0.59 μmol/min (-28%, NS) in innervated kidneys. Urine flow increased markedly in denervated kidneys by 73.2 ± 29.9 μmol/min (-60%, P<0.05) but not in innervated kidneys. 4. Fractional sodium excretion increased significantly in denervated kidneys in response to ANP (median 2.3% to median 3.0%, P<0.05). 5. Renal blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure were unchanged in response to ANP in either denervated or innervated kidneys. Pre-glomerular vascular resistance fell in denervated kidneys during ANP infusion. 6. The natriuresis and diuresis observed in the denervated kidneys, due to an increased fractional excretion of sodium without increases in GFR or glomerular capillary pressure, is consistent with effects of ANP on tubular reabsorption of sodium. 7. Thus, ANP produced a natriuresis and diuresis at a low dose in denervated but not in innervated kidneys. This indicates that reflex activation of renal nerves may antagonize the renal effects of ANP.