Ontogeny of atrial natriuretic polypeptide in the human heart

To elucidate the developmental changes of atrial natriuretic polypeptide in the human heart, we studied alpha-human atrial natriuretic polypeptide (alpha-hANP)-like immunoreactivity (alpha-hANP-LI) in the extracts from the hearts of three foetuses of 10, 14 and 22 weeks' gestation, a 1-day-old premature infant of 33 weeks' gestation, and two adults, alpha-hANP-LI levels in the atria of the three foetuses of 10, 14 and 22 weeks' gestation and the premature infant (31.4, 12.2, 9.25 and 15.3 nmol/g, respectively) were comparable to those in two adult atria (16.9 and 13.6 nmol/g). The ventricles also contained alpha-hANP-LI (0.763----0.0818 nmol/g with descending values with increasing gestational age) in the three foetuses and the premature infant although it was undetectable (less than 0.0162 nmol/g) in two adult ventricles. The highest alpha-hANP-LI concentration was observed in the auricles in all the hearts except in the premature infant. The concentration in the right auricle was higher than in the left during foetal life, whereas that in the left was the higher one after birth. High performance gel permeation chromatography coupled with radioimmunoassay revealed that alpha-hANP-LI in the atria and apexes of the foetuses and the premature infant consisted of gamma-hANP, beta-hANP and alpha-hANP, with gamma-hANP being the predominant form. Essentially similar gel filtration patterns were observed in the two adult atria. These results indicate that: ANP appears in human heart tissue early in foetal life; cardiac ventricles also contain ANP in the foetus, and there is probably no difference in posttranslational processing of the precursor molecule in foetal and adult hearts.     

Phasic plasma atrial natriuretic polypeptide changes in DOCA-salt hypertensive rats

We determined plasma and cardiac immunoreactive atrial natriuretic polypeptide (ir-ANP) levels in rats treated with deoxycorticosterone acetate (DOCA) and sodium chloride for 1, 7, and 28 days. Systolic blood pressure of DOCA-salt rats began to increase from the 7th day and reached 191 +/- 7 mmHg at the 28th day. One day after treatment with DOCA-salt, plasma levels of ir-ANP were increased compared to that of control rats. This was accompanied by decreased cardiac ir-ANP content. However, at the 7th day of DOCA-salt treatment, both plasma and cardiac ir-ANP levels of DOCA-salt rats were not different from those of control animals. At the 28th day, DOCA-salt rats had high plasma ir-ANP levels and no significantly different cardiac ir-ANP content compared to the controls. These data suggest that there are time-related changes in plasma ANP concentration during the development of DOCA-salt hypertension and higher plasma ANP levels might not necessarily be associated with a decreased cardiac ANP content.     

Changes in plasma atrial natriuretic polypeptide concentration during head-out water immersion and saline infusion in normal men

The physiological mechanism regulating secretion of human atrial natriuretic polypeptide (hANP) was examined by measuring plasma hANP by a specific radioimmunoassay during head-out total body water immersion (WI) and saline infusion in normal men. Seven healthy men were immersed in water for 1 hour, 6 normal men and women were given an infusion of 1 liter of normal saline over 1 hour and 8 normal men were given a similar infusion over 2 hours. During WI, the urinary volume (UV) and urinary Na excretion (UNaV) increased significantly, and the plasma hANP level increased significantly from 246 +/- 12 (mean +/- SE) pg/ml to 392 +/- 32 pg/ml after 35 +/- 5 min, but returned to the basal level after 90 min. The increase in hANP level was correlated with an increased UNaV between 30 to 60 min during WI. The plasma norepinephrine, renin activity, aldosterone and cortisol levels also decreased during WI. Saline infusion caused variable increases in the hANP level: the mean peak values of hANP and times of the peaks from the start of saline infusion were respectively 305 +/- 30 pg/ml after 30 +/- 3 min of infusion at a rate of 1L/1 hr and 285 +/- 25 pg/ml after 69 +/- 15 min of infusion at a rate of 1L/2 hrs. The time of the peak of plasma hANP during infusion at 1L/2 hrs was significantly longer than the peaks for WI or an infusion of saline at 1L/1 hr. Moreover, the peak hANP level was significantly smaller during either condition of saline infusion than during water immersion. These results indicate that i) acute central hypervolemia caused by WI increases hANP secretion, and this increase may participate in natriuresis during WI, and ii) saline infusion causes an increase in plasma hANP of variable magnitude, the increase being more rapid for a more rapid infusion of saline. This suggests that hANP is released into the circulation by acute volume expansion and plays a physiologically important role in maintaining blood volume homeostasis in man.     

Insulin-induced hypoglycaemia increases plasma concentrations of angiotensin II and does not modify atrial natriuretic polypeptide secretion in man

Summary Insulin-induced hypoglycaemia causes profound haemodynamic changes, commonly ascribed to catecholamine increase. The aim of the present study was to investigate the influence of insulin-induced hypoglycaemia on nonadrenergic factors potentially involved in haemodynamic regulation: angiotensin II and alpha-human atrial natriuretic polypeptide. Fourteen healthy male subjects, aged 25.5±0.74 years, body mass index 23.81±0.68 kg/m², received (after an overnight fast and at least 60 min rest in a supine position) an i.v. bolus injection of human regular insulin (Actrapid HM, Novo, Bagsvaerd, Denmark: 3.84 U/m²). Serial venous blood samples were drawn in the following 150 min, to measure plasma glucose, angiotensin II, alpha-human natriuretic polypeptide, and factors potentially involved in the regulation of the renin-angiotensin-aldosterone system. During the study, we observed a plasma glucose fall, reaching a nadir of 1.95±0.11 mmol/l between 25 and 30 min, and an increase of angiotensin II (from 7.6±0.8 to 13.5±1.1 pg/ml, p = 0.01, quadratic model evaluated by an analysis of the variance for repeated measures), whereas atrial natriuretic polypeptide remained unchanged. As far as the regulation of the renin-arigiotensin-aldosterone system is concerned, the increase of angiotensin II is attributable to the increased plasma renin activity, whereas angiotensin converting enzyme was not modified. The increase of plasma renin activity, in turn, is attributable both to the increased catecholamine concentrations and to the decreased potassium levels. Both adrenocorticotropic hormone and angiotensin II are potentially involved in the hypoglycaemia-induced increase of aldosterone concentrations.     

Determination of plasma alpha human atrial natriuretic polypeptide using monoclonal antibodies in patients with chronic renal failure

To clarify the molecular nature and dynamics of circulating alpha human atrial natriuretic polypeptide (alpha hANP) in chronic renal disease, the plasma concentrations of alpha hANP were determined by radioimmunoassays using two distinct monoclonal antibodies (MoAbs). One MoAb (10B1) recognized N-terminus of alpha hANP, while the other (C351) recognized the ring structure. The preliminary studies revealed a close correlation (r = 0.97, p less than 0.0001) between plasma alpha hANP measured with 10B1 and C351 MoAbs, supporting the theory that the main circulating form is alpha hANP(1-28). Therefore, the more sensitive radioimmunoassay using MoAb (C351) was used in the present studies. The plasma alpha hANP was 3.8 +/- 1.7 (mean +/- SD) in healthy subjects, 2.7 +/- 1.4 fmol/ml in patients with chronic glomerulonephritis without renal failure, 16.2 +/- 16.8 fmol/ml in patients with chronic renal failure, and 24.3 +/- 10.5 fmol/ml in patients under maintenance hemodialysis. Thus, the elevation of plasma alpha hANP was related to the stages of renal damage. Although the plasma alpha hANP in 18 patients under maintenance hemodialysis declined significantly (p less than 0.01) after hemodialysis, their levels (17.9 +/- 9.0 fmol/ml) after hemodialysis were still higher than those in healthy subjects. On the other hand, a positive correlation (r = 0.65, p less than 0.05) between alpha hANP and creatinine in blood was found only in the group of chronic renal failure before maintenance hemodialysis. These results suggest that an impaired metabolism of alpha hANP in the kidney might play an important role in the elevation of plasma alpha hANP as well as the stimulation of alpha hANP secretion caused by the expansion of extracellular fluid.     

Low plasma concentrations of atrial natriuretic peptide in untreated hypothyroid patients

A group of patients with primary hypothyroidism has been studied, and it is reported that low serum levels of thyroid hormones are accompanied by low plasma atrial natriuretic peptide (ANP) concentrations. While the correlation between ANP and thyroid hormone levels is strong, no correlation was found between ANP and heart rate or arterial blood pressure. It is suggested that thyroid hormones directly stimulate the release of ANP from atrial cardiocytes.     

Alpha-human atrial natriuretic polypeptide inhibits steroidogenesis in cultured human adrenal cells

The ability of synthetic alpha-human atrial natriuretic polypeptide-(1-28) (alpha hANP) to alter steroidogenesis by human adrenal glands was investigated in primary human adrenal cell cultures. alphahANP (10(-9)-10(-7) M) inhibited basal and ACTH (10(-8) M)-stimulated aldosterone, cortisol, and dehydroepiandrosterone (DHEA) secretion in a dose-dependent manner. alpha hANP inhibited aldosterone (IC50, 1.3 X 10(-8) M) and cortisol (IC50, 0.7 X 10(-8) M) secretion more potently than it did DHEA (IC50, 7.5 X 10(-8) M) secretion. ACTH dose-dependent (10(-10)-10(-8) M) increases in aldosterone, cortisol, and DHEA secretion were significantly inhibited by alpha hANP (10(-8) M). In addition, alpha hANP enhanced the accumulation of intracellular cGMP in a dose-dependent manner. As aldosterone, cortisol, and DHEA secretion from cultured human adrenal cells was inhibited by alpha hANP, the site of inhibition of steroidogenesis by alpha hANP is probably localized in the early pathway of steroidogenesis in human adrenal cells. The results also suggest a link between inhibitory effects of alpha hANP and accumulation of intracellular cGMP.     

Plasma atrial natriuretic polypeptide concentrations during and after reversion of paroxysmal supraventricular tachycardias

Plasma concentrations of immunoreactive atrial natriuretic polypeptide were raised in 22 of 23 patients with paroxysmal supraventricular tachycardia and in all seven patients with atrial flutter. Plasma concentrations of atrial natriuretic polypeptide rose soon after the onset of supraventricular tachycardia. A sample taken 30 minutes after reversion to sinus rhythm (pharmacological or non-pharmacological) showed a significant fall in 19 of the 23 patients with paroxysmal supraventricular tachycardia and all seven patients with atrial flutter. Because atrial natriuretic polypeptide has powerful natriuretic and diuretic properties, an increase may contribute considerably to the polyuria that is often associated with episodes of supraventricular tachycardia.     

Circulating atrial natriuretic polypeptide in essential hypertension

To investigate the significance of atrial natriuretic polypeptide (ANP) in essential hypertension, we measured plasma ANP concentrations in 43 subjects with essential hypertension uncomplicated by cardiac or renal failure, in 16 subjects with borderline hypertension, and in 17 normotensive control subjects. Plasma ANP levels were significantly higher in hypertensive subjects compared to borderline hypertensive subjects (p less than 0.05) and normotensive control subjects (p less than 0.05). Hypertensive subjects with left ventricular hypertrophy (LVH) had higher plasma ANP levels than the hypertensive group as a whole (p less than 0.05). A significant positive correlation was observed between mean blood pressure and plasma ANP level in the hypertensive group (n = 43, gamma = 0.77, p less than 0.01). Furthermore, plasma ANP level was decreased significantly after 4 weeks of effective antihypertensive therapy compared with the initial value (p less than 0.05). These results suggest that plasma ANP is frequently elevated in hypertensive subjects with markedly high blood pressure or LVH, and it can be reduced by effective therapy with antihypertensive drugs.     

Influence of plasma alpha-human atrial natriuretic polypeptide on natriuretic and diuretic effects in patients with nephrotic syndrome

The physiological mechanism regulating secretion of alpha-human atrial natriuretic polypeptide (alpha hANP) was studied by measuring plasma alpha hANP (P alpha hANP) with radioimmunoassay during water immersion (WI). Twelve healthy volunteers and sixteen patients with nephrotic syndrome were immersed in water for 4 hours. During WI, alpha hANP level and urinary cGMP excretion (UcGV) increased significantly both in volunteers and patients, the urinary volume (UV) and urinary Na excretion (UNaV) also increased significantly. The mean peak values of alpha hANP and UcGV in volunteers were significantly lower than those in the patients, whereas the mean values of UV and UNaV in the former were significantly higher than those in the latter. The increase in alpha hANP level in volunteers correlated positively with the increase of UNaV, UV and UcGV during WI. The close correlations between the increased alpha hANP level and the increased UNaV, UV and UcGV was shown in the patients. These results suggest that alpha hANP is released into the circulation by acute central hypervolemia and plays a physiologically important role in maintaining water and electrolytes homeostasis in normal subjects and that the increased alpha hANP level in nephrotic syndrome makes compensatory regulation in water and electrolytes disorders.     

Plasma concentrations of alpha-human atrial natriuretic polypeptide and cyclic GMP in patients with heart disease

Plasma concentrations of immunoreactive alpha-human atrial natriuretic polypeptide (i alpha-hANP) and cyclic guanosine monophosphate (cGMP) were measured in 70 patients with heart disease. Plasma concentrations of i alpha-hANP were directly related to the severity of heart disease (F = 29.61, p less than 0.001). Plasma concentrations of i alpha-hANP were well correlated with pulmonary capillary wedge pressure (PCWP; r = 0.64, p less than 0.001), mean pulmonary arterial pressure (PAP; r = 0.62, p less than 0.001), and mean right atrial pressure (RAP; r = 0.75, p less than 0.001). Plasma concentrations of cGMP were also directly related to the severity of heart disease (F = 13.61, p less than 0.001) and highly correlated with plasma concentrations of i alpha-hANP (r = 0.73, p less than 0.001). Plasma concentrations of cGMP were also closely correlated with PCWP (r = 0.69, p less than 0.001), mean PAP (r = 0.61, p less than 0.001), and mean RAP (r = 0.60, p less than 0.001). The i alpha-hANP concentrations of plasma samples obtained from the coronary sinus were approximately fourfold higher than those of samples obtained from the pulmonary artery, whereas cGMP concentrations were comparable in plasma samples obtained from either site. Elevation of cGMP concentrations following intravenous infusion of synthetic alpha-hANP was comparable in plasma samples obtained from the coronary sinus and the pulmonary artery. These findings suggest that elevated plasma concentrations of i alpha-hANP in cardiac patients result from an increase in the secretion of ANPs, which is probably accelerated by elevation of right or left atrial pressure, and that plasma concentrations of cGMP reflect circulating levels of alpha-hANP.     

Plasma atrial natriuretic polypeptide concentrations during and after reversion of paroxysmal supraventricular tachycardias.

Plasma concentrations of immunoreactive atrial natriuretic polypeptide were raised in 22 of 23 patients with paroxysmal supraventricular tachycardia and in all seven patients with atrial flutter. Plasma concentrations of atrial natriuretic polypeptide rose soon after the onset of supraventricular tachycardia. A sample taken 30 minutes after reversion to sinus rhythm (pharmacological or non-pharmacological) showed a significant fall in 19 of the 23 patients with paroxysmal supraventricular tachycardia and all seven patients with atrial flutter. Because atrial natriuretic polypeptide has powerful natriuretic and diuretic properties, an increase may contribute considerably to the polyuria that is often associated with episodes of supraventricular tachycardia.     

Low atrial natriuretic peptide plasma concentrations in 100 patients with essential hypertension

Although atrial natriuretic peptide (ANP) plays a key role in electrolyte and volume regulation and causes direct vasorelaxation, controversial results have been reported in hypertensive patients. We studied 58 men and 42 women, aged 19 to 78 years, with essential hypertension (blood pressure: 150 to 210/95 to 110 mm Hg) using 24 h blood pressure recording, treadmill exercise and x-ray of the chest. In 70 patients ANP plasma concentrations were found to be completely within the normal range of healthy controls (17 to 38 fmol/mL; n = 50) and 52% were detected within the lower third or even below the normal range. In mild to moderate essential hypertension a diminished secretion of ANP may be responsible for an elevated blood pressure in these patients.     

Plasma concentration of atrial natriuretic polypeptide in patients with atrial tachycardia

To investigate the mechanisms of polyuria associated with tachycardia, we measured plasma concentrations of alpha-human atrial natriuretic polypeptide (alpha-hANP) and cGMP in 6 patients with paroxysmal tachycardia. Plasma concentrations of immunoreactive alpha-hANP and cGMP increased by +69% (p less than 0.05) and +100% (p less than 0.05), respectively, during both paroxysmal atrial tachycardia and atrial fibrillation. To examine whether tachycardia per se raises the secretion of alpha-hANP, we also determined plasma concentrations of alpha-hANP and cGMP in 5 patients during rapid atrial pacing. The pacing-induced tachycardia also increased both of the plasma concentrations. Further, the examinations of cardiac and renal functions in patients with complete atrioventricular block during rapid pacing revealed that each of the increases in atrial pressures, urinary sodium excretion and creatinine clearance were in parallel with the change in plasma concentration of alpha-hANP. These results suggest that an increase in plasma concentration of alpha-hANP during paroxysmal tachycardia is mainly due to elevation of atrial pressure and that this increase in alpha-hANP contributes to tachycardia polyuria.     

Thyrotropin-releasing hormone increases plasma atrial natriuretic peptide levels in human

The effect of thyrotropin-releasing hormone (TRH) on plasma atrial natriuretic peptide (ANP), TSH, prolactin, cortisol and aldosterone levels in 26 patients with normal pituitary and thyroid gland function was examined. Bolus iv injection of 200 micrograms TRH produced, between 0 and 60 min, a significant gradual rise of plasma ANP concentrations from 30.4 +/- 2.3 to 54.8 +/- 6.4 pg/ml (mean +/- SE). Plasma prolactin and TSH concentrations increased four- and six-fold of basal values with peak responses at 15 and 30 min, respectively, whereas plasma cortisol and aldosterone concentrations remained unchanged after the drug treatment. The patients had no significant changes in blood pressure or pulse rate. We conclude that there may be indirect mechanism(s) which result in increased ANP levels after TRH administration.     

Biochemical mechanism of release of atrial natriuretic polypeptide

To define transmembrane and intracellular mechanisms of production and release of atrial natriuretic polypeptide (ANP) in the absence of mechanical atrial stretch, we studied the direct effects of physiological stimuli on isolated adult rat atrial myocytes maintained under tissue culture. Although stimulation of beta-adrenergic receptors on the surface of atrial myocytes by isoproterenol did not affect ANP release, adrenergic alpha-1 receptor stimulation by methoxamine enhanced ANP release with reciprocal intracellular ANP reduction. When muscarinic receptors were stimulated by acetylcholine, ANP release was accelerated and intracellular ANP reduced. The activation of the phosphatidylinositol system, which is a common pathway for muscarinic and alpha-1 adrenergic receptor stimulation, was thus considered to regulate ANP release, but not ANP production.     

Raised plasma concentrations of atrial natriuretic peptide are independent of left atrial dimensions in patients with chronic atrial fibrillation

The aim of the present study was to determine whether left atrial size--a likely indicator of atrial stretching--correlates with the plasma concentration of atrial natriuretic peptide and whether this relation is different in patients in sinus rhythm and in those with atrial fibrillation. Arterial plasma concentrations of immunoreactive atrial natriuretic peptide (ir-ANP), adrenaline, noradrenaline, aldosterone, and vasopressin were measured in 13 patients in sinus rhythm without apparent heart failure and in 13 patients in atrial fibrillation. The two groups were matched for left atrial diameter and the ratio of the left atrial diameter to the diameter of the aortic root (assessed by echocardiography). There were no significant differences in age, heart rate, blood pressure, or left ventricular end diastolic diameter between the two groups. Left atrial diameters varied from 33 to 60 mm. The mean (SD) plasma concentration of ir-ANP was significantly higher (35 (21) pmol/l) in the patients with atrial fibrillation than in those in sinus rhythm (12 (11) pmol/l). The concentration of plasma aldosterone was also higher in patients with atrial fibrillation (831 (366) v 523 (211) pmol/l). Concentrations of adrenaline, noradrenaline, and vasopressin were similar in both groups. None of the hormone concentrations correlated with left atrial dimensions. These results indicate that plasma concentrations of ir-ANP and aldosterone are highly sensitive indicators of changes in haemodynamic function during atrial fibrillation. They also underscore the difficulties of correlating echocardiographic assessment of patients with plasma concentrations of a vasoactive hormone.