Appearance of beta-human atrial natriuretic peptide in collagen disease.

To elucidate the circulating forms of human atrial natriuretic peptide (hANP) in collagen disease, we analysed plasma samples obtained from 21 patients with systemic lupus erythematosus, rheumatoid arthritis or progressive systemic sclerosis with no clinical evidence of cardiac involvement. The findings were compared with those obtained from 21 healthy control subjects. Plasma hANP-like immunoreactivity was normal in all but three of the controls and in two patients with the nephrotic syndrome due to lupus nephritis. Reverse-phase high-performance liquid chromatography, gel permeation chromatography and subsequent radioimmunoassay for hANP revealed that the circulating hANP consisted of alpha-hANP, beta-hANP and gamma-hANP in the patients with collagen disease whereas alpha-hANP predominated in the control group. beta-hANP appeared in 18 of the 21 patients but was not observed in the controls. These data suggest that beta-hANP circulates in the plasma of patients with collagen disease even when no myocardial involvement is apparent and that the appearance of beta-hANP is not always associated with an increase in total plasma hANP-like immunoreactivity. Thus the appearance of beta-hANP in plasma is not a phenomenon specific to congestive heart failure.     

Myosin isoenzyme distribution in overloaded human atrial tissue

Using nondenaturing polyacrylamide gel electrophoresis, we have identified two distinct myosin isoenzymes in human atrial tissue that correspond to the V1 and V3 isomyosins found in rat ventricular tissue. Normal left and right atrial appendages have approximately 50% V3. When the left atrium was exposed to hemodynamic overload secondary to mitral stenosis, the percent V3 increased to 77 +/- 10% (n = 10); exposure to hemodynamic overload secondary to mitral regurgitation caused an increase to 70 +/- 14% (n = 6). Changes in the isoenzyme pattern were seen in the right atria of patients with mitral stenosis and markedly elevated pulmonary arterial pressures compared with control subjects and patients with mitral stenosis without severe pulmonary hypertension. Several clinical variables were examined to determine which factors might influence isoenzyme expression. Age, sex, the presence of atrial fibrillation, and pulmonary capillary wedge pressure did not predict the isoenzyme pattern. However, patients with mitral valvular disease and only slightly enlarged left atria tended to have a higher percent V3 than those with massively enlarged atria. These data confirm that human atrial tissue, like rat ventricular tissue, can alter its isomyosin composition in response to a hemodynamic load. The data further suggest that the isoenzyme shift is an early adaptation to the imposed load.     

Increased plasma levels of atrial natriuretic peptide in patients with congestive heart failure

Atrial natriuretic peptide (ANP) is a recently discovered hormone,originating from atrial myocardium. The peptide (or family ofpeptides) induces potent diuretic/natiuretic, vasorelaxing andaldosterone inhibitory effects. We have investigated plasmaconcentrations of immunoreactive ANP in 10 patients with congestiveheart failure (CHF). Mean plasma ANP concentrations were morethan three times higher in CHF patients than in a matched controlgroup. High plasma ANP concentrations in pathophysiologicalconditions with a high preload combined with salt and waterretention is consistent with a physiological role of this hormoneto correct hypervolemia by causing natriuresis and diuresis.It is concluded that ANP homeostasis is altered in patientswith CHF and that this hormone may be of importance in the pathophysiologyof CHF.     

Discordant atrial natriuretic peptide and brain natriuretic peptide levels in lone atrial fibrillation

OBJECTIVES: We sought to characterize natriuretic peptide levels in a cohort of rigorously characterized subjects with lone atrial fibrillation (AF). BACKGROUND: Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are sensitive biomarkers of cardiac contractile dysfunction. Both peptides have been reported to be elevated in cohorts with AF, but previous studies have included subjects with underlying structural heart disease. We studied these hormones in 150 subjects with lone AF. METHODS: Study subjects had electrocardiographic evidence of at least one episode of AF and a structurally normal heart on echocardiography. Subjects were excluded if they had a history of a myocardial infarction, rheumatic heart disease, cardiomyopathy, significant valvular disease, hyperthyroidism, or hypertension that preceded the onset of AF. Control subjects were obtained from a healthy outpatient primary care population. Plasma pro-ANP and N-terminal pro-BNP (nt-pro-BNP) levels were determined using commercially available immunoassays. RESULTS: A total of 150 serial subjects with lone AF were enrolled and studied, the majority during normal sinus rhythm. Median levels of nt-pro-BNP were significantly elevated in subjects with lone AF as compared with control subjects (166 vs. 133 fmol/ml, p=0.0003). There was no significant difference in pro-ANP levels between subjects with lone AF and control subjects (1,730 vs. 1,625 fmol/ml, p=0.90). CONCLUSIONS: Discordant natriuretic peptide levels were observed in this homogeneous population of subjects with lone AF. This biomarker pattern, which is present even in sinus rhythm, may represent an underlying subclinical predisposition to this common arrhythmia.     

Effects of chronically administered atrial natriuretic factor in aldosterone-infused hypertensive rats

To assess the pathophysiological role of atrial natriuretic factors in mineralocorticoid hypertension, we studied the effects of chronic infusion of synthetic atrial natriuretic factor on blood pressure and sodium-water excretion in rats with aldosterone salt-induced hypertension. Administration of synthetic atrial natriuretic factor (150 micrograms/kg/day) to rats made hypertensive by 7-day infusion of aldosterone (100 micrograms/kg/day) and sodium loading with 1% NaCl as drinking water returned the blood pressure to control levels, and the antihypertensive effect was not associated with any changes in urine volume and urinary sodium excretion. These results indicate that atrial natriuretic factors may be involved in the regulation of blood pressure in mineralocorticoid hypertension, independent of the renal effects of these substances.     

Release of atrial natriuretic peptide-like immunoreactive material during stretching of the rat atrium in vitro

In 1979 De Bold showed that the numbers of atrial specific granules varied with changes in water and electrolyte balance of the whole animal. Two years later, he showed that atrial extracts had a natriuretic effect. The active principle has now been identified as a polypeptide formed by cleavage of a larger precursor molecule. The rate of release of atrial natriuretic peptide-like immunoreactive material by the isolated, perfused rat heart has been shown to be increased when the right atrial pressure is raised. The mechanism of release remains, however, unknown. We describe, here, experiments which show a transient release of atrial natriuretic peptide-like immunoreactive material from isolated rat atria subjected to a constant load in an organ bath. The release appears to be specific in that it is not accompanied by a parallel release of other peptides contained in nerve fibres or of creatine kinase contained in myocytes.     

Dehydration-induced alterations in rat brain vasopressin and atrial natriuretic factor immunoreactivity

Potent natriuretic and spasmolytic peptides present in cardiac extracts recently have been identified. These atrial natriuretic factors (ANF) exert vascular and renal actions quite contrary to those of vasopressin (AVP). The ability of ANF to inhibit AVP secretion suggested a role for the peptides in the control of AVP release. The present studies report the measurement of ANF-like immunoreactivity within brain regions associated with the hypothalamo-neurohypophyseal tract and demonstrate significant water deprivation-induced reductions in ANF content of several structures (neural lobe, organum vasculosum lamina terminalis, suprachiasmatic and supraoptic nuclei) but not in others (median eminence, paraventricular nucleus, cortex and pituitary). The data suggest the production of ANF-like peptides within the brain and, further, the involvement of central ANF in extracellular fluid volume regulation.     

Increased plasma atrial natriuretic factor in catecholamine-producing tumor patients.

The aim of this study was to evaluate plasma levels of ANF in patients with catecholamine-secreting tumors with and without hypertension and to relate ANF secretion to levels of plasma and urinary catecholamines and blood pressure. Twenty-one pheochromocytoma (15 with sustained, 6 with paroxysmal hypertension), 6 neuroblastoma (1 hypertensive) patients and 28 aged-matched controls were studied in basal conditions. Plasma and urinary norepinephrine (NE),epinephrine (E), dopamine (DA) and DOPA were determined by HPLC-ED and plasma ANF by RIA. Both neuroblastoma and pheochromocytoma patients had significantly higher plasma ANF levels than controls. Neuroblastomas showed higher ANF concentration than pheochromocytomas. No differences were found in plasma ANF between hypertensive and normotensive patients. Pheochromocytomas with ANF levels within the normal range had plasma and urinary NE and urinary DA and DOPA levels significantly higher than patients with high ANF. Plasma ANF levels were unrelated to systolic or diastolic blood pressure or heart rate. A negative correlation between plasma ANF and urinary DA was found only in the patients groups. In conclusion, plasma ANF was increased in pheochromocytoma and neuroblastoma patients. Our data suggest that the excessive catecholamine secretion is not responsible for the increased ANF secretion in these patients. The significance of the relationships among plasma ANF and urinary and plasma catecholamines requires further investigation.     

Redistribution of creatine kinase isoenzymes in chronically overloaded myocardium

Chronic overload due to an experimental abdominal aortic stenosis in rats causes hypertrophy of ventricles and a parallel increase of the MB and BB isoforms of creatine kinase (CK) in cardiac tissue. The CK isoenzyme profile was determined using a new two-step method combining anion exchange chromatography and electrophoresis. In overloaded ventricles a shift was observed from the MM isoform which decreased (from 407 +/- 10 mumol X min-1 X g-1 ww in sham-operated to 370 +/- 0.13, in the overloaded group, p less than 0.05) towards the MB and BB forms whose activity was enhanced (from 56 +/- 4 and 6.5 +/- 0.7 to 77 +/- 6 and 10.1 +/- 1.2, respectively, p less than 0.02). These modifications were more pronounced (318 +/- 15, 83 +/- 15 and 15.1 +/- 2.5, for the MM, MB and BB forms respectively, p less than 0.01) in rats having a very marked hypertrophy and whose ventricular/body weight ratio (expressed in mg of ventricles per g) was above 3. Moreover this ratio correlates both with the amount of the MB form (r = 0.32, p less than 0.05) and with the percentage of the B monomer (r = 0.51, p less than 0.01). This shift, like that previously described for lactate dehydrogenase and myosin, favoured the fetal form and this supports the hypothesis that overloaded myocytes improve their efficiency by expressing some of the isoforms normally present in the fetus.     

Increased capillary hydraulic conductivity induced by atrial natriuretic peptide

The small molecular weight peptide, atrial natriuretic peptide (ANP), produces marked sodium and water excretion. The peptide, extracted from several species of vertebrate heart, also has been shown to increase glomerular filtration and reduce plasma volume. Several mechanisms have been proposed to account for the action of the peptide but remain undefined. In the present report, the ANP-induced alterations in transcapillary water movement were directly assessed. The modified Landis technique was used to measure single capillary hydraulic conductivity (Lp) of vessels from the frog mesenteric circulation. In 6 individual microvessels, Lp was measured under control conditions and again during perfusion with 10 X 10(-6) M ANP. The Lp increased in each vessel by a mean of 3.79-fold (+/- 2.09 SD). In 4 of these vessels, an additional measurement of Lp was repeated under control conditions; the capillary filtration coefficient returned to control levels. It was concluded that ANP directly and reversibly elevates capillary hydraulic conductivity; this response is independent of changes in capillary hydrostatic pressure or surface area.     

Gastrin-releasing peptide-like immunoreactivity in porcine follicular fluid and ovary

Porcine follicular fluid was found to contain gastrin-releasing peptide (GRP) by radioimmunoassay. High pressure liquid chromatography of the extracted material showed two peaks of GRP immunoreactivity that closely resembled the C-terminal fragments of GRP, GRP18-27 and GRP14-27. Immunohistochemical studies revealed specific staining for GRP in the granulosa cells of adult porcine ovary. These results demonstrate the presence of substances which behave like authentic GRP-like peptides in porcine ovary and follicular fluid and suggest that these peptides may play a paracrine and/or autocrine role in the regulation of the ovarian function.     

Plasma levels of atrial natriuretic hormone in Cushing's syndrome

To examine a possible role for atrial natriuretic hormone (ANH) in the water and electrolyte disturbances associated with hypercortisolism, plasma ANH levels were measured in 18 patients with endogenous Cushing's syndrome. Nine patients had elevated plasma ANH levels compared to normal subjects. The mean plasma ANH concentration [72.5 +/- 13.0 (+/- SE) pg/mL (23.5 +/- 4.2 pmol/L)] in the Cushing's syndrome patients was significantly higher than that in 40 normal subjects [37.6 +/- 1.9 pg/mL (12.2 +/- 0.62 pmol/L)]. A significant positive correlation was found between plasma ANH and cortisol levels in individual patients. There were no significant correlations, on the other hand, between plasma ANH concentrations and PRA, plasma aldosterone levels, or mean blood pressure. After treatment, plasma ANH concentrations decreased in all 6 patients who had elevated plasma ANH levels preoperatively. In 1 patient with Cushing's disease, plasma ANH levels changed in parallel with plasma cortisol concentrations during o,p'DDD treatment. Fifteen patients who were receiving long term synthetic glucocorticoid therapy for the treatment of miscellaneous diseases had a significantly higher mean plasma ANH level [50.2 +/- 4.0 (+/- SE) pg/mL (16.3 +/- 1.3 pmol/L)] than that in normal subjects. These results suggest that plasma ANH levels are elevated in a substantial number of patients with Cushing's syndrome due to either a direct stimulatory effect of glucocorticoid on atrial ANH secretion or, alternatively, intravascular volume expansion resulting from excessive cortisol secretion.     

Increased urinary levels of thyrotropin-releasing hormone immunoreactivity in acute pancreatitis

Thyrotropin-releasing hormone (TRH) has been shown to be present and have actions in the human gastrointestinal tract. We have studied urine TRH immunoreactivity (TRH-ir) levels in healthy subjects and patients with acute pancreatitis, gallstones, ulcerative colitis, or acute gastritis. The urine samples were prepurified by SP-Sephadex-C-25 cation exchange chromatography, subjected to reverse-phase high-pressure liquid chromatography, and assayed in our TRH radioimmunoassay. The mean urine TRH immunoreactivity values of healthy subjects were 4.42 +/- 1 ng/l (x +/- SEM); of patients with acute pancreatitis on the 1st day of hospitalization, 23 +/- 7 ng/l; on the 2nd day, 7 +/- 1 ng/l; and on the 3rd day 9 +/- 2 ng/l. Only the urine TRH levels of the pancreatitis patients on day 1 differed significantly (p less than 0.05) from the levels of the healthy subjects. Circulating TRH appears to be derived mostly from the pancreas, where the islets during acute pancreatitis are affected, and TRH is released into circulation and urine.     

Increased secretion of atrial natriuretic polypeptide in response to cardiac pacing

Effects of cardiac pacing on secretion of atrial natriuretic polypeptide (ANP) were examined in 20 patients during cardiac catheterization under control conditions. The plasma ANP concentration in the coronary sinus (900 +/- 115 pg/ml) was significantly higher than those in the aorta (147 +/- 19 pg/ml) and the femoral vein (105 +/- 15 pg/ml) (p less than 0.001). The plasma ANP concentration was also significantly higher in the aorta than in the femoral vein (p less than 0.001). Its concentration at all three sites significantly increased during cardiac pacing (from 900 +/- 115 to 1461 +/- 218, from 147 +/- 19 to 250 +/- 36, and from 105 +/- 15 to 150 +/- 24 pg/ml, respectively). However, mean right atrial pressure and mean pulmonary capillary wedge pressure showed no significant changes between control conditions and during pacing (5 +/- 1 vs 6 +/- 1, and 8 +/- 1 vs 8 +/- 1 mmHg). Furthermore, there was no significant correlation between ANP secretion and the pressure in both atria. Thus, cardiac pacing can release ANP from the heart without increasing atrial pressure.     

Plasma atrial natriuretic Peptide and brain natriuretic Peptide levels after radiofrequency catheter ablation of atrial fibrillation

It has been reported that plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels are elevated in patients with atrial fibrillation (AF). The aim of this study was to investigate the change in these patients after pulmonary vein isolation (PVI). In 66 patients with paroxysmal AF (PAF) and without any structural heart disease, plasma ANP and BNP levels were measured before and 3 months after successful PVI. At baseline, in 14 patients, ANP and BNP levels were elevated, and in 52 patients, only BNP levels were elevated. There were no significant relations between the attack frequency or the duration of PAF episodes and ANP or BNP levels. Neither ANP nor BNP level at baseline was a valid predictor of AF recurrence. Even in 31 patients (47%) with recurrent PAF, attacks of PAF were significantly reduced. In 66 patients with elevated ANP and/or BNP levels at baseline, levels were significantly reduced after PVI independent of PAF recurrence (ANP: 69.0+/-23.0 vs 25.0+/-7.7 pg/ml, p<0.0001; BNP: 58.4+/-50.7 vs 22.5+/-27.1 pg/ml, p<0.0001). In 42 patients without AF recurrences, ANP and BNP levels were reduced to within the normal range. In conclusion, in patients with PAF without any structural heart disease, ANP and/or BNP levels were elevated. In those patients, relief of the AF burden by successful PVI significantly reduced elevated plasma ANP and BNP levels.     

Relationship between plasma atrial natriuretic peptide levels and atrial pressure in man

In an attempt to clarify the mechanisms regulating the release of atrial natriuretic peptide (ANP) in man, ANP levels in pulmonary arterial plasma determined by RIA were correlated to hemodynamic variables in 17 patients with heart disease who underwent cardiac catheterization and angiocardiography. In addition, plasma ANP levels in various blood vessels were determined in 7 patients with heart disease and in 7 normal subjects to determine the source and the site of removal of circulating ANP. A significantly positive correlation was found between plasma ANP levels and mean pulmonary arterial wedge pressure, while the correlation between plasma ANP levels and mean right atrial pressure was not significant. After the injection of contrast medium, both mean right arterial pressure and plasma ANP levels increased, and a significant positive correlation was found between the two variables. When ANP levels in plasma collected from various blood vessels were compared, the highest levels were found in the coronary sinus. Plasma ANP levels in the renal vein were the lowest and were 50% of the levels in the aorta. Plasma ANP levels in the superior vena cava and internal jugular vein were higher than that in the antecubital vein. Analysis of immunoreactive ANP in pooled plasma by high performance liquid chromatography revealed that the retention time of the main ANP peak coincided with that of synthetic human alpha ANP. These results indicate that circulating ANP mainly originates from the heart, the kidney rapidly takes up a significant amount of ANP from the circulation, and an increase in both left and right atrial pressure triggers ANP release in man.     

Increased right or left atrial pressure stimulates release of atrial natriuretic peptides in conscious dogs

To compare release of immunoreactive atrial natriuretic peptides (iANP) caused by distention of the right and left atria, dogs were prepared with occluding cuffs around either the ascending aorta (n = 5) or the pulmonary artery (n = 4). Graded inflation of the ascending aortic cuff for 60 min caused increments in left atrial pressure (LAP) but no change or a decrease in right atrial pressure (RAP). Plasma iANP increased significantly (P less than 0.01) in response to increases in LAP as small as 2.9 +/- 0.4 mmHg. There was a significant correlation between the increment in LAP and the rise in plasma iANP (r = 0.64, n = 25, P less than 0.01). Graded inflation of the pulmonary artery cuff caused increments in RAP and a fall in LAP. Plasma iANP increased significantly (P less than 0.01) in response to increases in RAP as small as 2.8 +/- 1.1 mmHg. Also, there was a significant correlation between the increments in RAP and the rise in plasma iANP (r = 0.69, n = 20, P less than 0.01). These results indicate that physiologic increases in either RAP or LAP is sufficient to cause increased plasma levels of iANP in conscious dogs.