Pharmacokinetic characterization of the postdistribution phase of prohormone atrial natriuretic peptides amino acids 1-98, 31-67, and atrial natriuretic factor during and after rapid right ventricular pacing in dogs.

Release rate constants and disappearance rate constants were determined for three atrial natriuretic peptides consisting of amino acids 1-98 (i.e., proANF 1-98), the midportion of the ANF prohormone consisting of amino acids 31-67 (i.e., proANF 31-67) and amino acids 99-126 (i.e., ANF) after right ventricular pacing at 100, 125, 150, and 180 bpm in six male mongrel dogs. Right atrial and femoral vein blood was obtained at baseline, and at 5, 12, 19, 26, 56, 86, 116, 146, and 206 minutes after right ventricular pacing. Resulting plasma concentration-time data derived parameters were compared. The disappearance rate constants for atrial and femoral venous proANF 1-98 were 0.0144 +/- 0.0087 (X +/- SD) and 0.0175 +/- 0.0075 min-1, respectively (t = 0.6158) and release rate constants were 0.1569 +/- 0.1504 and 0.0670 +/- 0.0393 min-1, respectively (t = 1.8269; P greater than .05). The proANF 31-67 disappearance rate constants were 0.0139 +/- 0.0082 and 0.0148 +/- 0.0132 min-1, respectively (t = 0.1192) and release rate constants were 0.0957 +/- 0.0414 and 0.1984 +/- 0.1762 min-1, respectively (t = 1.4812). The ANF elimination phase disappearance rate constants were 0.0663 +/- 0.0273 and 0.1116 +/- 0.0539 min-1 (t = 2.0923, P greater than .05), respectively, and the release rate constants were 0.1335 +/- 0.0532 and 0.1638 +/- 0.0520 min-1 (t = 0.7878, P greater than .05), respectively. These data indicate that proANF 1-98 and proANF 31-67 circulating beta post-distribution half-lives are approximately 45 minutes whereas beta half-life of ANF is 10 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Specific binding site for pro atrial natriuretic factors 1-30, 31-67, and 99-126 on distal nephrons, proximal tubules, renal cortical and medullary membranes.

Two peptides with natriuretic and diuretic properties consisting of amino acids (a.a.) 1-30 and 31-67 of the 98 a.a. N-terminal end of the prohormone of atrial natriuretic factor (proANF), which normally circulates in humans and animals, were investigated to determine if they have specific binding sites on distal nephrons, proximal tubules, renal cortical and medullary membranes. Competitive binding experiments revealed that proANFs 1-30, 31-67, and 99-126 (i.e., C-terminus; ANF) each had specific and separate binding sites. The dissociation constants (Kd) for proANFs 1-30, 31-67, and 99-126 binding to renal cortical membranes were similar at 9.8, 5.1, and 4.7 nM, respectively. In renal medullary membranes, on the other hand, proANF1-30 (Kd = 3.7 nM) and proANF31-67 (Kd = 2.9 nM) had a 10-fold higher binding affinity than ANF (Kd = 56 nM). All three peptides had very weak binding to proximal tubules with the respective Kds for proANF1-30, proANF31-67, and ANF of 892, 789, and 550 nM indicating a 50- to 100-fold less affinity for their binding sites in proximal tubules than in distal nephrons (Kds of 4.9, 5.3, and 11 nM, respectively). Each peptide bound to the respective kidney membranes or tubules between 10(-8) and 10(-11) M but could only bind to the other peptides' receptors at concentrations of 10(-6) and 10(-7) M. Neither insulin, growth hormone, nor adrenocorticotrophic hormone competitively inhibited the binding of proANF 1-30, proANF 31-67 or ANF. These results suggest that proANF 1-30 and proANF31-67 do not work through the ANF receptor but rather have their own separate and distinct receptors to mediate their diuretic and natriuretic effects in the kidney.

Exercise increases the circulating concentration of the N-terminus of the atrial natriuretic factor prohormone in normal individuals.

Recently two peptides consisting of amino acids (aa) 1 to 30 and 31 to 67 of the N-terminus of the 126 aa prohormone of atrial natriuretic factor (proANF), as well as atrial natriuretic factor (ANF, aa 99 to 126; C-terminus), were found to have vasodilatory and natriuretic properties. These peptides, as well as ANF, circulate in humans as part of the N-terminus of the prohormone. To determine the effect of graded exercise on the circulating concentrations of the N-terminus and C-terminus of the ANF prohormone in normal persons, 12 healthy individuals (mean age 45 +/- 2 years) were evaluated before, for 2 hours after, and during bicycle exercise at a work loads of 25, 50, 75, 100, 125, 150, and 175 W. Both the N- and C-terminus of the ANF prohormone were released simultaneously with graded exercise in direct proportion to the intensity of the work load, measured objectively via maximal oxygen consumption (VO2max), respiratory quotient, and heart rate. Both the N-terminus and C-terminus of the ANF prohormone had strong positive correlations (p less than 0.001) with blood pressure, heart rate, VO2max, and respiratory quotient. Following exercise, the C-terminus returned to preexercise levels within 30 minutes, while the N-terminus remained significantly elevated at 30 and 60 minutes postexercise, reflecting the longer half-life of the N-terminus in the circulation.

Acute and sustained release of the atrial natriuretic factor prohormone N-terminus with acute myocardial infarction.

This investigation was designed to determine if acute ischemic cardiac injury causes the release of the 98 amino acid (aa) N-terminus of the 126 aa atrial natriuretic factor prohormone (pro ANF). Seventeen patients with acute myocardial infarction, but without clinical evidence of congestive heart failure, had their circulating concentrations of the whole N-terminus (ie, pro ANF 1-98), the midportion of the N-terminus of the ANF prohormone (consisting of aa 31-67; pro ANF 31-67) and creatine phosphokinase (CPK) monitored daily for 14 days. All seventeen patients had elevated plasma pro ANF 1-98 and pro ANF 31-67 concentrations at the time of presentation. Maximal increase on day three post-infarction correlated with the size of infarction estimated by the maximal CPK (r = 0.675; p less than 0.05) but did not correlate with the amount of left ventricular dysfunction. Another three patients with acute myocardial infarction were treated with tissue plasminogen activator (tPA). The measured pro ANF 1-98 and pro ANF 31-67 levels in these patients were within our normal range and significantly lower (p less than 0.001) than seen in patients with acute myocardial infarction not given thrombolytic therapy. Six patients with unstable angina, likewise, had normal circulating pro ANFs 1-98 and 31-67 concentrations during prolonged episodes of chest pain. These data suggest that myocardial necrosis but not ischemia triggers the release of the entire 126 aa prohormone.

Increased release of the N-terminal and C-terminal portions of the atrial natriuretic factor prohormone during immersion-induced central hypervolemia in cirrhotic humans.

The role of peptides from the N-terminus and C-terminus of the 126 amino acid (a.a.) atrial natriuretic factors (ANF) prohormone in modulating renal sodium and water handling in cirrhotic patients has not been defined. Eight cirrhotic individuals were evaluated; their mean basal circulating concentration of the C-terminus (a.a. 99-126; i.e., ANF) was 25 +/- 2 fmol/ml, not different from the 22 +/- 1 fmol/ml value found in 54 normal volunteers. On the other hand, the basal circulating concentrations of the whole N-terminus (a.a. 1-98) and the midportion of the N-terminus (namely a.a. 31-67; pro ANF 31-67) of the ANF prohormone in these cirrhotic subjects of 704 +/- 52 and 654 +/- 83 fmol/ml were significantly elevated (p less than 0.05; ANOVA) in comparison to control values (531 +/- 25, 317 +/- 22 fmol/ml, respectively). Following equilibration on a 10 mmol/day sodium diet, the responsiveness of the N-terminus and C-terminus of ANF prohormone to 3 h of water immersion, which induces marked acute central volume expansion, was evaluated in these 8 seated cirrhotic patients. There was a prompt increase in the circulating concentrations of immunoreactive (ir) pro ANF 1-98 (whole N-terminus), ir pro ANF 31-67, and ir ANF (C-terminus) within 15 min of immersion (p less than 0.05; ANOVA) compared to their preimmersion values. The response of circulating ir pro ANF 1-98, pro ANF 31-67, and ANF concentrations in these 8 cirrhotic subjects to immersion was significantly greater (p less than 0.05; ANOVA) than that of 7 healthy volunteers undergoing an identical 3-hour immersion study. With cessation of immersion, the C-terminus decreased within 30 min to a concentration not significantly different from preimmersion values, whereas the N-terminus and pro ANF 31-67 remained significantly elevated after 1 h.

Increased circulating concentration of the N-terminus of the atrial natriuretic factor prohormone in persons with pheochromocytomas.

To investigate the possible relationship of hypertension and the N-terminus of the atrial natriuretic factor (ANF) prohormone which contains two peptides [i.e. pro ANF-(1-30) and pro-ANF-(31-67)] with blood pressure-lowering effects, we examined the circulating levels of the N-terminus of the ANF prohormone in three patients with pheochromocytomas before surgery, during an increase in their blood pressure with surgical manipulation of their tumors, and after surgery when their blood pressures returned to normal. The circulating levels of the whole N-terminus [amino acids 1-98; pro-ANF-(1-98)] and pro-ANF-(31-67) from the midportion of the N-terminus of the ANF prohormone were increased 2-fold in patients with both extraadrenal and intraadrenal pheochromocytomas. In both the intraadrenal and extraadrenal patients N-terminus [pro-ANF-(1-98)] and pro-ANF-(31-67) circulating levels increased further during surgical manipulation and returned to normal after surgical removal of their respective tumors. Each of these pheochromocytomas was found to have pro-ANF-(1-30) and -(31-67)-binding sites that were functional, since they could enhance the guanylate cyclase-cGMP system 2-fold in these pheochromocytomas. The entire 126 amino acids of the prohormone were present within each of the pheochromocytomas, since both the whole N-terminus and C-terminus (i.e. ANF) of the prohormone were present. Examination of the pheochromocytomas by electron microscopy revealed electron-dense granules similar to those in the heart, which have been associated with the synthesis and storage of the ANF prohormone. We conclude that 1) the whole N-terminus [pro-ANF-(1-98)] and pro-ANF-(31-67) of the ANF prohormone circulate at higher concentrations in persons with pheochromocytomas and return to normal with removal of the tumors; 2) pheochromocytomas contain specific binding sites for pro-ANF-(1-30) and -(31-67); 3) these binding sites are functional, since pro-ANF-(1-30) and -(31-67) could enhance the enzyme guanylate cyclase within these tumors; and 4) the entire 126 amino acids of the ANF prohormone are present within these tumors, which have electron-dense granules associated with polypeptide hormone synthesis, suggesting that the ANF prohormone is being synthesized within the pheochromocytomas.

The N-terminus of the atrial natriuretic factor prohormone in the pleural fluid of congestive heart failure patients.

To investigate the possibility that the prohormone of atrial natriuretic factor might be secreted into the pleural fluid of patients with congestive heart failure who are known to have high concentrations of both the N-terminus and C-terminus of this prohormone circulating in their plasma, six patients with class 2 New York Heart Association classified congestive heart failure had the simultaneous measurement of plasma and pleural fluid N-terminal and C-terminal atrial natriuretic factor prohormone concentrations. The 98 amino acid (aa) N-terminus, the midportion of the N-terminus consisting of aa 31-67 of the 126 aa ANF prohormone (ie, pro ANF 31-67), and the C-terminus (aa. 99-126, ANF) were found in high concentrations in the pleural fluid of all of these patients. The concentrations of the N-terminus (ie, pro ANF 1-98), and pro ANF 31-67 in pleural fluid were nearly equal to their concentration in plasma of these patients. Their plasma levels were more than double the plasma concentrations of pro ANFs 1-98 and 31-67 in 54 persons without congestive heart failure. These preliminary findings demonstrate that all 126 amino acids of the ANF prohormone are present in pleural fluid of patients with congestive heart failure since both the 98 aa N-terminus and the C-terminus (aa 99-126) are present. Whether or not the N-terminus, which contains diuretic and natriuretic peptides, secretion into pleural fluid helps clear the fluid present in the lung in congestive heart failure could not be determined from the present investigation.

Prohormone atrial natriuretic peptides 1-98 and 31-67 increase with exercise in congestive heart failure patients.

Recently two peptides consisting of amino acids (a.a.) 1-30 and 31-67 of the N-terminus of the 126 a.a. prohormone of atrial natriuretic factor (pro ANF), as well as atrial natriuretic factor (ANF, a.a. 99-126; C-terminus) were found to have vasodilatory and natriuretic properties. These peptides, as well as ANF, circulate in man as part of the N-terminus of the prohormone. To determine the effect of graded exercise on the circulating concentration of the N-terminus and C-terminus of the ANF prohormone in persons with abnormal salt and water metabolism, 12 individuals with stable congestive heart failure (CHF) were evaluated before and after bicycle exercise testing and the results were subdivided based on the maximal exercise they could achieve. In all of the CHF patients, the circulating concentration of the whole N-terminus (ie, a.a. 1-98), the midportion of the N-terminus (pro ANF 31-67), which circulates as a distinct 3900 molecular weight (m.w.) peptide after being proteolytically cleaved from the N-terminus, and the C-terminus (ANF) increased with exercise. The patients who were able to achieve 100 and 125 watts of workload had a greater maximal oxygen consumption and, in general, a greater percent increase in the circulating concentration of both the N-terminus and the C-terminus of the ANF prohormone than those who had less exercise capacity. Evaluation of the echocardiographic, radionucleotide, and the exercise parameters revealed that the circulating concentrations of these atrial peptides correlated best with left atrial dimension, but that left ventricular systolic and diastolic dimensions also correlated positively with their concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased release of the N-terminal and C-terminal portions of the prohormone of atrial natriuretic factor during immersion-induced central hypervolemia in normal humans.

The role of peptides from the N terminus and C terminus of the 126 amino acid atrial natriuretic factor (ANF) prohormone in modulating renal sodium and water handling has not been defined. Since water immersion to the neck (NI) provides an acute central volume expansion identical to that produced by 2 liters of saline but without plasma compositional change, immersion to the neck was used to assess the N-terminal and C-terminal portions of the ANF prohormone response to acute central blood volume expansion in seven seated sodium-replete normal subjects. Both the C terminus, which contains amino acids 99-126 and is identical to ANF, and the whole N terminus (i.e., amino acids 1-98) increased promptly with NI and peaked after 1 hr of immersion. A Mr 3900 peptide from the midportion of the N terminus consistent with amino acids 31-67 (i.e., pro-ANF-31-67) also increased with NI and followed a pattern of increasing circulating concentration nearly identical to that of the whole N terminus of the prohormone, except that its maximal concentration was at the second hour of the 3 hr of NI. With cessation of immersion, ANF decreased to preimmersion levels within 1 hr whereas the N terminus and pro-ANF-31-67, although their circulating concentrations were decreasing, were still significantly elevated at 1 hr. These findings suggest that the increase in plasma ANF, the N terminus of the ANF prohormone, and pro-ANF-31-67 from the midportion of the N terminus, with natriuretic properties similar to ANF, contribute to the natriuretic response to NI, implying a physiologic role for these atrial peptides in modulating volume homeostasis in humans.

Increased plasma concentration of atrial natriuretic factor with squamous cell carcinoma invasion of the right and left atria of the heart.

Atrial natriuretic factor is a new peptide hormone synthesized in the heart which has potent natriuretic, diuretic, and vasodilatory properties. A 47-year-old man with squamous cell carcinoma of the lung resected 6 months previously presented with syncope secondary to hypotension and a low serum sodium. He was evaluated to determine if atrial natriuretic factor (ANF) might be the etiology of this clinical picture. His plasma concentration of atrial natriuretic factor was increased three-fold over that of 70 normotensive person. Further evaluation revealed metastatic lesions in the right and left cardiac atria with the mass on the left occluding 75% of the left atrial chamber. The mass effect in the atria increasing atrial stretch and atrial pressure one would expect was the main contributor to the increased ANF level. The contribution of direct tumor invasion into the atria and/or production of atrial natriuretic factor by the tumor itself to produce this elevated plasma level of atrial natriuretic factor could not be determined, but this markedly elevated level of atrial natriuretic factor does appear to be the etiology of this patient's clinical picture.

Acute and sustained release of atrial natriuretic factor with acute myocardial infarction.

The present investigation was designed to determine if acute ischemic cardiac injury causes the release of atrial natriuretic factor (ANF). Seventeen patients with acute myocardial infarction but without clinical evidence of congestive heart failure had their circulating concentration of ANF and creatine phosphokinase monitored daily for 14 days. All 17 patients had an elevated plasma ANF concentration at time of presentation. Maximal increase in ANF was on day 2 and 3 post-infarction. This maximal increase correlated with the size of infarction estimated by the maximal creatine phosphokinase concentration (r = 0.475; p less than 0.05), but did not correlate with the amount of left ventricular dysfunction. ANF began to decrease by day 4 post-infarction and was normal at 10 days post-infarction in 14 of the 17 (82%) patients. At 12 days post-infarction, all 17 patients had normal ANF levels. Another three patients with acute myocardial infarction were treated with tissue plasminogen activator (tPA). The measured ANF levels in these patients were within our normal range and were significantly lower (p less than 0.001) than those seen in patients with acute myocardial infarction not given thrombolytic therapy. Six patients with unstable angina likewise had normal circulating ANF concentrations during prolonged episodes of chest pain. These levels were also significantly lower (p less than 0.001) than the 17 patients with acute infarcts not given tPA. The distinct pattern of release of ANF may be useful as an adjunct to serum cardiac enzymes in determining if a myocardial infarction has occurred.

The N-terminus and a 4,000-MW peptide from the midportion of the N-terminus of the atrial natriuretic factor prohormone each circulate in humans and increase in congestive heart failure.

Two peptides consisting of amino acids 1-30 and 31-67 of the N-terminus of the prohormone of atrial natriuretic factor (pro-ANF) that have vasodilatory and natriuretic properties were investigated to determine if they circulate in humans. Specific and sensitive radioimmunoassays were developed to amino acids 1-30, 31-67, and 99-126 of pro-ANF. Evaluation of human plasma that had been subjected to reverse-phase high-pressure liquid chromatography suggested that pro-ANFs 1-30 and 31-67 as well as ANF were distinct peaks in human plasma corresponding exactly to pure synthetic peaks of these peptides on high-pressure liquid chromatography. Molecular weight determination of the endogenous immunoreactive peptides measured in plasma by G-50 Sephadex gel permeation chromatography revealed that the pro-ANF 1-30 radioimmunoassay recognized a peptide of 10,000 MW, which is consistent with it measuring the whole N-terminus of pro-ANF (amino acids 1-98) but without ANF (C-terminus) attached to it. The pro-ANF 31-67 radioimmunoassay recognized mainly (more than 95%) a peptide of 3,900-4,000 MW, which corresponds closely with its actual molecular weight of 3,878. Our ANF radioimmunoassay recognizes a peptide in plasma of 3,000 MW with the known molecular weight of ANF being 3,081. The mean circulating concentrations of immunoreactive pro-ANF 1-98, pro-ANF 31-67, and ANF in 54 control subjects were 531 +/- 25, 371 +/- 18, and 22 +/- 1 fmol/ml (+/- SEM), respectively. Thirty patients with varying severity of congestive heart failure were also studied. The N-terminus, C-terminus, and pro-ANF 31-67 increased: twofold for New York Heart Association functional Class II, threefold to ninefold for Class III, and 10- to 20-fold for Class IV patients with congestive heart failure. Thus, the N-terminus and a 4,000-MW peptide from the midportion of the N-terminus of pro-ANF as well as ANF circulate normally and increased proportionately to the increasing severity of congestive heart failure. However, because the pro-ANF 31-67 radioimmunoassay was the only assay that discriminated between patients with Class I congestive heart failure and control subjects, this assay may be the most useful to accurately classify the severity of congestive heart failure.

Atrial natriuretic factor in the pleural fluid of congestive heart failure patients.

To investigate the possibility that atrial natriuretic factor might be secreted into the pleural fluid of patients with congestive heart failure who are known to have high concentrations of this new peptide hormone circulating in their plasma, six patients with class 2 New York Heart Association classified congestive heart failure had simultaneos measurement of plasma and pleural fluid atrial natriuretic factor concentrations. Atrial natriuretic factor was found in high concentrations in the pleural fluid of all of these patients. The concentration of atrial natriuretic factor in pleural fluid was nearly equal to the concentration in plasma of these patients. Their plasma levels were double the plasma concentration of this peptide hormone in 54 persons without congestive heart failure. These preliminary findings demonstrate that atrial natriuretic factor is present in pleural fluid of patients with congestive heart failure, but whether or not this secretion of atrial natriuretic factor into the pleural fluid helps the lung clear the fluid present in the lung in congestive heart failure cannot be determined from the present investigation.

Prohormone atrial natriuretic peptides 1-30 and 31-67 increase in hyperthyroidism and decrease in hypothyroidism.

Hyperthyroidism characteristically has natriuresis and vasodilation associated with it, whereas hypothyroidism is associated with impaired water excretion and vasoconstriction. This investigation was designed to determine if the plasma concentration(s) of three newly described hormones synthesized in the heart are increased in patients with hyperthyroidism and/or decreased in patients with hypothyroidism compared to normal subjects. The three hormones consist of amino acids 1-30, 31-67, and 99-126 (ANF) of the 126 amino acid prohormone of atrial natriuretic factor. Prohormone atrial natriuretic peptides (pro ANFs) 1-30, 31-67, and ANF were increased threefold, fourfold, and twofold respectively in hyperthyroid patients compared to the mean circulating concentration of 54 healthy persons without thyroid disease. Plasma concentrations of the three peptides in hypothyroid patients were only one-half that of the 54 persons without thyroid disease. With appropriate treatment of hyperthyroidism and hypothyroidism, the levels of the three peptides returned to normal. The peptide hormones increased proportionately with the increasing dosages of L-thyroxine of 50 micrograms/day and 100 micrograms/day in the hypothyroid patients. In persons with hypothyroidism complicated by congestive heart failure, the levels of pro ANFs 1-30, 31-67, and 99-126 were increased, demonstrating that abnormalities of salt and water metabolism are a strong stimulus to the release of these peptides.

Prohormone atrial natriuretic peptides 1-30, 31-67, and 99-126 increase in proportion to right ventricular pacing rate.

To determine whether heart rate contributes to release of three new peptide hormones synthesized in the heart, right ventricular pacing at rates of 100, 125, 150, and 180 bpm was performed in six dogs with measurement of the plasma concentration of these peptides at each pacing rate while right atrial and systemic blood pressures were simultaneously monitored. These three peptides of the 126-amino-acid prohormone of atrial natriuretic factor (ANF), consisting of amino acids 1-30 (pro ANF 1-30), 31-67 (pro ANF 31-67), and 99-126 (ANF), increased incrementally at paced heart rates of 125, 150, and 180 bpm (r = 0.8, p less than 0.001). Right atrial pressure decreased with increasing heart rate but systemic blood pressure did not decrease until the heart rate was 180 bpm, at which time these peptides had obtained their maximal circulating concentrations. After pacing, mean right atrial pressure and levels of ANF returned to prepacing values within 30 minutes. Mean arterial blood pressure, on the other hand, increased throughout the 120-minute period after pacing. At 2 hours after pacing, levels of pro ANFs 1-30 and 31-67 were elevated compared with prepacing values. These data demonstrate that, at heart rates of 125 bpm and above, pro ANF 1-30, pro ANF 31-67, and ANF (99-126) are simultaneously and incrementally released in direct proportion to heart rate. The sustained elevation in pro ANFs 1-30 and 31-67 seen 2 hours after pacing suggests that they may contribute to the prolonged diuresis seen after cardiac pacing or tachycardia.

Increased circulating concentration of atrial natriuretic factor in persons with pheochromocytomas.

To investigate the possible relationship of atrial natriuretic factor (ANF) to hypertension, we examined the circulating levels of ANF in 3 patients with pheochromocytomas before surgery, during increase of their blood pressure with surgical manipulation of their tumors, and after surgery when their blood pressures returned to normal. The circulating levels of ANF were increased 2-fold in patients with both extra-adrenal and intra-adrenal pheochromocytomas. In both the intra-adrenal and extra-adrenal patients their ANF levels increased further during surgical manipulation and returned to normal after surgical removal of their respective tumors. Each of these pheochromocytomas was examined and found to have atrial natriuretic receptors that were functional since ANF could enhance the guanylate cyclase - cyclic GMP system two-fold in these pheochromocytomas. We conclude that ANF circulates at higher concentrations in persons with pheochromocytomas and returns to normal with removal of the tumor. In addition, pheochromocytomas contain specific ANF receptors and ANF itself within these tumors.

Two new hormones: prohormone atrial natriuretic peptides 1-30 and 31-67 circulate in man.

Two peptides consisting of amino acids 1-30 and 31-67 of the N-terminal end of the prohormone of atrial natriuretic factor (pro ANF) which vasodilate aortas in vitro, lower blood pressure in vivo, and have natriuretic properties were found to circulate in 54 normal human volunteers. The mean circulating concentration of pro ANF 1-30 was 1861 +/- 87 pg/ml (SEM) while pro ANF 31-67 mean concentration was 1478 +/- 71 pg/ml versus a level of 67 +/- 3 pg/ml for atrial natriuretic factor (ANF). In chronic renal failure their mean concentrations increased to 40,484 +/- 6,929 pg/ml (SEM), 108,566 +/- 16,888 pg/ml, and 348 +/- 81 pg/ml for pro ANFs 1-30 and 31-67 and ANF respectively. Since pro ANF 1-30 and pro ANF 31-67 circulate in man and have physiologic effects they meet the criteria of two new hormones.

Circadian rhythm of prohormone atrial natriuretic peptides 1-30, 31-67 and 99-126 in man.

Two peptides consisting of amino acids 1-30 and 31-67 of the N-terminal end of the prohormone of the atrial natriuretic factor (pro ANF), vasodilate aortas in vitro, lower blood pressure in vivo, and have natriuretic properties similar to the atrial natriuretic factor (ANF, amino acids 99-126 of the prohormone). It has been recently discovered that pro ANF 1-30 and pro ANF 31-67 as well as ANF circulate in man. To determine if these three peptide hormones have a circadian variation in their circulating plasma concentrations, eight housestaff volunteers were studied on a day when they were in the hospital for 24 hr. These 5 men and 3 women, ages 25 to 39 had blood samples taken at 0800, 1200, 1600, 2000, 0000, 0400 and 0800 on the following day. One-half of these house officers were up all night while the other half went to sleep from midnight to 0800 and had their 0400 plasma samples drawn while in a supine position. The peak level for all three peptide hormones was at 0400 for both supine and upright subjects. It was concluded that there are circadian rhythms in normal, active people of these three peptide hormones, whose peak levels are at 0400 irrespective of posture.

Acquired renal cystic disease: two cases of associated adenocarcinoma and a renal ultrasound survey of a peritoneal dialysis population.

Long-term dialysis patients frequently develop acquired renal cystic disease (ARCD). The discovery of ARCD and renal cell carcinoma in one of our hemodialysis patients led us to review the literature. ARCD has been described mainly in the maintenance hemodialysis (MH) population. Therefore, we investigated 20 peritoneal dialysis (PD) patients for ARCD using ultrasonography. Seven patients (35%) had detectable cysts and two patients (10%) had multiple bilateral cysts. One patient had a large asymptomatic complex cyst that proved to be an adenocarcinoma. Our study suggests that ARCD is relatively common in the PD population, and we speculate that it may be related more to length of time in end-stage renal disease (ESRD) than to the mode of dialysis. The potential for malignant change appears to justify a routine screening examination with ultrasonography and/or computerized tomography (CT) to detect this recently described and probably underrecognized entity.

Human prepro atrial natriuretic factors 26-55, 56-92, and 104-123 increase renal guanylate cyclase activity.

Human prepro atrial natriuretic factors 26-55, 56-92, and 104-123 as well as human atrial natriuretic factor (4-28) in the present investigation increased renal cortical and medullary cyclic GMP levels and maximally enhanced particulate guanylate cyclase activity [E.C. 4.6.1.2] two-fold in whole kidney homogenates, renal cortical and medullary membranes, and in isolated distal nephrons at their 1 microM concentrations. Dose-response relationships revealed that the half maximal [ED50] activation of guanylate cyclase was at their 10 nM concentrations in rat, rabbit, and dog kidneys. Both human atrial natriuretic factor and the prepro factors decreased adenylate cyclase activity. These results suggest that prepro factors 26-55, 56-92, 104-123 may also be functionally active.