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 release of the N-terminus of the atrial natriuretic factor prohormone with increasing absolute atmospheres of pressure in a hyperbaric chamber and reversal with oxygen therapy.

Increasing atmospheres of absolute pressure (ATA) on the cardiopulmonary system results in a marked diuresis. The present investigation was designed to determine if the diuresis observed with increasing ATA is associated with increased release of the N-terminus of the atrial natriuretic factor (ANF) prohormone that contains two potent diuresis-producing hormones consisting of amino acids (aa) 1-30 (pro ANF 1-30; long-acting sodium stimulator) and aa 31-67 (pro ANF 31-67; vessel dilator) of this 126 aa prohormone. Seven healthy volunteers (mean age, 31 years) had the circulating concentration of the N-terminus of the ANF prohormone evaluated at 1, 2, and 3 ATA in a monoplace hyperbaric chamber by two specific and sensitive radioimmunoassays that immunologically recognize (1) the whole 98 aa N-terminus and (2) the midportion of the N-terminus consistent with aa 31-67 (pro ANF 31-67). With increasing ATA from 1 (sea level) to 2 (equivalent to 33 feet of sea water), the circulating concentrations of both the whole N-terminus and pro ANF 31-67 increased threefold. At 3 ATA (66 feet of sea water), their circulating concentrations increased sixfold over their concentrations, at 1 ATA. With the addition of 100 percent O2 while at 3 and 2 ATA, the circulating concentrations of both the whole N-terminus and pro ANF 31-67 immediately decreased to their prehyperbaric ATA levels and remained there with further decompression to 1 ATA and removal of O2 supplementation. The increased circulating concentration of the N-terminus of the ANF prohormone containing two peptides with potent diuretic effects during increasing atmospheres of absolute pressure may help to explain the diuresis that has been observed with increasing ATA.

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.

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.

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.

Release of atrial natriuretic factor with increasing absolute atmospheres of pressure in a hyperbaric chamber and reversal with oxygen therapy.

Diving is associated with a marked diuresis which can be accurately reproduced in a hyperbaric chamber where the pressure of a specific depth can be precisely controlled. The present investigation was designed to determine if the diuresis observed with diving is associated with increased release of a new diuresis-producing hormone, atrial natriuretic factor (ANF). Seven experienced divers (3 men and 4 women; average age of 31 years) had their circulating concentration of atrial natriuretic factor measured at 1, 2 and 3 atmospheres of absolute pressure (ATA) in a monoplace hyperbaric chamber while breathing air. With the simulated dive to 33 feet (2 ATA), the circulating concentration of ANF increased 3-fold and at a depth of 66 feet (3 ATA) ANF increased 6-fold over the concentration at 1 ATA. With the addition of 100% oxygen while at depths of 33 and 66 feet, the concentration of ANF immediately decreased to its pre-dive concentration and remained there with further decompression to surface air and removal of oxygen supplementation. Thus, the increased release of ANF with depth may help to explain the diuresis observed with diving.

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.