Reciprocal paracrine pathways link atrial natriuretic peptide and somatostatin secretion in the antrum of the stomach.

Atrial natriuretic peptide (ANP) as well as its receptor, NPR-A, have been identified in gastric antral mucosa, suggesting that ANP may act in a paracrine fashion to regulate gastric secretion. In the present study, we have superfused antral mucosal segments obtained from rat stomach to examine the paracrine pathways linking ANP and somatostatin secretion in this region.ANP (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion (EC(50), 0.3 nM). The somatostatin response to ANP was unaffected by the axonal blocker tetrodotoxin but abolished by addition of the selective NPR-A antagonist, anantin. Anantin alone inhibited somatostatin secretion by 18+/-3% (P<0.005), implying that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion. Somatostatin (1 pM to 1 microM) caused a concentration-dependent decrease in ANP secretion (EC(50), 0.7 nM) that was abolished by addition of the somatostatin subtype 2 receptor (sst2) antagonist, PRL2903. Neutralization of ambient somatostatin with somatostatin antibody (final dilution 1:200) increased basal ANP secretion by 70+/-8% (P<001), implying that endogenous somatostatin inhibits ANP secretion. We conclude that antral ANP and somatostatin secretion are linked by paracrine feedback pathways: endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion, and endogenous somatostatin, acting via the sst2 receptor, inhibits ANP secretion.

Effects of kaliuretic peptide on sodium and water excretion in persons with congestive heart failure.

Kaliuretic peptide, a 20-amino acid peptide hormone synthesized in the heart, enhances urine flow twofold, whereas atrial natriuretic peptide (ANP) enhances urine flow four- to 11-fold in healthy persons. The present investigation was designed to (1) determine whether kaliuretic peptide may have beneficial diuretic effects in persons with congestive heart failure (CHF), and (2) compare its beneficial effects with ANP in the treatment of CHF. Kaliuretic peptide (100 ng/kg body weight/min) given intravenously for 60 minutes to subjects with New York Heart Association class III CHF increased urine flow fourfold (p <0.001), which was maximal 212 hours after its infusion was stopped. Kaliuretic peptide enhanced sodium excretion threefold in subjects with CHF (p <0.01). Kaliuretic peptide increased the urinary excretion rate of potassium ion and fractional excretion of potassium 3.5- and twofold (p <0.05), respectively. ANP (same concentration) did not significantly enhance urine flow. ANP enhanced sodium excretion two- to sixfold in half of the CHF subjects, whereas it had no effect on sodium excretion in the other half. ANP did not significantly increase fractional excretion of sodium but did increase fractional excretion of potassium (p <0.05) during the first 20 minutes of its infusion. ANP-infused patients with CHF became hypotensive. None became hypotensive secondary to kaliuretic peptide. These data indicate that the diuretic properties of kaliuretic peptide in persons with CHF, as opposed to those of ANP, are not diminished (but rather are increased) compared with their effects in healthy persons. In patients with CHF, kaliuretic peptide causes a natriuresis-a feature not observed in those without sodium retention.

Evidence supporting a physiological role for proANP-(1-30) in the regulation of renal excretion.

The experiments, performed in pentobarbital sodium-anesthetized rats, consisted of a 1-h equilibration period followed by two 30-min control periods. Subsequently, synthetic rat pro atrial natriuretic peptide (ANP) [proANP-(1-30)] (n = 8) was given as a bolus of 10 microg in 1 ml of 0.9% saline followed by an infusion at 30 ng/min (20 microl/min) for six additional periods. Control rats (n = 6) received only 0.45% saline in the appropriate volumes. Mean arterial pressure, renal blood flow, and glomerular filtration rate did not change significantly in either group during the proANP-(1-30) infusion. Urine flow and potassium excretion increased approximately 50% in the proANP-(1-30)-infused group only (P < 0.05). Sodium excretion and fractional excretion of sodium, expressed as the change from their own baselines, were significantly increased by the proANP-(1-30) infusion (P < 0.05), whereas cGMP excretion was similar in both groups. These results suggest that the rat sequence of proANP-(1-30) produces a natriuresis in the rat independent of changes in hemodynamics and renal cGMP production. In a second study, rats (n = 8) were prepared as above and pretreated with 0.4 ml iv of rabbit serum containing an antibody directed against proANP-(1-30) (anti-proANP group). The rats were volume expanded with 3 ml of 6% albumin in Krebs and observed for 3 h to determine if the anti-proANP would attenuate the responses to volume expansion. Control rats (n = 7) received 0.4 ml of normal rabbit serum. The elevation in potassium excretion in response to volume expansion was significantly attenuated in the anti-proANP group (P < 0.05). Sodium excretion and urine flow responses also tended to be reduced but not significantly. These results suggest that in the rat, proANP-(1-30) plays a physiological role in regulating renal excretion.

Increased bioactivity of rat atrial extracts: relation to aging and blood pressure regulation.

The purpose of this study was to evaluate the possible role of atrial factor(s) in the regulation of cardiovascular homeostasis and their relationship to aging. Rats were anesthetized and received jugular vein, carotid artery, and bilateral ureteral catheterization. After a half-hour equilibration period, the rats received 0.5 ml of atrial extract with a concentration of proANP (atrial natriuretic peptide) of 150 microg/ml prepared from either aged (18-20 month, "aged extract group", n = 12) or young (2-3 month, "young extract group", n = 12) rats. Mean arterial pressure (MAP) and renal function were monitored over five 20-minute periods. The atrial extract caused MAP to fall significantly in the aged extract group (p < .05) but MAP was unchanged in young extract group. There was a significant difference in MAP between the two groups (p < .05). Urine output increased significantly in both groups after extract infusion (p < .05 in both cases). Sodium and potassium excretion showed similar responses. However, the diuresis, natriuresis, and kaliuresis after extract infusion would have been expected to be relatively lower in the aged extract group compared to the young extract group considering the significantly lower MAP in the aged extract group. High performance gel permeation chromatography (HP-GPC) analysis of the atrial extract showed an increased quantity of a large molecular weight C-terminal peptide in atrial extracts from aged rats compared to young rat atria. Plasma levels of ANP and proANP 1-30 both increased significantly after extract infusion in both aged and young groups, and there was no significant difference in ANP concentration between the two groups. However, the concentration of proANP 1-30 was significantly increased in the aged group compared to the young group after extract infusion. These results suggest that changes in the structure or processing of proANP in aging may contribute to the different hemodynamic responses.

Regulation of atrial natriuretic peptide gene expression in gastric antrum by fasting.

Atrial natriuretic peptide (ANP) gene expression was localized in the rat gastric antrum using immunohistochemistry and in situ hybridization to mucosal cells in the lower portion of the antropyloric glands. Colocalization of immunoreactive ANP, long-acting natriuretic peptide, i.e., proANP-(1-30), and serotonin in these cells identified them to be enterochromaffin cells. Fasting for 72 h in 8-mo-old (adult) rats produced a significant (P < 0.05) decrease in the levels of ANP prohormone mRNA, immunoreactive proANP-(1-30) and ANP to approximately 33% of that of fed rats. Fasting in 1-mo-old rats had no effect on these parameters. Transcripts for natriuretic peptide receptor subtypes NPR-A, NPR-B, and NPR-C were found in both mucosa and muscle tissues of the antrum. ANP, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) stimulated the production of cGMP in antral mucosa in vitro with a potency of ANP > BNP >> CNP, suggesting that these receptors were functional. We conclude that fasting decreases ANP prohormone mRNA and its gene products, long-acting natriuretic peptide, and ANP in the antrum of adult rats.

Comparison of vessel dilator and long-acting natriuretic peptide in the treatment of congestive heart failure.

BACKGROUND: Long-acting natriuretic peptide (LANP; proANF 1-30) and vessel dilator (proANF 31-67) enhance sodium and water excretion in healthy human beings. The current investigation was designed to compare the beneficial effects of LANP and vessel dilator in persons with congestive heart failure (CHF). METHODS AND RESULTS: LANP and vessel dilator (100 ng/kg body weight/min, respectively) were given intravenously for 60 minutes to subjects with New York Heart Association class III CHF (n = 17) while their urine volume and sodium and potassium excretion were monitored. Vessel dilator increased urine flow more than 5-fold, which was still increased (P <.001) 3 hours after stopping its infusion. Vessel dilator enhanced sodium excretion 3-fold in subjects with CHF (P <.01), which was still significantly (P <.01) elevated 3 hours after infusion. The effects of LANP were diminished, with urine flow only increasing 2-fold (P <.05). The fractional excretion of sodium increased maximally 6-fold secondary to vessel dilator and 3-fold with LANP. The CHF control patients had no changes in the above parameters. Part of the diminished response to LANP was found to be caused by its rapid decrease in the circulation of individuals with CHF. CONCLUSIONS: These results indicate that vessel dilator has significant beneficial diuretic and natriuretic properties, which are not diminished, whereas the effects of LANP are diminished in human beings with CHF compared with healthy individuals.

Elevated atrial natriuretic peptides and early renal failure in type 2 diabetic Goto-Kakizaki rats.

The present investigation was designed to determine if atrial natriuretic peptides (ANPs) are increased in a spontaneous model of non-obese type 2 diabetes, the Goto-Kakizaki (GK) rat. Four peptide hormones originating from the ANP prohormone were increased twofold (P < .05) to sixfold (P < .01) in the circulation of GK rats compared with nondiabetic Wistar rats from which the GK colony was originally derived. Thus, ANP, long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide were (mean +/- SE) 497 +/- 78, 1,285 +/- 105, 457 +/- 45, and 385 +/- 87 pg/mL in GK rats, versus 78 +/- 23, 542 +/- 77, 137 +/- 26, and 134 +/- 33 pg/mL, respectively, in Wistar rats. In evaluating the cause of the increased ANPs, the blood volume of GK rats (16.2 +/- 0.4 mL) was significantly (P < .01) increased compared with Wistar rats (9.5 +/- 0.3 mL). The ventricles of GK rats were not dilated when examined by transthoracic echocardiography, but the venous system was markedly distended. GK rats had a 48% to 79% decrease in renal function (ie, increased serum creatinine and blood urea nitrogen [BUN]) compared with Wistar rats. These results indicate that circulating ANPs are increased in the GK spontaneously diabetic rat secondary to (1) increased blood volume, which leads to increased synthesis and release of ANPs, and (2) renal failure, which results in a delayed metabolic processing of these peptides. The early combined increases of the four atrial peptides collectively may contribute to the hyperfiltration that occurs in early diabetes mellitus.

Endotoxin-induced atrial natriuretic factor release: in vivo and in vitro studies.

OBJECTIVE: We evaluated the effects of coliform endotoxin on the circulating levels of atrial natriuretic factor and renal function. To understand the direct effects of endotoxin in the release of atrial natriuretic factor by cardiac tissue, studies in isolated rat atria were performed. STUDY DESIGN: In vivo studies were used. Anesthetized dogs were studied, with one group receiving isotonic saline solution (n = 6) and the other group receiving 50 microg/kg of coliform endotoxin (n = 7) as a continuous infusion over a 4-hour period. Cardiovascular parameters, renal function, and circulating levels of atrial natriuretic factor were measured at specified time intervals. In another set of experiments with in vitro studies left atria from Sprague-Dawley rats were isolated and perfused. In the control group (n = 9) the standard Krebs perfusate was used. In the endotoxin group (n = 9) coliform endotoxin was added at a concentration of 250 microg/mL to the standard perfusate. Atrial pressure was used as an index of stretch, and atrial natriuretic factor was measured from the perfusate. RESULTS: Administration of endotoxin resulted in decreased blood pressure (P < .05) with a concomitant increase in heart rate. Renal artery flow, however, showed an increase (P < .05) initially followed by a return to its baseline value, with a sustained increase occurring in the saline solution control group. A significant (P < .05) and sustained increase in the circulating levels of atrial natriuretic factor after endotoxin infusion did not prevent the decrease in fractional sodium excretion (P < .05) and creatinine clearance despite an increase in the urinary output. Serum sodium, serum potassium, and osmolalities, however, remained relatively stable. The study pertaining to isolated atria showed that in the presence of low atrial pressures, addition of endotoxin had no significant effect on the release of atrial natriuretic factor. With the increase in atrial pressure atrial natriuretic factor release was significantly higher in the group directly exposed to endotoxin compared with the control group. CONCLUSIONS: These studies demonstrate that the slow infusion of coliform endotoxin results in increased circulating levels of atrial natriuretic factor. This increase is in part due to the direct effect of endotoxin on the heart as indicated by studies in isolated atria. Our data suggest that atrial natriuretic factor in endotoxemia acts in an integrative manner with other hormones on a variety of target organs to modulate cardiovascular function and fluid balance.

Vessel dilator enhances sodium and water excretion and has beneficial hemodynamic effects in persons with congestive heart failure.

BACKGROUND: Vessel dilator, a 37-amino acid peptide hormone synthesized in the heart, enhances urine flow 4- to 12-fold and sodium excretion 3- to 6-fold in healthy humans. The present investigation was designed to determine whether vessel dilator might have similar beneficial effects in persons with congestive heart failure (CHF). METHODS AND RESULTS: Vessel dilator (100 ng/kg body weight per minute) given intravenously for 60 minutes to NYHA class III CHF subjects increased urine flow 2- to 13-fold, which was still increased (P<0.001) 3 hours after its infusion was stopped. Vessel dilator enhanced sodium excretion 3- to 4-fold in CHF subjects (P<0.01), which was still significantly (P<0.01) elevated 3 hours after infusion. Vessel dilator decreased systemic vascular resistance 24%, pulmonary vascular resistance 25%, pulmonary capillary wedge pressure 33%, and central venous pressure 27% while increasing cardiac output 34%, cardiac index 35%, and stroke volume index 24% without significantly affecting heart rate or pulmonary artery pressure in the CHF subjects. The control CHF patients did not have any changes in the above parameters. CONCLUSIONS: These results indicate that vessel dilator has significant beneficial diuretic, natriuretic, and hemodynamic properties in humans with congestive heart failure.

Alterations in the opioid control of LHRH release from hypothalami isolated from aged male rats.

Several lines of evidence have suggested that the opioid control of gonadotropin secretion in the male rat is altered with aging. Because neural control of gonadotropins is mediated through luteinizing hormone releasing hormone (LHRH) secreting neurons, we examined the postulated changes in the opioid control of gonadotropins more directly by studying isolated hypothalamic fragments in vitro. Hypothalami from young (75-90 days) and old (18-20 months) males were examined for their ability to release LHRH when incubated with increasing doses of naloxone in a semi-static culture system. Serum concentrations of testosterone and luteinizing hormone (LH) in the donor animals were both significantly lower in old male rats compared with young males. Basal secretion of LHRH was similar in both age groups. Two-way repeated measures ANOVA indicated that naloxone stimulated a significant dose-dependent increase in the release of LHRH into the media. ANOVA also indicated a significant effect of age. We conclude that the changes in the endogenous opioid systems reported to occur with aging are, in fact, linked to differences in LHRH secretion and thus to differences in the dynamic relationship between testosterone and LH in older male rats.

Alterations in atrial natriuretic peptide (ANP) secretion and renal effects in aging.

Aging is associated with hypertension and electrolyte disturbances. The purpose of this study was to determine the effect of aging upon secretion and renal actions of atrial natriuretic peptide (ANP). Rats were anesthetized and received tracheal, jugular vein, carotid artery, and bilateral uretheral catheterization. One set of young (2-3 mo) rats (Group 2, n = 9) and one set of old (18-21 mo) rats (Group 4, n = 7) received bilateral atrial appendectomies. Control young (Group 1, n = 8) and old (Group 3, n = 8) rats received a sham appendectomy. All rats were infused (iv) with 6% albumin in Krebs buffer, sufficient to increase blood volume by 15%. Finally, each rat was injected with ANP (1 microgram/kg). Sodium excretion rate (U(Na+)V) in response to volume expansion was significantly decreased in all groups compared to Group 1 (young control, p < .05). All groups demonstrated a striking increase in U(Na+)V with the ANP injection, but the response was greatest in young control rats when factored by body weight (p < .05). There were no significant differences in MAP between the groups, suggesting that the differences in U(Na+)V observed were not the result of hemodynamic factors. Isolated perfused atria from young (n = 9) and old (n = 8) rats were subjected to stretch and endothelin stimulation (50 nM). Atria from young rats showed a dramatic increase in ANP secretion in response to atrial stretch and a further marked increase in secretion in response to endothelin, whereas both of these responses were markedly attenuated in old rats (p < .05). These results suggested that the secretion and renal effects of ANP are impaired in aging. Changes in secretion and actions of ANP in aging could contribute to the development of hypertension or heart failure.

Endothelin and nitric oxide interact to regulate stretch-induced ANP secretion.

The purpose of this study was to determine the nature of the permissive effect of atrial stretch on atrial natriuretic peptide (ANP) secretion and the mechanism for the rapid termination of endothelin (ET) signaling following the removal of ET-dependent stimuli. Basal ANP release was not affected by either an elevation or inhibition of nitric oxide (NO) activity, but stretch-stimulated ANP release was significantly reduced from 144 +/- 20% to -3 +/- 7% of the baseline by increased NO activity. Furthermore, while the response to ET alone at low pressure was 37 +/- 13% of the baseline ANP secretion rate (P > 0.05), this response increased to 137 +/- 27% (P < 0.05) when NO activity was blocked, a response equal to the control high-pressure response (144 +/- 20%). Thus the reduction in NO activity is a permissive effect of stretch, and NO can rapidly terminate an ET-stimulated ANP response. Therefore, stretch-induced ANP secretion is regulated by a reciprocal interaction between locally produced ET, which appears to increase, and NO, which appears to decrease.

Endoscopic approach for benign tumor ablation of the forehead and brow.

Resection of benign tumors of the forehead and brow raises aesthetic concerns. An endoscopic subperiosteal approach to benign bony and soft-tissue tumors in the supraorbital and frontotemporal regions permits extirpation of these masses without producing visible facial scars. Therefore, this technique was used for tumor resection in 4 patients. This procedure demonstrated magnified visualization of the masses, and safe access for excisional biopsy and bony contouring. In addition to more acceptable surgical scars, patients experienced no significant postoperative morbidity and a reduced incidence of swelling, discomfort, and scalp anesthesia. Therefore, we conclude that the endoscopic subperiosteal approach is a favorable alternative for resection of suitable tumors.

Mechanism of anoxia-induced atrial natriuretic peptide release in the isolated rat atria.

Our laboratory has recently shown that locally produced endothelin (ET) is involved in the atrial natriuretic peptide (ANP) response to a physical stimulus, stretch. The aim of this study was to determine if factors locally produced in the atria were involved in the ANP response to a chemical stimulus, anoxia. Reduced oxygen tension is a potent stimulus of ANP release, and our results show that, when isolated perfused atria were exposed to anoxic conditions, the ANP secretion rate increased by a maximum of 129 +/- 8% of the baseline. Exposure to anoxia caused neither an elevation in perfusate creatinine phosphokinase, a change in atrial morphology detectable by electron microscopy, nor interfered with the return toward the baseline ANP secretion rate with reoxygenation, suggesting that this response was not due to myocyte damage. When the atria were pretreated with either 3 microM BQ-123, an endothelin receptor inhibitor, or 10 microM indomethacin, a cyclooxygenase inhibitor, the ANP response to anoxia was nearly abolished. To clarify the association between ET and prostaglandins, we showed that the ANP response to 50 nM ET-1 was totally blocked at both high and low pressure by 10 microM indomethacin, but the increased contractility response to ET was unaffected. Therefore, we have concluded that the anoxia-induced ANP response is mediated by locally produced ET, which, in turn, stimulates the production of prostaglandins. Prostaglandins appear to be responsible for the increased ANP secretion rate.

Endothelin acts as a paracrine regulator of stretch-induced atrial natriuretic peptide release.

Several lines of evidence suggest a paracrine regulatory role for endothelin (ET) in the release of atrial natriuretic peptide (ANP). To investigate this possibility, we used the ET A-type receptor (ETA-R) competitive inhibitor cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123) in isolated perfused atria to determine the effect of endogenously produced ET on the release of ANP. Initially, we found that high pressure (8-10 mmHg) increased the mean ANP secretion rate by 117.3 +/- 21.2% (P < 0.05). Next, we found that at high pressure 50 nM of exogenously applied ET significantly augmented the stretch-induced release of ANP (P < 0.05) and that this response could be significantly attenuated in a dose-dependent manner by 1 and 3 microM BQ-123 (P < 0.05). These experiments proved the efficacy of the inhibitor in our model. Subsequently, we found that the stretch-induced release of ANP was significantly reduced to 51.5 +/- 13.0 and 22.3 +/- 11.8% by 1 and 3 microM BQ-123, respectively (P < 0.05). Because the perfused atria model eliminates systemic cardiovascular effects, allows control and direct recording of the intra-atrial pressure, and preserves the potential endothelium-myocyte control system, we conclude that the stretch-induced release of ANP is partially regulated by ET and that the ET is locally produced and constitutes a paracrine control system.

Salt excretory capacity in natives adapted to moderate high altitude living after acute mobilization to sea level.

The sodium excretory capacity of six normal subjects born and raised at moderately high altitude (2600 m) was evaluated at high altitude (HA), and after acute mobilization to sea level (SL). The ability of these individuals to respond to an acute salt load was evaluated by infusing a volume of 100 ml.m-2 body surface area (BSA) of 5% sodium chloride solution over a 30-min time period in both experimental conditions. HA natives were able to excrete a significantly greater salt load at HA than at SL (41.8% vs. 31.6%, respectively, p < 0.05) in 3 h. No changes in plasma atrial natriuretic factor (ANF) concentration were found in either experimental condition. Despite an increase in serum osmolality, no vasopressin (AVP) response was noted either at HA or SL. No correlation between serum AVP levels and urine c-AMP concentrations was found. The enhanced excretory response to a salt load at HA was not explained by the measured hormonal changes. The lack of AVP response to increased serum osmolality, both at HA and SL, in high altitude adapted subjects is presently unexplainable.

Antibodies to ICAM-1 protect kidneys in severe ischemic reperfusion injury.

ICAM-1 has been implicated in the pathophysiology of ischemic-reperfusion injury in a number of organs, but its role in mediating severe ischemic-reperfusion injury in the kidney has not been extensively studied. Uninephrectomized Sprague Dawley rats were pretreated with either control monoclonal antibody (mAb) or mAb to ICAM-1 and subjected to 60 min of renal artery occlusion. The serum creatinine, complete blood count and kidney histo-pathological damage scores (PDS) (Scale:0-4) were assessed prior to and 24 hours after ischemia. Mean serum creatinine (mg/dl) 24 hours after ischemia was significantly decreased in the anti-ICAM-1 group (1.38 +/- 0.23, p < 0.001) compared to control (2.87 +/- 0.34). PDS was also reduced in anti-ICAM-1 (2.55 +/- 0.20, p < 0.05) group compared to control (3.35 +/- 0.30). These data demonstrate that blocking ICAM-1 significantly mitigates severe ischemic acute renal failure, findings which may lead to improved therapy for this condition.

Secretion and renal effects of ANF prohormone peptides.

1. Atrial natriuretic factor (ANF) and pro ANF peptide appears to be secreted simultaneously from the atria in response to atrial stretch. 2. The major peptide forms secreted from rat atria appear to be ANF (pro ANF 99-126) as the primary C-terminal peptide and pro ANF 1-30 as the primary N-terminal peptide, as opposed to 1-67 or 1-98. 3. The plasma concentrations of ANF and pro ANF 1-30 are increased by acute stimulation with blood volume expansion and the plasma levels of ANF and N-terminal ANF prohormone peptides are chronically elevated by high salt diet. 4. Pro ANF 31-67 produces a natriuresis which is not dependent on an increase in renal cGMP excretion, decreases in plasma renin activity (PRA) or elevations in plasma ANF concentration.

Atrial natriuretic peptide fragments in dogs with experimental heart failure.

1. This study in the canine arteriovenous (AV) fistula model of high-output heart failure (HOHF) evaluated the chronic temporal changes in plasma ANF and pro ANF 31-67 and their relationship to body-fluid balance and the renin-aldosterone axis. In addition, the haemodynamic, hormonal and renal excretory effects of synthetic pro ANF 31-67 infusions were examined in normal and AV fistula dogs with compensated HOHF. 2. Following the construction of the AV fistula, the dogs exhibited chronic parallel elevations in right atrial pressure and the plasma concentrations of ANF and pro ANF 31-67. The gradual increases in the two peptides were associated with a gradual decrease in plasma renin activity and the re-establishment of sodium balance. 3. In normal and compensated AV fistula dogs, synthetic pro ANF 31-67 produced similar significant reductions in arterial blood pressure, right atrial pressure and elevations in urinary sodium excretion. These effects were not associated with increases in plasma or urinary cyclic GMP (cGMP). 4. These results suggest that the elevation in the endogenous circulating levels of pro ANF 31-67 in the AV fistula dogs may represent one chronic adaptive mechanism to achieve body fluid homeostasis. Furthermore, via potentially different mechanisms of action, ANF and pro ANF 31-67 may coordinate and contribute to the regulation of haemodynamic and renal function during physiological and pathophysiological situations.