Immunoreactive Atrial Natriuretic Factor Levels Research Articles

Volemie Status Influences the Response of Plasma Atrial Natriuretic Factor to Positive Airway Pressure

STUDY OBJECTIVE; To evaluate interactive effects of volemic status and positive end-expiratory pressure (PEEP) on the plasma levels of atrial natriuretic factor (ANF) in assist-controlled mechanical ventilation (MV). Three successive protocols applied in randomized order to each participant. Clinical investigation laboratory. Twenty-one young, healthy adults. The three protocols were as follows: (1) MV+PEEP, normovolemia; (2) MV+PEEP, hypervolemia; and (3) spontaneous breathing (SB), hypervolemia. In protocols 1 and 2, a preliminary period of SB lasting 2 h was followed by MV alone (0.5 h), MV+20 cm H2O PEEP (1 h), and a recovery period of SB (1.5 h). Hypervolemia was induced by the continuous i.v. infusion of 3 L of 0.9% NaCl in 5 h (protocols 2 and 3). Heart rate, BP, and the plasma levels of immunoreactive ANF and catecholamines were measured serially. During hypervolemia, ANF significantly decreased when PEEP was added to MV (protocol 2: from 31.1 +/- 2.7 to 20.7 +/- 1.5 fmol/mL; p < 0.01). This did not occur in normovolemia (protocol 1: from 20.0 +/- to 16.7 +/- 1.2 fmol/mL; p = NS). The different effects of MV+PEEP in normovolemia and hypervolemia were not related to differences in circulating catecholamine levels. These results demonstrate for the first time (to our knowledge) that volemic status modulates the response of plasma ANF to PEEP in humans. The role of ANF in the water and salt retention induced by MV with PEEP might be limited to hypervolemic conditions.

Hemodynamics in transgenic mice with overexpression of atrial natriuretic factor.

The circulatory effects associated with lifelong plasma atrial natriuretic factor (ANF) elevation were examined by generating transgenic mice, which constitutively express a fusion gene consisting of the transthyretin promoter and the ANF structural gene. These mice have chronically elevated ANF levels as compared with their nontransgenic siblings. Transgenic animals exhibited immunoreactive ANF levels that were nearly fivefold higher than those measured in nontransgenic littermates. Systemic and regional hemodynamics and blood volumes were explored by using modifications of the reference microsphere and dilution techniques. Mean arterial pressure was reduced by 24 mm Hg, associated with a 27% reduction in total heart weight. This chronic reduction in blood pressure was due to a 21% reduction in total peripheral resistance, whereas cardiac output, stroke volume, and heart rate were not significantly altered, despite a 15% elevation in plasma volume. Transgenic mice displayed reductions of 35%, 33%, 32%, and 19% in muscle, skin, brain, and renal vascular resistance, respectively, whereas coronary and splanchnic resistances were not significantly altered. The findings complement earlier data from chronically infused normotensive mammals and suggest that these mice are an excellent model for investigating the effects of lifelong ANF elevation.

Heterogeneous regulation of renal atrial natriuretic factor receptor subtypes in one-kidney, one clip hypertensive rats.

To investigate the regulation of papillary atrial natriuretic factor (ANF) receptors and the differential regulation of glomerular ANF receptor subtypes in one-kidney, one clip (1-K,1C) hypertension. Plasma immunoreactive ANF levels and atrial and ventricular ANF content were measured in 1-K,1C rats and their normotensive uninephrectomized controls. Glomerular and papillary ANF receptor subtypes were characterized by competitive radioligand binding assay. Stimulation of cyclic GMP (cGMP) production, by increasing ANF doses, was examined in isolated glomeruli. Plasma amino-terminal ANF levels were higher in 1-K,1C than in control rats. ANF concentrations in the left atrium were lower and ventricular ANF concentrations were higher in the 1-K,1C group. Competition binding curves for glomerular membranes revealed the presence of two binding sites (ANF-R1 and ANF-R2) in both groups. Total glomerular ANF receptor density was lower in 1-K,1C rats than in their normotensive controls. Both receptor subtypes were downregulated in 1-K,1C rats and their relative proportion was similar to that in glomerular preparations from the controls. ANF-stimulated cGMP production by isolated glomeruli was lower in 1-K,1C than in normotensive rats. In papillary membranes, ANF was bound to a homogeneous population of high-affinity binding sites in both groups. A modest augmentation in the density of papillary ANF receptors was observed in 1-K,1C rats. Glomerular and papillary ANF receptors may be regulated differently in the presence of elevated plasma ANF levels. The present results indicate that the downregulation of glomerular ANF-R1 and the reduced cGMP response may lead to altered sodium and water handling by the kidney of 1-K,1C hypertensive rats.

Atrial natriuretic factor in experimental acute Chagas' disease.

The atrial myocyte of the mammalian heart produces atrial natriuretic factor (ANF) (de Bold et al. 1981), a polypeptide hormone that participates in the regulation of extracellular fluid volume and blood pressure (de Bold 1985). Changes in ANF synthesis and storage have been observed in a wide spectrum of myocardial pathologies (Morii et al. 1989; Tsunoda et al. 1986) and have been related to the development of congestive heart failure. The heart, particularly the atrial muscle, is the main target of Trypanosoma cruzi during the acute period of infection (Tafuri 1979). We have previously shown a drastic decrease in the number of specific atrial granules, the site of ANF storage, and in the natriuretic activity of atrial extracts in acute Chagas' disease in rats (Piazza et al. 1992). In the present work, we characterized changes in cardiac and plasma immunoreactive ANF levels in acute Chagas' infection together with parasitological, serological, electrocardiographic and histopathological changes. Wistar rats (28+3 days of age) were injected intraperitoneally with 6 x 105 trypomastigotes of the T. cruzi X-1 strain obtained from infected mice (Cano and Rubiolo 1985). A control group was inoculated with the same volume of blood from healthy mice. The acute phase of Chagas' disease was studied until 40 days postinfection (p.i.). The parasitaemia course was followed using the direct method of Hoff (1974) in blood drawn by cardiac puncture twice a week p.i. The serological response was evaluated using three standard methods, indirect haemagglutination (Rubiolo and Vottero-Cima 1979), indirect immunofluorescence (Camargo 1966)

An atrial natriuretic factor analogue at low doses attenuates forearm reflex vasoconstriction to cardiopulmonary receptor deactivation in patients with hypertension

Contrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings, particularly at low, biologically, significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47,663, anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (−10 mm Hg × 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 μg/kg/min × 60 min, which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 μg/kg/min × 60 min, each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell × 30 min). Forearm blood flow (venous plethysmography), intraarterial blood pressure, and heart rate were monitored continuously, and venous immunoreactive ANF, plasma renin activity, aldosterone level, and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values, an indirect index of sympathetic discharge, were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit, decreased aldosterone level and plasma renin activity, whereas resting norepinephrine levels, blood pressure, and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion, but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action, ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF. Blood flow increased dose-relatedly during the local administration of ANF, but lower body negative pressure still constricted forearm arterioles. Thus the effect of the peptide, event at low, possibly physiologic concentrations, was not related to a direct vasorelaxant action and was more likely related to an interaction with the cardiopulmonary baroreceptor control system. Autonomic modulation may be a relevant blologic action of ANF in patients with hypertension.

Chronic vs. acute hemodynamic effects of atrial natriuretic factor in conscious rats

The present study was designed to examine acute (2 h) and chronic (5 day) effects of pathophysiological elevations of plasma atrial natriuretic factor (ANF) in conscious normotensive rats. Acute infusion of ANF (100 ng.kg-1.min-1; n = 15) resulted in a decrease in mean arterial pressure (MAP) of 5 +/- 3 mmHg, which was associated with a 23 +/- 4% decrease in cardiac output (CO) and a 27 +/- 6% increase in total peripheral resistance (TPR). Hematocrit increased from 41.9 +/- 0.7 to 46.0 +/- 0.6%, which is suggestive of vascular volume contraction. Chronic infusion of ANF (n = 9) produced a significant fall in MAP from a control value of 114 +/- 2 to 100 +/- 3 and 99 +/- 2 mmHg on days 1 and 5, respectively. CO decreased significantly (27 +/- 2%) and TPR increased (21 +/- 5%) on day 1; neither variable was significantly different from control on day 5. Plasma immunoreactive ANF levels were significantly elevated during acute (791 +/- 76 pg/ml) and chronic (626 +/- 202 pg/ml) ANF infusion compared with control values of approximately 100 pg/ml. The results indicate that elevations in plasma ANF within the pathophysiological range can significantly alter systemic hemodynamics, initially mediated by a decrease in CO. Autoregulatory phenomena may counteract these hemodynamic effects, returning CO to control levels and reducing TPR when the elevations in plasma ANF are chronically sustained.

Acute and long-term changes in plasma levels of atrial natriuretic factor in patients with renal replacement therapy

In 14 patients on hemodialysis who received kidney grafts from living related donors, plasma levels of immunoreactive atrial natriuretic factor (Ir-ANF) were determined in a sequence covering the last hemodialysis treatment, the day of transplantation, and a follow-up period of 6-12 months. The geometric mean value before dialysis was 196 pg/ml, the range 32-634. Weight loss during dialysis was 1.5 +/- 1.1 kg (mean +/- SD), but only a nonsignificant reduction in Ir-ANF levels occurred. On the day of transplantation, plasma Ir-ANF levels increased from 143 pg/ml before to 391 post-transplantation (P = 0.02, n = 12), probably in response to deliberate volume expansion. Post-transplant Ir-ANF levels correlated significantly to diuresis during the first 24 h, which ranged from 3.7 to 17.81 (mean 6.6; r = 0.65, P = 0.02). On day 2, mean 24 h diuresis decreased to 3.3 +/- 1.41. Most patients had reached their true dry weight by day 5, but Ir-ANF levels remained high, the geometric mean being 180 pg/ml. During further follow-up and preserved graft function (GFR range 34-88 ml/min per 1.73 m2 body surface area), Ir-ANF levels declined to a geometric mean of 63 pg/ml by 2-6 months and to 36 at 12 months post-transplant. We conclude that plasma Ir-ANF levels are chronically elevated in patients with chronic renal failure but may be further stimulated by acute overhydration. Transplanted kidneys initially respond to the increased levels but adapt within a day. Even with good graft function, normalization of plasma Ir-ANF requires several weeks or months.

The inotropic effect of atrial natriuretic factor in the anesthetized rabbit

This study was designed to investigate whether atrial natriuretic factor (ANF) administered over the physiological, pathological and pharmacological range has a negative inotropic action on the heart. Anesthetized rabbits were infused with increasing doses of ANF (0.05, 0.25 and 0.5 micrograms kg-1 min-1), while measuring hemodynamic variables including the maximum rate of change of left ventricular pressure (dP/dtmax) as an index of inotropic state. Plasma levels of immunoreactive ANF (iANF) were measured to relate the hemodynamic changes to actual plasma levels of the peptide. Administration of ANF was associated with decreases in blood pressure, left ventricular pressure and dP/dtmax so that after 0.5 micrograms kg-1 min-1 infusion, these variables had decreased by 21 +/- 2 mmHg, 21 +/- 5.3 mmHg and 925 +/- 175 mmHg/s, respectively (P less than 0.01). There were no significant changes in right atrial pressure, left ventricular end-diastolic pressure or heart rate. Since dP/dtmax can be influenced by changing hemodynamic variables and baroreflex changes, a second group of rabbits was studied in which afterload and heart rate were held artificially constant. Again, in this group of rabbits, infusions of AFN led to decreasing inotropic state, so that at the highest infusion rate, a 14% decrease in dP/dtmax was observed (P less than 0.05). By comparison, hydralazine, a drug which causes active vasodilatation but no direct inotropic action, significantly (P less than 0.01) decreased blood pressure, left ventricular pressure and dP/dtmax when infused at a rate of 10 micrograms kg-1 min-1. However, in animals in which afterload was controlled, hydralazine did not affect any of the variables measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Requirement for Solutions with Oncotic Pressure to Release ANF During Blood Volume Expansion in Conscious and Anesthetized Rats

We examined the effect of a 30% blood volume expansion with either blood, isotonic saline, or isotonic saline plus albumin on the release of immunoreactiveatrial natriuretic factor (IR-ANF) in conscious and barbiturate-anesthetized rats. Immediately prior to volume expansion, resting plasma IR-ANF levels were significantly ( p < 0.05) higher in the conscious animals (61 ± 5 pg mL , n = 19) compared to the anesthetized animals (41 ± 3 pg mL , n = 19) . Volume expansion with blood from donor rats significantly ( p < 0.05) elevated IR-ANF in both groups, but the increase in the conscious rats (+492 ± 32 pg mL , n = 6) was significantly ( p < 0.05) greater than that of the anesthetized rats (74 ± 25 pg mL , n = 6) . Similarly, volume expansion with isotonic saline containing 38 mg mL albumin significantly ( p < 0.05) elevated IR-ANF levels in both groups, but the increase in the conscious group (379 ± 102 pg mL , n = 7) was significantly ( p < 0.05) greater than that of the anesthetized group (94 ± 32 pg mL , n = 7) . These elevations in IR-ANF levels were not significantly different between either of the conscious groups or either of the anesthetized groups. Volume expansion with isotonic saline alone did not have any significant effect upon resting IR-ANF levels in either conscious (+8 ± 14 pg mL , n = 6) or anesthetized (−7 ± 6 pg mL , n = 6) animals. From these results, it would appear that a) isotonic saline alone does not stimulate IR-ANF release when used to expand blood volume, and b) barbiturate anesthesia significantly lowers resting plasma IR-ANF levels and attenuates the release of IR-ANF in response to volume expansion.

Acute and long-term changes in plasma levels of atrial natriuretic factor in patients with renal replacement therapy

Abstract. In 14 patients on hemodialysis who received kidney grafts from living related donors, plasma levels of immunoreactive atrial natriuretic factor (Ir-ANF) were determined in a sequence covering the last hemodialysis treatment, the day of transplantation, and a follow-up period of 6–12 months. The geometric mean value before dialysis was 196 pg/ml, the range 32–634. Weight loss during dialysis was 1. 5 1. 1 kg (mean SD), but only a nonsignificant reduction in Ir-ANF levels occurred. On the day of transplantation, plasma Ir-ANF levels increased from 143 pg/ml before to 391 post-transplantation (P= 0. 02, n= 12), probably in response to deliberate volume expansion. Post-transplant Ir-ANF levels correlated significantly to diuresis during the first 24 h, which ranged from 3. 7 to 17. 81 (mean 6. 6; r= 0. 65, P= 0. 02). On day 2, mean 24 h diuresis decreased to 3. 3 1. 41. Most patients had reached their true dry weight by day 5, but Ir-ANF levels remained high, the geometric mean being 180 pg/ml. During further follow-up and preserved graft function (GFR range 34–88 ml/min per 1. 73 m2 body surface area), Ir-ANF levels declined to a geometric mean of 63 pg/ml by 2–6 months and to 36 at 12 months post-transplant. We conclude that plasma Ir-ANF levels are chronically elevated in patients with chronic renal failure but may be further stimulated by acute overhydration. Transplanted kidneys initially respond to the increased levels but adapt within a day. Even with good graft function, normalization of plasma Ir-ANF requires several weeks or months.

Relationship between atrial granularity and release of atrial natriuretic factor in rats with diabetes mellitus

We examined the effect of a 25% blood volume expansion on the release of atrial natriuretic factor (ANF) in conscious Wistar rats (13-15 wk old) injected 6 wk earlier with streptozotocin (55 mg/kg iv, diabetic) or saline (1 ml/kg iv, control). The diabetic rats demonstrated a significant (P less than 0.05) resting hypotension (132 +/- 2/91 +/- 1 mmHg, systolic/diastolic) and bradycardia (340 +/- 5 beats/min) compared with the controls (145 +/- 2/98 +/- 2 mmHg, 377 +/- 8 beats/min). Resting plasma immunoreactive (IR) ANF levels were significantly (P less than 0.05) elevated in the diabetic rats (control: 72 +/- 4 pg/ml; diabetic: 87 +/- 4), although resting right atrial pressures were not different (control: 6.0 +/- 0.8 cmH2O; diabetic: 5.2 +/- 0.6). Volume expansion with donor blood from similarly treated animals significantly (P less than 0.05) elevated IR ANF levels in both groups, but the increase in the saline-injected group (+527 +/- 80 pg/ml) was significantly (P less than 0.05) greater than that of the streptozotocin-injected group (+323 +/- 45 pg/ml). Both groups showed similar elevations in right atrial pressure (control: +1.8 +/- 0.3 cmH2O; diabetic: +1.6 +/- 0.4). Morphological examination of tissue taken from right atria demonstrated no difference in cardiocyte volume percent per unit of tissue but a significant (P less than 0.05) reduction in the relative frequency of occurrence of atrial granules in the diabetic group. The cause of the reduction in atrial granularity in these animals is as yet unknown.

Influence of hypothermic cardiopulmonary bypass on atrial natriuretic factor levels

Atrial natriuretic factor (ANF) is a peptide released from the heart in response to atrial distension. This peptide causes diuresis, vasodilatation, decreased blood pressure, and antagonizes the renin-aldosterone and antidiuretic hormone neuraxes. The influence of cardiopulmonary bypass and cardiac surgery on the circulation and release of ANF is unknown. Plasma ANF concentrations were therefore determined in patients undergoing coronary artery revascularization (CABG) and mitral valve replacement (MVR). Peptide levels were unchanged following anaesthetic induction. Plasma ANF concentrations decreased significantly during hypothermic (less than or equal to 28 degrees C) cardiopulmonary bypass in both patient groups. After 60 minutes of cardiac bypass, ANF declined from (mean +/- SEM) 512 +/- 132 to 20 +/- 6 pg.ml-1 (P less than 0.05) during MVR, and from 178 +/- 41 to 110 +/- 48 pg.ml-1 during CABG (P less than 0.05). Rewarming during bypass was associated with an increase in ANF concentration in both groups. Heparin anticoagulation and protamine reversal had no effect on immunoreactive ANF levels. In patients undergoing CABG, there was a linear relationship between plasma ANF concentration (pg.ml-1) and right atrial pressure (mmHg) prior to cardiopulmonary bypass (r = 0.86, P less than 0.005). However, one and three hours after cardiopulmonary bypass there was no significant relationship between right atrial pressure and ANF plasma levels. These results suggest that reduction in plasma ANF concentration occurs during hypothermic cardiopulmonary bypass. Furthermore, the proportional relationship between atrial distension and circulating ANF concentration was altered following cardiac surgery.

Ventricles as a major site of atrial natriuretic factor synthesis and release in cardiomyopathic hamsters with heart failure.

The aim of the present study was to correlate in cardiomyopathic hamsters with congestive heart failure the levels of atrial and ventricular atrial natriuretic factor (ANF) messenger RNA (mRNA) with immunoreactive ANF (IR-ANF) plasma levels and the relative amount of IR-ANF released by the whole heart versus isolated ventricles in the Langendorff preparation. High-performance liquid chromatography analysis of the forms of ANF present in plasma and in the Langendorff effluent of whole heart versus isolated ventricles was also performed. As previously found for cardiac IR-ANF, the levels of ANF mRNA decreased gradually in atria and increased in an analogous fashion in ventricles with the severity of congestive heart failure. Plasma IR-ANF levels (C-terminal) were more elevated in moderate than in severe congestive heart failure, as were the IR-ANF levels in the Langendorff effluent of the whole heart. On the contrary, the effluent of isolated ventricles from animals in severe heart failure yielded more IR-ANF than that from hamsters in moderate heart failure. Thus, while the isolated ventricles from controls contributed 35.8% of IR-ANF released by the whole heart, ventricles from hamsters in moderate heart failure contributed 17.5%, and those from hamsters in severe heart failure contributed 73.9%. These results indicate that atrial cardiocytes contribute more IR-ANF than their ventricular counterpart in moderate heart failure and that ventricles are a major source of plasma IR-ANF in severe heart failure. Analysis of IR-ANF from plasma and the Langendorff effluent from whole hearts and isolated ventricles revealed that the ventricles are the major source of the propeptide (and of its cleaved products) found in the circulation of cardiomyopathic hamsters. These results suggest that ANF synthesis and secretion do not increase conjointly in atria but do increase in ventricles during congestive heart failure.

Atrial Natriuretic Factor During the Perinatal Period: Equal Depletion in Both Atria'

Data in the literature concerning atrial natriuretic factor (ANF) physiology in the fetus and newborn, although limited, suggest significant activity during the perinatal period. To characterize further ANF physiology during this time, we documented immunoreactive ANF (IR-ANF) concentrations in the right and left atria before and immediately after birth as well as in the hearts of immature and adult rats. There was a significant decrease in the concentration of IR-ANF in both right and left atria on the d before birth that persisted for the first 48 h of life [d 20 fetal right 570 (106, 90), left 580 (86, 75); d 21 fetal right 270 (70, 55), left 214 (117, 75); 1 d right 206 (39, 33), left 229 (41, 35); 2-d right 352 (35, 32), left 237 (26, 23) [geometric mean (upper SE, lower SE) in ng ANF/mg protein]. Repletion of ANF stores began in the right atrium on d 2 of life and in the left atrium between d 2 and 5. The highest levels of IR-ANF were observed at d 15 [d 5 right 1439 (53,51), left 1547 (83,79); d 15 right 2034 (90,86), left 1943 (108, 102); adult right 1380 (119, 109), left 963 (118, 105)]. In contrast to normal adult animals, factors mediating the observed change affect both atria equally during the perinatal period. The concentration of IR-ANF in the right and left atrium of the fetal, newborn, and immature animals was equal. These data document significant alterations in intraatrial IR-ANF concentrations in the perinatal period.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of vasopressors on atrial natriuretic factor and hemodynamic function in humans.

To assess the effects of vasopressors on plasma levels of immunoreactive atrial natriuretic factor (ANF), 13 normal men were studied on two occasions. On the experimental day, subjects received sequential 15-minute intravenous infusions of angiotensin II in doses of 4, 8, and 16 pmol/kg/min. Following a 30-minute recovery period, subjects received sequential 15-minute infusions of phenylephrine in doses of 0.4 and 0.8 micrograms/kg/min. Right atrial pressure, mean pulmonary capillary wedge pressure, pulmonary artery pressure, mean systemic arterial pressure, and plasma levels of renin activity, aldosterone, angiotensin II, and immunoreactive ANF were obtained sequentially throughout the protocol. During the control day, vehicle was infused and plasma samples were obtained for hormone measurements. Infusion of angiotensin II and phenylephrine increased mean systemic arterial pressure in a stepwise fashion. Both right atrial pressure and pulmonary capillary wedge pressure increased significantly during both doses of phenylephrine, but only the highest dose of angiotensin II significantly increased atrial pressures. Plasma levels of immunoreactive ANF increased parallel with the changes in right atrial pressure and pulmonary capillary wedge pressure, with significant increases occurring only at the highest dose of both pressors. Angiotensin II and aldosterone levels increased and renin activity decreased during infusion of angiotensin II. There were no significant changes in plasma levels of immunoreactive ANF during the control day. These studies demonstrate that infusion of vasopressors increases plasma levels of ANF, but only when the vasopressor effect is associated with significant increases in right atrial and pulmonary capillary wedge pressures. Atrial stretch is the most likely mediator of the increase in plasma levels of immunoreactive ANF during vasoconstriction.

Atrial natriuretic factor in experimental and human hypertension.

Plasma levels of immunoreactive atrial natriuretic factor (IR-ANF) were evaluated by radioimmunoassay in several models of experimental hypertension and in human hypertension. Plasma levels of IR-ANF are consistently increased in all models of experimental hypertension studied so far. This is accompanied by a decrease of IR-ANF levels in the left atrium at certain times. Plasma levels of IR-ANF are not increased in human essential hypertension, except in the severe form (diastolic blood pressure above 110 mmHg). Peripheral levels of IR-ANF in renovascular hypertension do not differ from normal but are increased above normal in aortic blood.

Immunoreactive atrial natriuretic factor is increased in ovine model of endotoxemia

A bolus of Escherichia coli endotoxin (1.5 micrograms/kg) was administered to chronically instrumented sheep. Immunoreactive atrial natriuretic factor (IR-ANF) was measured in extracted plasma by radioimmunoassay. There was a thirteenfold increase in IR-ANF 2 h after endotoxin administration, and IR-ANF levels remained significantly elevated during the first 6 h. A marked diuresis and natriuresis occurred between 4 and 6 h. ANF not only affects renal function but is also associated with decreased cardiac output, increased peripheral resistance (in sheep), and decreased capillary absorption (in rats). These renal and hemodynamic changes are also characteristic of the early (first 6 h) response to endotoxin. Therefore ANF should be considered as a potential mediator of renal and hemodynamic changes induced by sepsis. It is difficult to determine if ANF elevation is an epiphenomenon or a causative factor, because no antagonist of ANF is currently available.

The heart as an endocrine gland.

The sequence of atrial natriuretic factor (ANF) has been determined, as well as the complete structure of the rat and human complementary DNA and gene. ANF and ANF messenger RNA are present not only in atria but also in ventricles. The circulating form of ANF has been identified as the C-terminal of the molecule, ANF (Ser 99-Tyr 126). The isolated secretory granules of rat atrial cardiocytes contain only pro-ANF (Asn 1-Tyr 126). An enzyme (IRCM-SP1) has been isolated from heart atria and ventricles. This enzyme is highly specific in cleaving ANF (Asn 1-Tyr 126), to yield ANF (103-126), (102-126), and (99-126). In target cells, ANF produces a rise in cyclic guanosine 3',5'-monophosphate (cGMP) due to activation of particulate guanylate cyclase, and inhibition of adenylate cyclase leading in some cases to a decrease in cyclic adenosine 3',5'-monophosphate (cAMP). ANF produces relaxation of rabbit and rat aortic strips, inhibits steroidogenesis in both zona glomerulosa and zona fasciculata cells, and inhibits the release of arginine vasopressin from the isolated rat hypothalamohypophysial preparation in vitro but decreases AVP release in vivo only at pharmacological doses. In all forms of experimental hypertension, plasma levels of ANF are increased and, at some time periods, atrial levels are also decreased. The ventricular levels of immunoreactive ANF are also increased in renal hypertension. Infusion of ANF by minipumps decreases the blood pressure near control levels in several models of experimental hypertension. In cardiomyopathic hamsters with heart failure, the atrial levels of immunoreactive ANF are decreased while the plasma and ventricular levels are increased.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of opioids on rat plasma atrial natriuretic peptide

The effect of multiple opioid receptor agonists on plasma immunoreactive atrial natriuretic factor (IR-ANF) was studied in conscious non-hydrated rats. We found that μ-opioid receptor agonists, given subcutaneously, increased plasma IR-ANF, while κ-receptor agonists did not alter the plasma levels of IR-ANF. The μ-agonist fentanyl (0.05 mg/kg) caused a 10-fold increase in the concentration of IR-ANF, maximal levels being reached within 5–10 min. U 50,488-H and ethylketocyclazocine (EKC), both selective κ-receptor ligands, were ineffective in this respect. The effect of fentanyl upon plasma IR-ANF was completely abolished by pretreatment with the narcotic antagonist naltrexone, proving opioid receptor specificity of the fentanyl effect. The quaternary antagonist N-methylnaltrexone (1 mg/kg) failed to block the fentanyl-induced increase of ANF, suggesting that opiates bring about their action on ANF via a central mechanism.

Effects of volume change on circulating immunoreactive atrial natriuretic factor in rats.

The mammalian atrial hormone atrial natriuretic factor (ANF) has been shown to have potent natriuretic and diuretic actions as well as vasodilator effects when released into the circulation. To investigate how the levels of the circulating form of this peptide change with alteration of intravascular fluid volume, we measured immunoreactive ANF in the plasma of Wistar rats after acute saline load, acute furosemide treatment, and chronic water restriction. Circulating levels of immunoreactive ANF increased significantly (p less than 0.001) 1 minute after acute saline load and returned to normal levels within 5 minutes. Volume contraction induced by furosemide treatment of chronic water restriction significantly reduced the circulating immunoreactive ANF. These data indicate that acute volume expansion causes an immediate release of immunoreactive ANF into the general circulation and acute volume contraction results in a decline of circulating levels of immunoreactive ANF, which is maintained during chronic volume contraction. These results suggest that the atria detect alterations in intravascular fluid volume and respond by changing the levels of ANF acutely as well as chronically and thereby participate in the regulation of body fluids and, perhaps, of blood pressure.