Increase In Atrial Natriuretic Peptide Research Articles

Induction of cardiac natriuretic peptide gene expression in rats trained in hypobaric hypoxic conditions.

Adaptation of cardiac muscle to prolonged hypobaric hypoxia (770-740 mbar, 2,250-2,550 m), endurance training, and their combination was studied in rats by investigating the gene expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in atria and ventricles. Rats were assigned into the following groups according to the barometric conditions and physical activity; normobaric sedentary (NS), normobaric training, hypobaric sedentary (HS), and hypobaric training (HT). Experimental periods were 10, 21, and 56 days; the groups at 91 days served as recovery groups from exposure to and training in normobaric and hypobaric conditions for 56 days. The right ventricular hypertrophy in HT rats at 10 days and 56 days was associated with elevated BNP mRNA levels (2.1- and 1.7-fold, P < 0.05, respectively), whereas hypobaric exposure without training was not sufficient to significantly increase ventricular BNP gene expression, although it lead to hypertrophy of the right ventricle. Right and left atrial BNP mRNA levels were also increased (up to 3.9-fold, P < 0.01) in 10-day HS and 10-day HT groups. ANP mRNA levels in right ventricle and left ventricular epicardium were over twofold higher (P < 0.05-0.01) in 10-day HS and 10-day HT groups in comparison to 10-day NS group. Plasma immunoreactive ANP concentration was increased (P < 0.05) in both hypobaric groups up to 21 days. The results show that exposure to hypobaric hypoxia itself and endurance training in hypobaric, hypoxic conditions lead to a marked early increase in ventricular and atrial ANP and BNP mRNA levels. The adaptational response to hypoxia was more pronounced when the oxygen availability was lowered additionally by endurance training carried out in hypobaric hypoxic conditions.

Does plasma ANP participate in natriuresis induced by alpha-MSH?

alpha-Melanocyte-stimulating hormone (alpha-MSH; 0.6 and 3 nmol) micro-injected into the anteroventral region of the third ventricle (AV3V) induced a significant increase in diuresis without modifying natriuresis or kaliuresis. Intraperitoneal (ip) injection of alpha-MSH (3 and 9.6 nmol) induced a significant increase in urinary sodium, potassium and water excretion. Intraperitoneal (3 and 4.8 nmol) or iv (3 and 9.6 nmol) administration of alpha-MSH did not induce any significant changes in plasma atrial natriuretic peptide (ANP), suggesting that the natriuresis, kaliuresis and diuresis induced by the systemic action of alpha-MSH can be dissociated from the increase in plasma ANP. These preliminary results suggest that alpha-MSH may be involved in a gamma-MSH-independent mechanism of regulation of hydromineral metabolism.

Effects of adenosine infusion on renal function, plasma ANP and ADH concentrations and central hemodynamics in anesthetized pigs

1. 1. The effect of high-dose adenosine administration on atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) release is not completely understood, and data concerning the effect of adenosine on renal and systemic hemodynamics in the pig are lacking. Measurements of central hemodynamics, renal blood flow and urine production were made in anesthetized pigs during infusion of adenosine. The relationship between these parameters and the plasma concentrations of ANP, ADH and renal renin production was examined. 2. 2. Adenosine infusion at the rate of 140 mg/kg per minute resulted in a significant decrease in systolic, diastolic and mean arterial blood pressure as well as pulmonary arterial pressure. However, cardiac output and renal blood flow remained unchanged during adenosine infusion. Likewise, heart rate remained unchanged until the end of infusion when it increased significantly. Plasma ANP and ADH concentrations increased significantly within 30 min after adenosine infusion, reaching peak levels at 30 to 60 min. However, despite the significant decrease in arterial blood pressure, renal renin production did not change significantly. 3. 3. The adenosine-induced rise in ANP, which is normally released by atrial stretch, may represent a direct effect of adenosine on the cardiac myocytes. The increase in ADH may be a result of decreased arterial blood pressure triggering stimulatory signals from the aortic arch and carotid body receptors to hypothalamic-pituitary sites of ADH production/release. Urine flow decreased dramatically within 30 min of adenosine infusion. Thus adenosine infusion at the given rate led to marked reduction in systemic and pulmonary arterial pressures without significant change in cardiac output, heart rate and renal blood flow. This was associated with a marked increase in plasma ANP and ADH levels with no significant change in renal renin production despite a marked reduction in arterial blood pressure. 4. 4. Maintenance of renal blood flow despite marked reduction in perfusion pressure suggests that, at high doses, adenosine induces renal vasodilation in pigs as opposed to a combined afferent and efferent vasoconstriction known to occur under different experimental conditions.

Correlations between ANP concentrations in atria, plasma and cerebral structures and sodium chloride preference in Wistar rats.

We determined whether ANP (atrial natriuretic peptide) concentrations, measured by radioimmunoassay, in the ANPergic cerebral regions involved in regulation of sodium intake and excretion and pituitary glad correlated with differences in sodium preference among 40 Wistar male rats (180-220 g). Sodium preference was measured as mean spontaneous ingestion of 1.5% NaCl solution during a test period of 12 days. The relevant tissues included the olfactory bulb (OB), the posterior and anterior lobes of the pituitary gland (PP and AP, respectively), the median eminence (ME), the medial basal hypothalamus (MBH), and the region anteroventral to the third ventricle (AV3V). We also measured ANP content in the right (RA) and left atrium (LA) and plasma. The concentrations of ANP in the OB and the AP were correlated with sodium ingestion during the preceding 24 h, since an increase of ANP in these structures was associated with a reduced ingestion and vice-versa (OB: r = -0.3649, P < 0.05; AP: r = -0.3291, P < 0.05). Moreover, the AP exhibited a correlation between ANP concentration and mean NaCl intake (r = -0.4165, P < 0.05), but this was not the case for the OB (r = 0.2422). This suggests that differences in sodium preference among individual male rats can be related to variations of AP ANP level. Earlier studies indicated that the OB is involved in the control of NaCl ingestion. Our data suggests that the OB ANP level may play a role mainly in day-to-day variations of sodium ingestion in the individual rat.

Changes in maternal heart dimensions and plasma atrial natriuretic peptide levels in the early puerperium of normal and pre-eclamptic pregnancies.

To measure plasma atrial natriuretic peptide (ANP) in relation to maternal haemodynamics and body fluid balance in the early puerperium following uncomplicated pregnancy and pre-eclampsia. A longitudinal study from late pregnancy and into the early postpartum period (days 1 to 3 and days 4 to 6) compared with nonpregnant controls. Eleven women with uncomplicated pregnancies, 12 women with pre-eclampsia and 12 healthy, nonpregnant women. Maternal heart dimensions determined by M-mode echocardiography, concentrations of ANP, and daily urine output and sodium excretion. After delivery increases in left atrial dimensions, represented as mean (SEM), from 33.2 (1.6) to 37.7 (1.7) mm and ANP levels from 7.9 (1.1) to 19.0 (2.7) pmol/L were observed at 1-3 days postpartum in normal pregnant women, but we were not able to demonstrate a significant increase in diuresis and natriuresis. In the third trimester left atrial dimensions (38.4 (1.2) mm) and ANP levels (15.4 (2.2) pmol/L) were greater in pre-eclampsia. ANP levels rose further in pre-eclamptic women in the early puerperium (27.4 (7.4) pmol/L) with an increase in diuresis and natriuresis, while left atrial dimensions did not change significantly (39.4 (1.7) mm). A pericardial effusion was found in 11 pre-eclamptic but in only three healthy pregnant women. A concommitant increase in left atrial dimensions and ANP in the early puerperium following uncomplicated pregnancies is consistent with the mechanism of atrial stretch as a stimulus for ANP release, although the biological significance of this finding remained unclear. A significantly higher release of ANP in the early puerperium after pregnancies complicated by pre-eclampsia may be a mechanism which promotes the renal elimination of excessive body fluids and sodium.

Relaxin stimulates atrial natriuretic peptide secretion in perfused rat heart.

Relaxin, a reproductive hormone of the insulin-like growth factor family, increases heart rate in experimental animals but its other actions on cardiac function and cellular mechanisms responsible for the positive chronotrophic effect remain unknown. We have studied the actions of human recombinant gene-2 relaxin on the release of atrial natriuretic peptide (ANP) and cardiac function (heart rate, contractile force, perfusion pressure) as well as the underlying signal transduction mechanisms by using the isolated perfused spontaneously beating rat heart preparation. The administration of relaxin into the perfusion fluid at concentrations of 1.5, 3 or 10 nM for 30 min caused a dose-dependent sustained increase in heart rate, while contractile force and perfusion pressure remained unchanged. In addition, infusion of relaxin at a concentration of 10 nM into the perfusate produced a gradual 1.5-fold increase in immunoreactive ANP (IR-ANP) secretion (from 456 +/- 76 to 701 +/- 124 pg/ml, F = 4.5, P < 0.001). The ANP secretory and chronotrophic effects of relaxin appear to involve the activation of protein kinase C, since administration of a protein kinase C inhibitor staurosporine at a concentration of 30 nM completely blocked the effect of relaxin (10 nM) on IR-ANP secretion (P < 0.001) and heart rate (P < 0.001). A cAMP-dependent protein kinase inhibitor, H-89 (100 nM), also substantially reduced the ANP secretory effect of relaxin and attenuated the increase in heart rate during the sustained phase of the relaxin infusion (P < 0.001). KN-62 (3 microM), a Ca2+/calmodulin-dependent protein kinase inhibitor, decreased the positive chronotrophic effect of relaxin (P < 0.001) but did not influence significantly the effect of relaxin on IR-ANP release in isolated perfused rat heart preparation. These results provide the first evidence that relaxin stimulates the secretion of ANP from isolated perfused rat hearts. Our results also suggest that relaxin modulates ANP secretion by activation of protein kinase C and cAMP-dependent protein kinase pathways.

Stimulation by Corticotropin-Releasing Factor of Atrial Natriuretic Peptide and Brain Natriuretic Peptide Secretions from Cultured Neonatal Rat Cardiomyocytes

The new functional role of corticotropin-releasing factor (CRF) in the regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) release was investigated using cultured neonatal rat cardiomyocytes. Treatment with CRF (10−10-10−6M) resulted in dose- and time-dependent increase in ANP and BNP secretion, up to 2.5-fold and 1.8-fold above control values, respectively. The effect was significant at 6 hr and persisted for at least 36 hr. The effect of CRF (10−7M) was partially blocked by α -helical CRF(9-41) (10−7M), a specific CRF receptor antagonist. The effect of CRF (10−7M) was not only blunted by cAMP-dependent protein kinase A (PKA) inhibitor, H-89 (10−5M), but also by protein kinase C inhibitors, H-7 (50 μ M) and Calphostin C (10−6M). H-7 (50 μ M) and Calphostin C (10−6M) alone lowered basal ANP and BNP levels. Furthermore, CRF (10−7M) stimulates protein synthesis up to 1.2-fold. These results indicate that CRF stimulates ANP and BNP secretions through the CRF receptor and, at least in part , via PKA activation during cardiac hypertrophy.

Clinical, adrenergic and heart endocrine measures in chronic atrial fibrillation as predictors of conversion and maintenance of sinus rhythm after direct current cardioversion.

The aim of this study was to evaluate clinical, adrenergic and endocrine factors that could predict sinus rhythm maintenance after direct current cardioversion in chronic atrial fibrillation. Nineteen patients with chronic non-rheumatic atrial fibrillation (mean duration 6 +/- 5 months) were studied. They were exercised 24 h before cardioversion at maximum effort with the Naughton protocol. Heart rate and blood pressure at rest and exercise were recorded and blood samples were taken for the assessment of adrenergic activity, by measuring cyclic adenosine monophosphate, heart endocrine function, atrial natriuretic peptide and its second messenger, cyclic guanosine monophosphate. Fifteen of the 19 patients were initially converted to sinus rhythm (eight patients with external and seven patients with internal DC shocks). After 3 months eight patients remained in sinus rhythm and 11 had relapsed, most of them within the first month. On exercise the chronotropic response was lower in the group who remained in sinus rhythm than in the group in atrial fibrillation (peak heart rate 147 +/- 11 beats.min-1 vs 165 +/- 24 beats.min-1 P = 0.02). During exercise, the systolic blood pressure in the sinus group reached higher values than in the group who relapsed (192 +/- 17 mmHg vs 176 +/- 18 mmHg, P = 0.03). Cyclic adenosine monophosphate increased significantly from rest to peak exercise in the sinus rhythm group (from 23 +/- 9 pmol.ml-1 to 31 +/- 15 mol.ml-1, P = 0.02) while it remained unchanged in the atrial fibrillation group (25 +/- 10 pmol.ml-1 to 24 +/- 8 pmol.ml-1, P = 0.02). For all 19 patients the difference in cyclic adenosine monophosphate between rest and exercise was negatively correlated with maximum heart rate (r = 0.58, P = 0.009). Atrial natriuretic peptide increased from rest to peak exercise in the sinus rhythm group (from 129 +/- 58 fmol.ml-1 to 140 +/- 66 fmol.ml-1) while it remained unchanged in the group in which atrial fibrillation persisted or recurred (from 112 +/- 58 fmol.ml-1 to 111 +/- 53 fmol.ml-1, P = 0.002). A significant correlation between atrial natriuretic peptide and cyclic guanosine monophosphate levels at exercise before cardioversion was found for the sinus rhythm group only (r = 0.76, P = 0.02). In patients with non-rheumatic chronic atrial fibrillation evaluation of clinical parameters such as heart rate and blood pressure changes during maximal exercise can be useful in the choice of suitable therapy. An inadequate increase in plasma cyclic-adenosine monophosphate and atrial natriuretic peptide on exercise could predict patients with more severe underlying disease, where cardioversion should not be recommended.

Cellular mechanism of angiotensin II-induced atrial natriuretic peptide release in rat right atrial tissue

This study presents an investigation of the mechanism of angiotensin II (Ang II)-induced atrial natriuretic peptide (ANP) release in superfused sliced right atria of rats. Ang II (0.1 μM) enhanced ANP release by 49 %. This phenomenon was significantly blocked by (Sara 1-Ileu 8) Ang II (1 μM) and losartan (0.1 μM). The use of neomycin (100 μM), a phospholipase-C inhibitor completely suppressed the effect of Ang II on ANP increase. To elucidate the intracellular mechanism of ANP released by Ang II, the role of protein kinase C (PKC) was determined by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and phorbol ester : 4-β-phorbol 12-myristate-13-acetate (PMA). We observed that PMA (0.1 μM) stimulated ANP release whereas H-7 (10 μM), an inhibitor of PKC in the presence of Ang II, prevented ANP increase. The role of calcium was also evaluated with 8-(N-N-diethylamino)-ocytyl-3,4,5, trimethoxy-benzoate (TMB-8) (10 μM) and N-(6-aminohexyl)-5-chloro-1-naphtalene sulfonamide (W-7) (10 μM), which completely inhibited ANP release by Ang II. Pre-treatment with diltiazem (10 (μM), an antagonist of the Ca + channel, did not prevent ANP increase due to Ang II, but A23187 (5 μM) enhanced ANP release by Ang II. These results suggest that PKC and intracellular calcium play an important role in ANP release under the influence of Ang II in rat atrial tissue.

Water balance during and after marathon running.

To describe the time course of plasma volume alterations and the changes in the plasma concentrations of hormones regulating water balance in relation to a marathon race, six experienced marathon runners (five men, one women) aged 28 (SD 6) years were studied during and for the 3 days following a treadmill marathon run at 68 (SD 5) percent of maximal oxygen consumption. Haematocrit, haemoglobin, plasma protein (Prot) and electrolyte (Na+, K+) concentration, osmolality (osm), plasma concentrations of renin (Ren), aldosterone (Ald) and atrial natriuretic peptide (ANP) were determined at rest in a sitting position (T(-30)), and then after 30 min in an upright posture (R(0)), while running a marathon at 10 km (R(10)), 30 km (R(30)) and 42.2 km (R end), and after the marathon at 30 min (T(30)), 60 min (T(60)), 120 min (T(120)) and 24 h (TD(+1)), 48 h (TD(+2)) and 72 h (TD(+3)). The changes in plasma volume (PV), Prot, osm and Na+ observed during the race were nonsignificant. Significant increases in plasma concentration of K+ [4.8 (SD 0.6) vs 5.5 (SD 0.6) mmol*1(-1); P <0.01], Ren [38(SD 57) vs 197 (SD 145) pmol*1(-1); P <0.02] and Ald [175 (SD 142) vs 1632 (SD 490) pmol*1(-1); P <0.01] were observed at R(end). A significant increase of ANP (P <0.05) was only found after R(10). Body mass significantly decreased by 2.0 kg (P <0.01) during the race in spite of the ingestion of 1.46 (SD 0.34)1 of a 5 percent glucose solution. Urinary volume and Na+ excretion dropped significantly after the completion of the marathon in comparison with the day before [2600 vs 1452 ml*day(-1)(P <0.02) and 161.3 vs 97.1 mmol*1(-1) (P <0.05)]. At TD(+1) and TD(+2) a significant increase in PV was noted, compared to T(-30). The lack of a decrease in PV during the marathon may have been due to the production of 402 g of metabolic water and by the release of 1280 g of water stored in glycogen complexes in muscle and liver. Thus, the hormone response during the marathon may have been due to the effects of the exercise itself and not to the effects of dehydration. The postmarathon PV expansion may be explained by a protein shift to the intravascular space and by renal sodium retention.

Augmented response in plasma atrial natriuretic peptide to dynamic exercise in patients with congestive heart failure.

Neurohormonal activation is present and neurohormonal responses to dynamic exercise are altered in patients with congestive heart failure (CHF). The aim of this study was to determine if the responses of atrial natriuretic peptide (ANP) normalized for peak oxygen consumption (peak VO2) to exercise are augmented in patients with CHF. Ventilatory and ANP responses were assessed in 28 patients with CHF (NYHA classes II: 16, III: 12), 17 patients in NYHA class I, and 14 normal subjects during symptom-limited cardiopulmonary exercise testing. Plasma ANP was measured at rest and immediately after peak exercise. The increase in ANP was divided by peak VO2 and this ratio [ANP-Exercise Ratio: (peak ANP-rest ANP)/peak VO2] was compared among the 3 groups. Peak VO2 (Normal, NYHA I, CHF: 29.9 +/- 1.7, 24.0 +/- 1.3, 17.4 +/- 0.8 ml/min per kg), anaerobic threshold and peak work rate were lower in patients with CHF. The resting ANP level was significantly higher in patients with CHF (Normal, NYHA I, CHF: 35.4 +/- 4.6, 42.9 +/- 5.8, 80.8 +/- 12.9 pg/ml). The ANP level increased during exercise in all 3 groups, and patients with CHF had a significantly higher ANP level than normal subjects and NYHA class I patients (Normal, NYHA I, CHF: 65.3 +/- 10.7, 75.9 +/- 14.4, 141.6 +/- 20.1 pg/ml). The ANP-Exercise Ratio in patients with CHF was significantly higher than those in normal subjects and NYHA class I patients (Normal, NYHA I, CHF: 0.96 +/- 0.26, 1.32 +/- 0.38, 3.59 +/- 0.72). These data suggest that patients with CHF but not those in NYHA class I have an augmented ANP response, as reflected by both absolute ANP levels and by the exercise ratio, which was normalized by the peak exercise level.

Time-dependent decreases of atrial natriuretic peptide release from the isolated rat atrium: evidence for a readily releasable pool

In vitro, atrial distension causes a rapid increase in atrial natriuretic peptide (ANP) release. This stretch-induced release, however, declines to baseline levels within minutes without significant depletion of the total hormone stores. It has been observed that the basal rate of ANP release from isolated atria also declines over time despite evidence that the tissue retains its viability. We examined this time-dependency of ANP release from isolated rat atria and some parameters that may explain the diminishing release. Mean ANP secretion was 60 pg/min for both spontaneously beating and electrically paced preparations. Although ANP secretion steadily declined over time, there was no time-dependent effect on the amplitude of intracellularly recorded action potentials. The total ANP content in atria obtained after dissection was 133 ± 28.9 μg/g ( n = 3) which was not significantly different from atria that were perfused for 3 h (137 ± 21.2 μg/g; n = 3). Only the 28-amino acid circulating form of ANP was released. The ANP mRNA appeared to be partially degraded in atria after 30 min equilibration or after perfusion for 3 h. These results demonstrated that ANP release from isolated atrial preparations declines steadily despite the maintenance of normal electrophysiological activity. This decline was not due to significant depletion of the ANP stores suggesting that a readily releasable pool of ANP exists and represents only a small fraction of the total hormone stores. Finally, degradation of ANP mRNA implies a reduction of de novo synthesis in our preparation which suggests that the observed depletion of the releasable pool was related to a decline in newly synthesized ANP.

Pulmonary Hypertension

The degree to which pulmonary angiography may contribute to serious complications in patients with pulmonary hypertension has not been clarified and remains a matter of debate. Accordingly, this study was designed (1) to detect the potential release of vasoactive peptides and (2) to investigate the hemodynamic response after administration of a nonionic contrast medium in patients with pulmonary hypertension undergoing pulmonary angiography. Allergy-mediating substances also were measured to monitor for possible anaphylactoid reactions. Pulmonary digital subtraction angiography was performed in 20 patients with pulmonary hypertension (mean pulmonary arterial pressure more than 20 mm Hg). Iopromide was administered as a total of 100 mL via a 7F catheter inserted from the right femoral vein. The injected volume and duration of injection (15 to 20 mL/sec) were kept constant. Hemodynamic parameters were continuously monitored, including electrocardiogram, heart rate, phasic and mean pulmonary arterial and peripheral arterial pressures. Blood samples were obtained before and after administration of contrast media to assay for the concentration of the following vasoactive peptides using radioimmunoassay techniques: renin, angiotensin-I-converting enzyme, angiotensin II, aldosterone, atrial natriuretic peptide, antidiuretic hormone, cyclic-guanosine monophosphate, and myoglobin, as well as allergy-mediating substances such as tryptase, eosinophil protein X, and eosinophil cationic protein. Administration of iopromide caused significant increases in atrial natriuretic peptide (from 61.3 +/- 11.8 to 94.0 +/- 16.7) and antidiuretic hormone (from 6.6 +/- 1.9 to 12.3 +/- 3.1), whereas renin significantly decreased (from 3.0 +/- 0.6 to 1.3 +/- 0.5). After administration of contrast media, there were no significant changes in the other measured vasoactive peptides, allergy-mediating substances, and monitored cardiovascular parameters. Administration of iopromide for pulmonary angiography in patients with pulmonary hypertension resulted in no appreciable hemodynamic alterations associated with the observed changes in atrial natriuretic peptide, antidiuretic hormone, and renin. No allergy-mediated reactions were observed in these patients.

Oxytocin mediates atrial natriuretic peptide release and natriuresis after volume expansion in the rat.

Our previous studies have shown that stimulation of the anterior ventral third ventricular region increases atrial natriuretic peptide (ANP) release, whereas lesions of this structure, the median eminence, or removal of the neural lobe of the pituitary block ANP release induced by blood volume expansion (BVE). These results indicate that participation of the central nervous system is crucial in these responses, possibly through mediation by neurohypophysial hormones. In the present research we investigated the possible role of oxytocin, one of the two principal neurohypophysial hormones, in the mediation of ANP release. Oxytocin (1-10 nmol) injected i.p. caused significant, dose-dependent increases in urinary osmolality, natriuresis, and kaliuresis. A delayed antidiuretic effect was also observed. Plasma ANP concentrations increased nearly 4-fold (P < 0.01) 20 min after i.p. oxytocin (10 nmol), but there was no change in plasma ANP values in control rats. When oxytocin (1 or 10 nmol) was injected i.v., it also induced a dose-related increase in plasma ANP at 5 min (P < 0.001). BVE by intra-atrial injection of isotonic saline induced a rapid (5 min postinjection) increase in plasma oxytocin and ANP concentrations and a concomitant decrease in plasma arginine vasopressin concentration. Results were similar with hypertonic volume expansion, except that this induced a transient (5 min) increase in plasma arginine vasopressin. The findings are consistent with the hypothesis that baroreceptor activation of the central nervous system by BVE stimulates the release of oxytocin from the neurohypophysis. This oxytocin then circulates to the right atrium to induce release of ANP, which circulates to the kidney and induces natriuresis and diuresis, which restore body fluid volume to normal levels.

Increased natriuretic peptides in fetal hearts of diabetic rats.

The main purpose of these studies was to determine whether diabetic pregnancy altered maternal and fetal atrial natriuretic peptide (ANP). Diabetes was induced in rats by intravenous injection of 40 mg streptozotocin/kg on day 2 of gestation. Immunoreactive ANP in plasma, amniotic fluid and hearts on day 20 of gestation was measured by radioimmunoassay; fetal cardiac natriuretic peptides (ANP, proANP and BNP) were separated by reverse-phase high pressure liquid chromatography. Diabetes caused an increase in fetal plasma insulin, placental weight, amniotic fluid volume, the ratio of the fetal heart to body weight, maternal and fetal plasma ANP, fetal cardiac ANP and fetal cardiac BNP. It is suggested that the maternal diabetes-induced increase in fetal ANP might be related to fetal myocardial hypertrophy and could contribute to hydramnios.

Atrial natriuretic peptide stimulates the expression of transforming growth factor-beta in cultured murine mesangial cells: relationship to suppression of proliferation.

Atrial natriuretic peptide (ANP) is a growth suppressor for a variety of different cell types including cultured mesangial cells. This study examined the effects of ANP on the expression and synthesis of transforming growth factor-beta (TGF-beta) in a cultured murine mesangial cell line (MMC). Full-length rat ANP as well as 8-bromo-cGMP, but not ring-deleted ANP analogues, induced, in a dose-dependent manner, TGF-beta 1 mRNA expression in MMC. Moreover, full-length ANP and 8-bromo-cGMP stimulated the synthesis and release of TGF-beta 1 into cell culture supernatants as measured by a specific enzyme-linked immunosorbent assay and mink cell bioassay. The induction of TGF-beta 1 by 10(-6) M ANP and 10(-4) M 8-bromo-cGMP for 24 h was also documented by western blotting of MMC culture supernatants. However, transient transfection studies in MMC with three different murine TGF-beta 1 reporter gene constructs revealed only little stimulation of activity after ANP treatment, suggesting that posttranscriptional activation may mainly contribute to TGF-beta mRNA induction. Functional studies demonstrated that the ANP-mediated inhibition of mitosis, induced by 5% fetal calf serum, is partly abolished in the presence of a neutralizing anti-TGF-beta 1-3 antibody. In addition, the antiproliferative effects of exogenous 8-bromo-cGMP are also attenuated by anti-TGF-beta 1-3 antibody. These findings indicate that ANP stimulates TGF-beta expression in MMC and that the antiproliferative effects of ANP in this cell line may be mediated, at least to some extent, by the endogenous induction of TGF-beta. An increase in intracellular cGMP is most likely the mediator of this TGF-beta 1 induction. Considering the fibrogenic effects of TGF-beta, these findings may be important in the development of glomerulosclerosis in situations with an increase in local or systemic ANP.

Effects of V1- and V2-vasopressin (AVP) antagonists on the pressor, AVP and atrial natriuretic peptide responses to a hypertonic saline infusion in conscious anephric rats.

To examine the role of vasopressin (AVP) receptors in the regulation of the hemodynamics and release of atrial natriuretic peptide (ANP), and the participation of renal nerve inputs in the osmotic AVP release, hypertonic saline (HS) was infused into conscious, bilaterally nephrectomized rats with non-peptide, selective antagonists for the V1-receptor or V2-receptor of AVP. In the control group, HS alone increased mean arterial pressure, plasma ANP and AVP, plasma volume and plasma osmolality, and decreased the heart rate. In the V1-receptor antagonist group, an increase in the mean arterial pressure and a decrease in heart rate were completely abolished and an increase in plasma ANP was attenuated. In the V2-receptor antagonist group, increases in mean arterial pressure and plasma ANP and a decrease in heart rate were attenuated. However, the ratio of the changes in heart rate to the changes in mean arterial pressure in the V2-receptor antagonist group is significantly higher than that in the control group. In both experimental groups, increases in plasma AVP, plasma volume and plasma osmolality were not different from those in the control group. These results suggest that a HS-induced increase in mean arterial pressure is mediated by the pressor effect of AVP, mainly through V1-receptors, and that the depressor effect of AVP through V2-receptors may not influence tonically HS-induced hypertension. Moreover, HS-induced increase in plasma ANP is mediated mainly by increases in plasma volume and blood pressure, but may not be affected by a direct action of AVP to the heart. Renal afferent nerve inputs may not have effects on the regulation of osmotic AVP release.

Effects of head-down tilt on atrial natriuretic peptide and the renin system in pregnancy.

We studied the effects of head-down tilt to 10 degrees for 30 minutes on plasma atrial natriuretic peptide and the renin-aldosterone system in 8 preeclamptic pregnant women, 8 healthy pregnant women, and 11 nonpregnant women of fertile age. Mean arterial blood pressure did not change in the pregnant groups but increased significantly in the nonpregnant control subjects. Heart rate decreased significantly in preeclamptic women but remained unchanged in both control groups. Baseline atrial natriuretic peptide concentration was significantly higher in both preeclamptic (66 +/- 4 pmol/L) and pregnant (54 +/- 6 pmol/L) control subjects compared with nonpregnant subjects (40 +/- 2 pmol/L), but the difference between the pregnant groups was not significant. Head-down tilting induced a significant increase in atrial natriuretic peptide only in healthy pregnant women. Baseline plasma renin activity and aldosterone concentrations were significantly higher in pregnant control subjects compared with both the preeclamptic and nonpregnant groups. The differences between the preeclamptic and nonpregnant control groups were nonsignificant. After head-down tilting, plasma renin activity decreased significantly only in nonpregnant control subjects, whereas aldosterone decreased significantly in preeclamptic and nonpregnant control subjects. In preeclampsia, atrial natriuretic peptide release followed blood pressure and not changes in cardiac output. When all 27 women were studied, a correlation between atrial natriuretic peptide and mean arterial pressure was found in the left lateral supine position. The results suggest that pregnant women developing preeclampsia lose their usual hemodynamic control and show reactions resembling the nonpregnant state when subjected to head-down tilt.

Possible regulation of renin release by ANP in dogs with heart failure.

We investigated whether atrial natriuretic peptide (ANP) contributed to the regulation of renin release during the development of experimental heart failure in dogs. Significant increases of plasma ANP and plasma guanosine 3',5'-cyclic monophosphate (cGMP) levels were observed in dogs with mild heart failure induced by 6 days of rapid ventricular pacing. However, plasma renin activity (PRA) was not elevated, despite the significant decreases in renal plasma flow and mean arterial pressure. An inverse correlation between PRA and the ratio of plasma cGMP to ANP (rs = -0.59, P < 0.05) was found in dogs subjected to 9 days of rapid pacing. In dogs with advanced heart failure induced by 15-24 days of rapid pacing, the plasma cGMP level did not increase further, despite the progressive increase in plasma ANP with the resultant significant increase in PRA (P < 0.05). These findings suggest that attenuation of the inhibitory effect of ANP on renin release during the development of severe heart failure may be an important factor in the activation of the renin-angiotensin system.

Neuroendocrine control of blood volume, blood pressure and cardiovascular function in horses

SummarySeveral body systems make critical contributions to the defence of blood volume, mean arterial pressure and plasma tonicity. These mechanisms ensure adequate blood flow to the working muscles and vital tissues along with the provision of adequate fluid volume for sweating and thermoregulation. The present paper integrates data from several recent studies that examined the neuroendocrine control of cardiovascular function in exercising horses. These studies focused on the effects of exercise on plasma concentrations of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), plasma renin activity (PRA) and aldosterone (ALDO), hormones associated with the regulation of blood pressure, the distribution of blood flow and the long term control of vascular fluid volume. Data were collected during incremental and endurance exercise, following frusemide administration and after splenectomy. Increases in ANP during exercise were associated with increased atrial pressure and stretching of the atrium. Increases in PRA and ALDO are correlated with increases in sympathetic activity during incremental exercise and with decreases in plasma Na+ and CI− concentrations. Plasma AVP increases later in exercise in response to fluid losses, increases in plasma osmolality, and decreases in right atrial pressure. AVP has a minimal effect on renal function during exercise and may be more important during recovery, when it stimulates thirst and drinking. Frusemide and splenectomy decrease atrial pressure, resulting in lower plasma ANP and greater plasma AVP concentrations during steady‐state submaximal exercise. The ANP and AVP responses are part of the neuroendocrine action of the cardiopulmonary baroreflex which appears to mediate the accommodation of the mobilised splenic reserve in the horse. In summary, exercise induced increases in ANP, AVP, PRA and ALDO in the horse appear to play an important role in cardiovascular homeostasis.