Increased Plasma Atrial Natriuretic Peptide Research Articles

Downregulation of pulmonary atrial natriuretic peptide receptors in rats exposed to chronic hypoxia.

We hypothesized that a downregulation in pulmonary atrial natriuretic peptide (ANP) receptors helps raise plasma ANP levels during chronic hypoxia. We measured in vivo pulmonary uptake and plasma clearance of 125I-ANP and in vitro pulmonary binding kinetics of 125I-ANP in normoxic and chronically hypoxic rats. Exposure to 21 days of hypobaric (0.5 atm) hypoxia did not decrease specific binding of 125I-ANP in the kidney, but pulmonary binding decreased 35 and 75% after 1 and 3 days of hypoxia, respectively, and increased 200% after 3 days of normoxic recovery from 21 days of hypoxia. The total binding capacity for ANP to lung membrane fractions from normoxic rats, chronically hypoxic rats, and rats that had recovered from hypoxia was 488 +/- 59, 109 +/- 17, and 338 +/- 48 fmol/mg, respectively (P < 0.05 for hypoxic vs. normoxic or recovered lung membranes). The area under the 125I-ANP plasma concentration curve for normoxic and hypoxic rats and normoxic rats that were infused with the ANP C-receptor ligand C-ANF-(4-23) was 3,292 +/- 216, 5,022 +/- 466, and 8,205 +/- 1,059 disintegrations.min-1.ml-1, respectively [P < 0.05 for hypoxic vs. normoxic or C-ANF-(4-23)-infused rats]. We conclude that pulmonary ANP clearance is reduced during chronic hypoxia secondary to a downregulation in pulmonary ANP clearance receptors. Reduced pulmonary clearance of ANP may represent an adaptation that contributes to increased plasma ANP levels during chronic hypoxia.

The Cushing Syndrome Induced by Atrial Natriuretic Peptide-Producing Thymic Carcinoid

Letters1 July 1994The Cushing Syndrome Induced by Atrial Natriuretic Peptide-Producing Thymic CarcinoidShuichi Okada, MD, Kihachi Ohshima, MD, and Masatomo Mori, MDShuichi Okada, MDGunma University of School of Medicine; Showa-machi, Maebashi 371; JapanSearch for more papers by this author, Kihachi Ohshima, MDGunma University of School of Medicine; Showa-machi, Maebashi 371; JapanSearch for more papers by this author, and Masatomo Mori, MDGunma University of School of Medicine; Showa-machi, Maebashi 371; JapanSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-121-1-199407010-00025 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:A 75-year-old Japanese man was hospitalized for hypokalemia. Levels of plasma adrenocorticotropic hormone (ACTH) and free cortisol in urine were elevated to 220 pg/mL (normal, 9 to 52 pg/mL) and 793 mg/d (normal, 30 to 100 mg/d), respectively. Blood concentration of corticotropin-releasing factor was 13.8 pg/mL (normal, <40 pg/mL). Chest radiographs and computed tomographic examinations showed an enlarged thymic gland and normal-sized adrenal glands. Venous samplings in the superior and inferior vena cava at several levels showed markedly increased plasma atrial natriuretic peptide concentrations near the thymic tumor (from 120 to 620 pg/mL). By contrast, plasma ACTH ...

Acute renal effects of neutral endopeptidase inhibition in humans.

The acute renal effects of neutral endopeptidase 24.11 (E-24.11) inhibition induced by a single oral dose of sinorphan (100 mg) were investigated in 10 healthy normotensive subjects on normal sodium diet. Sinorphan inhibited 90% of E-24.11 activity and increased plasma atrial natriuretic peptide (ANP) and urinary guanosine 3',5'-cyclic monophosphate (cGMP) by 70 and 100%, respectively. Sinorphan increased urinary sodium output by 50% (P < 0.001) and decreased fractional distal reabsorption by 4% (P < 0.01). Sinorphan increased glomerular filtration rate (GFR) and filtration fraction by 10% 1 h after administration and decreased renal plasma flow by 10%. Mean arterial pressure, renal vascular resistance, plasma aldosterone concentration, and renin activity were unmodified. Sinorphan decreased fractional clearance of neutral dextrans over the 34- to 52-A radius range. Applying the changes along with a hydrodynamic isopore with shunt model, sinorphan significantly increased capillary pressure gradient (delta P; 39 +/- 1 vs. 34 +/- 1 mmHg; P < 0.01), whereas ultrafiltration coefficient was unchanged. In conclusion, endopeptidase inhibition increased endogenous plasma ANP and cGMP generation and induced natriuresis through both an increase in filtered load and a decrease in distal tubular reabsorption of sodium. Sinorphan increases GFR, filtration fraction, and delta P, probably through an increase in efferent over afferent arteriolar resistance ratio.

Pharmacologic Profile of CGS 24128, a Potent, Long-Acting Inhibitor of Neutral Endopeptidase 24.11

We compared the pharmacologic profiles of thiorphan, a neutral endopeptidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-life (t1/2). Thiorphan and CGS 24128 inhibited NEP in vitro with IC50 values of 5.0 +/- 0.2 and 4.3 +/- 0.2 nM, respectively. After administration at 10 mg/kg intravenously (i.v.), the concentrations of CGS 24128 in the plasma were > 500 nM for 4 h but plasma thiorphan was detectable for only 60 min. Thiorphan 3 mg/kg administered intraarterially (i.a.) increased plasma atrial natriuretic peptide immunoreactivity (ANPir) levels by 58 +/- 12% in rats administered exogenous ANP(99-126). This response lasted < 60 min, whereas the same dose of CGS 24128 produced an average increase of 191 +/- 19% in ANPir concentrations that persisted for 4 h. ANP-induced (1 microgram/kg i.v.) natriuresis was significantly potentiated in anesthetized rats pretreated (60 min) with a bolus of CGS 24128 10 mg/kg i.v. The change in urinary sodium excretion (UNaV) produced by ANP was 28.8 +/- 4.0 and 15.8 +/- 1.8 muEq/kg/min in CGS 24128- and vehicle-treated rats, respectively. ANP-induced natriuresis was also greater during continuous infusion of thiorphan (5 mg/kg bolus + 0.1 mg/kg/min i.v.; delta UNaV = 29.2 +/- 5.8 and 13.8 +/- 3.2 muEq/kg/min in drug- and vehicle-treated rats, respectively) but not when thiorphan was administered as a bolus (10 mg/kg i.v.) 60 min before the ANP challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-Term Effects of Pentobarbital Anesthesia on the Atrial Natriuretic Peptide System in Rats

A long-term effect of pentobarbital treatment on the storage and release of atrial natriuretic peptide (ANP) was investigated in rats. The experimental group was treated with pentobarbital (50 mg/kg, ip), and the control group was injected with the vehicle only. They were used one week after the treatment. Male and female rats were used separately to see if there exists a sex difference in the response to pentobarbital. In male rats, the plasma ANP measured in a conscious state was significantly higher in the experimental group than in the control. The ANP content as well as the number of specific granules in the atrial tissue was significantly lower in the experimental group. In response to extracellular volume expansion (VE), amounting up to 5% of the body weight over 30 min, while the plasma ANP increased in the control, it did not significantly change in the experimental group. Urinary responses to the exogenous infusion of ANP did not differ in magnitude between the two groups. In female rats, neither the plasma level nor the atrial content of ANP (or the atrial granularity) was different between the experimental and control groups. Nor did the increase of plasma ANP in response to VE differ in magnitude between the two groups in female rats. These results indicate that pentobarbital may have a long-term effect on the storage and release of ANP.

Effect of intravenous atrial natriuretic peptide on gas exchange in humans

The aim of this work was to establish whether a physiological increase in atrial natriuretic peptide (ANP) plasma levels affects pulmonary gas exchange in humans. Ten volunteers received an infusion of either ANP (4 pmol · kg −1 · min −1) or physiological saline, for 60 min. Baseline measures of the alveolar-arterial P O2 difference and of the physiological dead space were within normal limits and remained stable during and after the infusion of ANP or saline, although plasma ANP and cGMP rose significantly ( p < 0.01) (mean ± SEM: ANP: 13.4 ± 3.9 to 56.0 ± 10.4 pmol/l ; cyclic GMP: 3.8 ± 0.3 to 17.0 ± 3.8 nmol/l ). We conclude that a physiological increase in plasma ANP does not affect pulmonary gas exchange significantly in humans.

Essential role of hypothalamic muscarinic and alpha-adrenergic receptors in atrial natriuretic peptide release induced by blood volume expansion.

Expansion of the blood volume induces natriuresis, which tends to return the blood volume to normal. This response is mediated at least in part by the release of atrial natriuretic peptide (ANP) into the circulation. Previous experiments have shown the participation of the anterior ventral third ventricular (AV3V) region of the hypothalamus in the ANP release that follows volume expansion. When injected into the AV3V region, the cholinergic drug carbachol induces natriuresis and the release of ANP. In the present experiments, microinjection of norepinephrine into the AV3V region induced natriuresis and an increase in plasma ANP. To determine whether cholinergic and alpha-adrenergic pathways are crucial to the volume expansion-induced release of ANP, certain receptor-blocking drugs were injected into the AV3V region of conscious rats. Thirty minutes later blood volume was expanded by intravenous injection of 2.0 ml/100 g of body weight of hypertonic saline (0.3 M NaCl). Microinjection of isotonic saline (2 microliters) into AV3V region of control animals 30 min prior to volume expansion had no effect on the 3-fold increase in plasma ANP concentrations measured 5 min after volume expansion. In contrast, although the receptor-blocking drugs did not alter the initial concentrations of plasma ANP 30 min later, just prior to volume expansion, blockade of muscarinic cholinergic receptors by intraventricular injection of 5 nmol (2 microliters) of atropine sulfate or methylatropine markedly reduced the response to volume expansion but did not obliterate it. Microinjection of the alpha receptor blocker phentolamine (5 nmol) into the AV3V 30 min prior to volume expansion also markedly suppressed the ANP response. Intraperitoneal (i.p.) injection of methylatropine (0.01 mmol/100 g of body weight), which does not cross the blood-brain barrier, also did not affect the basal levels of ANP 30 min after i.p. injection. But, in striking contrast with the blockade of the response to volume expansion induced by intraventricular injection of methylatropine, the response to volume expansion was markedly enhanced by i.p. injection of methylatropine. The results therefore indicate that hypothalamic muscarinic and alpha-adrenergic synapses are essential to release of ANP in response to volume expansion. These results are consistent with a hypothetical pathway for physiological control of ANP release which involves distension of baroreceptors within the right atria, carotid and aortic sinuses, and kidney which alters afferent input to brain stem noradrenergic neurons with axons projecting to the AV3V region. There they activate cholinergic interneurons by an alpha 1-adrenergic synapse. The cholinergic neurons in turn stimulate ANP neurons in this brain region via muscarinic receptors. The stimulation of these neurons activates efferent pathways which induce the release of ANP.

Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats

Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic pulmonary hypertension by reducing atrial natriuretic peptide (ANP) metabolism, but this hypothesis has not been confirmed. We measured NEP activity, guanosine 3',5'-cyclic monophosphate (cGMP) production, plasma ANP levels, and cardiac ANP synthesis in rats given an orally active NEP inhibitor (SCH-34826) during 3 wk of hypoxia. Under normoxic conditions, SCH-34826 had no effect on plasma ANP levels but reduced pulmonary and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg creatinine; P < 0.05). Under hypoxic conditions, SCH-34826-treated rats had lower plasma ANP levels (1,259 +/- 361 vs. 2,101 +/- 278 pg/ml; P < 0.05), lower right ventricular systolic pressure (53 +/- 5 vs. 73 +/- 2 mmHg; P < 0.05), lower right ventricle weight-to-left ventricle+septum weight ratio (0.47 +/- 0.04 vs. 0.53 +/- 0.03; P < 0.05), and less muscularization and percent medial wall thickness of peripheral pulmonary arteries (22 +/- 5 vs. 45 +/- 8% and 17 +/- 1 vs. 25 +/- 1%, respectively; P < 0.05 for all values) than did rats treated with vehicle alone. These values were not affected by SCH-34826 under normoxic conditions. SCH-34826 decreased right ventricular ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg protein; P < 0.05) but did not affect steady-state ANP mRNA levels. We conclude that NEP inhibition blunts pulmonary hypertension without increasing plasma ANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Central effects of interleukin-1 on blood pressure, thermogenesis, and the release of vasopressin, ACTH, and atrial natriuretic peptide.

To assess the central role of interleukin 1-beta (IL-1 beta) in the release of ACTH, vasopressin (AVP) and atrial natriuretic peptide (ANP) and in the regulation of blood pressure and thermogenesis, 3 ng (0.173 pM) x 100-1 x BW-1 (LIL), 30 ng (1.73 pM) x 100g-1 x BW-1 (MIL), and 150 ng (8.63 pM) x 100g-1 x BW-1 (HIL) of human IL-1 beta dissolved in sterile saline were injected intracerebroventricularly to conscious rats. In the control rats, saline alone (5 microliters) was administered. In three other groups, rats were pretreated with indomethacin, a cyclooxygenase inhibitor, given i.v. (1 mg x 100g-1 x BW-1); medium and high doses of IL-1 beta or its vehicle were given. In the LIL group, IL-1 beta increased blood pressure, body temperature and plasma AVP and ANP without any changes in heart rate (HR) and plasma ACTH. In the MIL group, plasma ACTH was increased, and changes in the other parameters were similar to those in the LIL group. In the HIL group, however, the pressor and thermogenetic responses were attenuated; plasma AVP, ACTH, and ANP were increased; and HR was unchanged. In the control (CON) group, none of these parameters was changed throughout the studies. Indomethacin abolished the AVP and ACTH responses to IL-1 beta, but potentiated the pressor and hypothermic responses and increased plasma ANP. These data suggest that the actions of IL-1 beta on AVP and ACTH release and thermogenesis, but not on blood pressure and the release of ANP, are modulated by the stimulated central production of prostaglandins.

Mineralocorticoid production of adrenal cortical adenomas

We studied in vitro and in vivo corticosteroid production as well as the presence of symptoms of an increased mineralocorticoid effect in patients with ‘silentrs adrenal cortical adenomas, and compared these results to those found in patients with classical mineralocorticoid excess syndromes. We found that under in vitro conditions, cells from ‘silent’ adrenal cortical adenomas ( n = 19) produced substantial amounts of both zona glomerulosa and fasciculata steroids, although the production of steroids in these cells was lower compared to that in mineralocorticoid-producing adenoma cells ( n = 26). Patients with aldosterone-producing and ‘silent’ adenomas had significantly increased plasma atrial natriuretic peptide levels, which remained non-suppressible after upright posture and furosemide administration. Of the 25 patients with ‘silent’ adenomas, 11 had low and non-stimulable plasma renin activity (PRA) before but, in most cases, not after adrenal surgery. When compared to those with normal PRA ( n = 14), patients with low PRA ‘silent’ adenomas ( n = 11) had higher blood pressure which was significantly reduced after surgery, and a mild hypokalemia before but not after surgery. Although basal plasma concentrations of aldosterone, 18-hydroxy-corticosterone, corticosterone, deoxycorticosterone, 18-hydroxy-DOC, cortisol, 11-deoxycortisol and 17-hydroxy-progesterone (17-OH-P) were not increased in either groups of ‘silent’ adenomas, ACTH stimulation produced a hyperreactive response for all measured steroids, of which an extremely high 17-OH-P seemed to be one of the most intriguing findings. We consider that these observations in ‘silent’ adrenal cortical adenomas may justify surgical intervention, irrespective of the size and potential malignancy of these adenomas.

Effects of Neutral Endopeptidase Inhibition on the Clearance of Exogenously Administered Endothelin in Sprague-Dawley Rats

The effects of the selective neutral endopeptidase (EC 3.4.24.11, NEP) inhibitor SQ 28,603 on endogenous plasma endothelin (ET) concentration and on the clearance from the circulation of exogenously administered synthetic human ET-1 were examined in Sprague-Dawley rats. Inhibition of NEP by SQ 28,603 (100 mumol/kg intravenously, i.v.) affected neither basal levels of plasma ET nor the circulatory clearance of an i.v. administered bolus dose (3 nmol/kg) of ET-1. ET-1 produced marked, statistically significant increases in plasma atrial natriuretic peptide (ANP) and cyclic GMP concentrations. SQ 28,603 markedly augmented the duration of the increases in plasma concentrations of ANP and cyclic GMP induced by exogenous ET-1. SQ 28,603 alone produced modest but statistically significant increases in plasma ANP and cyclic GMP concentrations that lasted for at least 30 min. These results clearly demonstrate that NEP does not contribute to the in vivo clearance of ET and support the hypothesis that NEP plays an important role in clearance of ANP from the circulation.

Effect of glucose, insulin, and hypertonicity on atrial natriuretic peptide levels in man

To determine the effect of hyperglycemia and hyperinsulinemia on atrial natriuretic peptide (ANP) levels in man, we studied normotensive nondiabetic volunteers (aged 25 to 63 years) during infusion of insulin and/or 20% dextrose (glucose clamp technique) to achieve three different states of “glycemia/hyperinsulinemia,” as follows: (1) euglycemia for 2 hours during infusion of insulin (80 mU · m −2 · min −1), resulting in plasma insulin levels of approximately 1,200 pmol/L (n = 9); (2) moderate stable hyperglycemia at a level of 11 mmol/L (198 mg/dL) for 2 hours, with infusion of glucagon-like peptide-1 (7–37) amide (GLP-1) during the second hour, which increased endogenous insulin responses to approximately 2,100 pmol/L (n = 9); and (3) marked stable hyperglycemia at a level of 18.5 mmol/L (330 mg/dL) for 2 hours, with endogenous insulin responses of approximately 720 pmol/L (n = 9). In addition, six patients with non-insulin-dependent diabetes mellitus were studied with the GLP-1 protocol at a hyperglycemic level of 14.5 mmol/L (261 mg/dL). In normal subjects, plasma ANP levels increased significantly from 3.0 ± 0.4 to 4.6 ± 0.8 pmol/L during marked hyperglycemia, but did not change during euglycemia or moderate hyperglycemia despite higher insulin levels ( P < .01, ANOVA). Sodium excretion rates were also highest during the marked hyperglycemic study (125 ± 14 v 91 ± 7 v 74 ± 10 μmol/min, P < .05, marked v moderate hyperglycemia v euglycemia). In diabetic subjects, ANP levels increased significantly from 12.5 ± 4.1 to 21.1 ± 5.0 pmol/L during hyperglycemia. To determine the contribution of hypertonicity to the increases in ANP levels, seven subjects underwent infusion of 5% saline and 0.9% saline on separate occasions to produce equivalent degrees of volume expansion. Hypertonicity was shown to contribute significantly to ANP elevation, as the increment in ANP levels was significantly greater with 5% saline than with 0.9% saline despite similar changes in plasma volume. In summary, marked hyperglycemia produced acutely can increase plasma ANP levels via a mechanism that is unrelated to hyperinsulinemia; the mechanism may be related to an increase in both plasma tonicity and volume. Hyperglycemia may contribute to the increased circulating ANP levels observed in diabetic subjects.

Brain atrial natriuretic peptide neurons play an essential role in volume expansion-induced release of atrial natriuretic peptide and natriuresis.

The brain atrial natriuretic peptide (ANP) neuronal system appears to be involved in the increase in plasma ANP which follows blood volume expansion in the rat. To determine if this neuronal system is essential to the natriuresis and increase in plasma ANP which follow volume expansion, highly specific antiserum against ANP (ANP-AB) and/or normal rabbit serum as a control was microinjected into the third cerebral ventricle (3V) of conscious rats, and the effect on the natriuresis and increase in plasma ANP induced by intravenous injection of 2 ml/100 g body weight of 0.3 M NaCl was examined. Although there was no effect of ANP-AB on initial levels of plasma ANP or natriuresis 3 h after 3V injection, the natriuresis in response to blood volume expansion was significantly inhibited. The increase in plasma ANP which followed volume expansion was also significantly reduced at 5 min but recovered at 15 min. The results indicate that the brain ANP neuronal system plays an essential role in the mediation of volume expansion-induced increase in plasma ANP and natriuresis. The failure to block these responses completely may be due to the use of an inadequate dose of antiserum or other brain mechanisms may be able to mediate these responses.

Possible role of endothelin acting within the hypothalamus to induce the release of atrial natriuretic peptide and natriuresis.

Since endothelin has been localized in neurons in areas involved in water and electrolyte metabolism, areas which also contain atrial natriuretic peptide (ANP) neurons, we determined whether endothelin would release ANP and induce natriuresis. Endothelin-3 (ET-3) in doses ranging from 38 to 760 pmol was microinjected into the third ventricle (3V) of conscious, water-loaded male rats, and the effect on natriuresis and plasma ANP was determined. ET-3 evoked a dose-related natriuresis beginning within 20 min of injection. Even the lowest dose tested (38 pmol) was effective. At a dose of 95 pmol, it produced a rapid increase of plasma ANP within 5 min peaking at 20 min. A slight kaliuresis and antidiuresis was observed at the 2 highest doses of 380 and 760 pmol. The urinary changes following 3V injection of ET-3 were similar to those evoked by ANP, except for the antidiuresis with increased sodium concentration which followed injection of the 2 higher doses. These results suggest that these 2 higher doses also released vasopressin. Alternatively, activation of the sympathetic nervous system by these higher doses may have decreased glomerular filtration rate and been in part responsible for the antidiuresis. The results with 3V injection of ET-3 contrasted sharply with those obtained following intravenous injection of the 95-pmol dose injected intraventricularly. This intravenous dose of ANP induced a transient decrease in sodium and potassium excretion and urine volume, maximal at 20 min, and had no effect on plasma ANP concentrations at 5 or 20 min after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of atrial natriuretic peptide and other vasoactive compounds on the uterine vascular bed of the nonpregnant sheep.

It has been reported that atrial natriuretic peptide (ANP) concentrations are elevated in pregnancy and further elevated in pregnancy-induced hypertension. Atrial stretch and volume expansion appear to be important stimuli for ANP release. During normal pregnancy, a striking change in hemodynamics occurs that may increase plasma ANP concentrations. ANP has potent natriuretic, diuretic, and smooth muscle relaxant activities. The biological effects of ANP during pregnancy may play an important role in the physiology and pathophysiology of pregnancy. Because of possible interactions during pregnancy due to secondary effects of maternal cardiovascular changes and physiological adaptation, the present study sought to evaluate and characterize the local effects of atriopeptin II on the uterine vascular bed of the nonpregnant sheep. Ewes with catheters in the femoral artery, femoral vein, and uterine artery and electromagnetic flow probes on the middle uterine arteries were monitored for blood pressure (BP), heart rate (HR), and uterine blood flow before and after the administration into the uterine artery of bolus injections of 2, 4, 20, and 40 x 10(-9) M (5, 10, 50, and 100 micrograms) of the synthetic ANP (atriopeptin II). For comparison purposes, the effects of prostaglandin I2 in doses of 1.2, 2.5, 12, and 25 x 10(-8) M (5, 10, 50, and 100 micrograms), vasoactive intestinal polypeptide in doses of 3, 9, 30, 90, 300, and 900 x 10(-11) M (0.1, 0.3, 1, 3, 10, and 30 micrograms), and bradykinin in doses of 9.4, 28, 94, 280, 940, and 2800 x 10(-11) M (0.1, 0.3, 1, 3, 10, and 30 micrograms) were also tested. Appropriate vehicles were tested and found to be without effect. All four compounds were found to be vasodilators of the nonpregnant uterine vasculature. ANP administered into the uterine artery decreased BP (87 +/- 4 mm Hg to 79 +/- 4 mm Hg with 50 micrograms [20 x 10(-9) M]), increased HR (90 +/- 5 bpm to 105 +/- 4 bpm), and significantly increased uterine blood flow (from 14 +/- 3 to 37 +/- 4 ml/min with a dose of 100 micrograms [40 x 10(-8) M, P < 0.05]). Prostaglandin I2 failed to alter BP, but caused significant increases on HR (100 +/- 4 to 124 +/- 13 bpm, P < 0.05) and uterine blood flow (17 +/- 4 to 73 +/- 10 ml/min, P < 0.05). Vasoactive intestinal polypeptide caused a significant tachycardia (97 +/- 10 to 158 +/- 9 bpm, P < 0.05) at the highest dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Physical manipulation of subcutaneously implanted cardiac muscle in rat increased plasma atrial natriuretic peptide concentration.

To examine the effects of physical stretch on cardiac muscle endocrine activity, the authors transplanted whole neonatal hearts subcutaneously into the back and the ears of the correspondent mother (n = 9). Seven days later, physical manipulation was applied on the implanted heart by stretching the skin and the subcutaneous tissue encasing the implanted cardiac muscle, for a period of five to ten minutes. Such manipulation was repeated approximately every seven days postoperatively for a total of two to four times for each rat. The plasma atrial natriuretic peptide (ANP) levels were measured by radioimmunoassay prior to and immediately following manipulation. Postmanipulation plasma ANP levels were found to increase from the premanipulation levels. At two weeks postimplant, the average increase was 290% with the highest single-specimen increase being nearly twelvefold. The increases observed at two and three weeks following implantation had Signed Rank Test p values of 0.015 and 0.042 respectively. The viability of the implanted hearts was confirmed by cell culture. Light microscopic immunocytochemistry detected ANP immunoreactivity in the implanted cardiocytes. The elevated plasma ANP concentration induced by the manipulation appeared to be correlated with the functional status of the implanted cardiocytes. (1) Subcutaneously transplanted neonatal myocardiocytes survived for at least three to four weeks while retaining the ability to produce ANP. (2) Physical manipulation of implanted heart induced ANP release. Therefore, cardiac ANP production and release is indeed stimulated by physical stretching.

Atrial natriuretic peptide in pregnancy: response to oral sodium supplementation.

1. The control of extracellular fluid volume (ECFV) in normal pregnancy may be related to changes in atrial natriuretic peptide. Previous studies in non-pregnant subjects have suggested that plasma atrial natriuretic peptide (ANP) increases in response to dietary sodium supplementation because of an increase in plasma volume, although this has not been measured directly. 2. Nine women who were pregnant in the third trimester undertook oral sodium supplementation (136 mmol) for 5 days in addition to their usual diet. Twenty-four hour urinary sodium excretion increased by 125 +/- 54 mmol/day (mean +/- s.d.; P less than 0.01). Plasma volume was unchanged, although total ECFV tended to increase (P less than 0.09 and bodyweight increased (1.3 +/- 1.4 kg; P less than 0.01) at the end of these diets. 3. Plasma ANP increased by 30.7 [8.6, 34.5] pmol/L (median [25th, 75th percentile]; P less than 0.05), while plasma renin concentration decreased significantly from 7.3 [6.2, 11.2] to 2.6 [1.7, 3.9] pmol angiotensin I/mL (P less than 0.01), as did plasma aldosterone concentration (1435 [1162, 1722] to 753 [595, 1110] fmol/mL; P less than 0.01). Plasma vasoactive intestinal peptide was unchanged. 4. Pregnant women respond to increased dietary sodium with an increase in plasma ANP in the absence of a significant increase in plasma volume. The acute regulation of plasma ANP in response to increases in dietary sodium in pregnant women does not appear to be mediated by changes in intravascular fluid volume.

Carotid-aortic and renal baroreceptors mediate the atrial natriuretic peptide release induced by blood volume expansion.

Our previous studies have shown that stimulation of the anteroventral third ventricle (AV3V) region of the brain increases atrial natriuretic peptide (ANP) release, whereas lesions of the AV3V region or median eminence of the tuber cinereum block the release of ANP caused by blood volume expansion. These results suggest that participation of the central nervous system is critical to this response. The role of baroreceptors in the response was evaluated in the current research by studying the response of plasma ANP to blood volume expansion induced by intravenous injection of hypertonic saline solution (0.3 M NaCl, 2 ml/100 g of body weight, over 1 min) in conscious, freely moving male rats. Plasma samples were assayed for ANP by radioimmunoassay. In sham-operated rats, blood volume expansion induced a rapid increase in plasma ANP: the concentration peaked at 5 min and remained elevated at 15 min after saline injection. One week after deafferentation of the carotid-aortic baroreceptors, basal plasma ANP concentrations were highly significantly decreased on comparison with values of sham-operated rats; plasma ANP levels 5 min after blood volume expansion in the deafferented rats were greatly reduced. Unilateral right vagotomy reduced resting levels of plasma ANP but not the response to blood volume expansion; resting concentrations of plasma ANP and responses to expansion were normal in bilaterally vagotomized rats. In rats that had undergone renal deafferentation, resting levels of ANP were normal but the response to blood volume expansion was significantly suppressed. The evidence indicates that afferent impulses via the right vagus nerve may be important under basal conditions, but they are not required for the ANP release induced by blood volume expansion. In contrast, baroreceptor impulses from the carotid-aortic sinus regions and the kidney are important pathways involved in the neuroendocrine control of ANP release. The evidence from these experiments and our previous stimulation and lesion studies indicates that the ANP release in response to volume expansion is mediated by afferent baroreceptor input to the AV3V region, which mediates the increased ANP release via activation of the hypothalamic ANP neuronal system.

Effectiveness of endopeptidase inhibition (Candoxatril) in congestive heart failure

Candoxatril is a novel, orally active inhibitor of neutral endopeptidase EC 3.4.24.11, the enzyme that degrades atrial natriuretic peptide (ANP). The acute and chronic (10 days treatment) hemodynamic and hormonal effects of candoxatril (150 mg twice daily) in 12 patients with moderately severe congestive heart failure were investigated in a randomized, placebo-controlled, double-blind study. On study day 1, candoxatril acutely increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After 10 days of treatment, basal ANP was increased and basal aldosterone was decreased. Body weight was reduced, most likely reflecting chronic natriuretic or diuretic effects, or both, and there was a trend toward increased cardiac index and reduced preload values. On study day 10, the acute effects of candoxatril were similar to those on day 1 (i.e., ANP was further increased, aldosterone was suppressed, and right and left ventricular filling pressures were decreased). Thus, candoxatril may offer a new and effective therapeutic approach in the treatment of heart failure.

Cicletanine Blunts the Pulmonary Pressor Response to Acute Hypoxia in Rats

Cicletanine (CIC) recently has been shown to lower systemic arterial pressure in hypertensive animals and man by a mechanism that may involve potentiation of the vasodilator effect of atrial natriuretic peptide (ANP). We previously have shown that ANP prevents acute hypoxia-induced pulmonary vasoconstriction and modulates the severity of chronic hypoxic pulmonary hypertension. The current study tested the hypothesis that CIC inhibits the pulmonary pressor response to acute hypoxia by a cyclic guanosine monophosphate (cGMP)-dependent mechanism. Catheters were placed in the pulmonary arteries of Sprague-Dawley rats through the right jugular vein using a closed chest technique, and in the aorta through the right femoral artery. After a 24 hour recovery, CIC (600 mg/kg) or vehicle was administered orally by gavage to conscious rats 4 hours prior to exposure to 10% oxygen at ambient pressure or to room air. Mean pulmonary arterial pressure (MPAP) and mean systemic arterial pressure (MSAP) and heart rate (HR) were monitored for 3 hours. CIC attenuated the acute pulmonary pressor response to hypoxia (MPAP = 24.5 +/- 1.0 mm Hg in the "hypoxic+CIC" group vs. 29.9 +/- 1.0 mm Hg in the "hypoxic+vehicle" group; p less than 0.05 at 3 hours of hypoxic exposure), but had no significant effect on MSAP or HR. CIC had no effect on MPAP, MSAP, or HR in air control rats. Acute hypoxia caused significant increases in plasma ANP and cGMP and in kidney cGMP content, but CIC administration did not alter these parameters further. This is the first demonstration that acute administration of CIC attenuates the pulmonary pressor response to acute hypoxia in conscious rats.