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To further elucidate the role of atrial natriuretic peptide (ANP) in preeclampsia, its metabolic clearance (MCRANP) was determined concomitantly with its effects on sodium excretion (UNa), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF). Ten untreated preeclamptic primigravidae (PET) were studied at 29-37 wk gestation and again 4 mo postpartum (PP). Basal plasma concentration of ANP was significantly increased in PET compared with PP (14.8 +/- 1.9 vs. 4.1 +/- 0.5 pmol/l, respectively; P < 0.0001). MCRANP in PET and PP was 5.0 +/- 0.8 and 4.9 +/- 0.5 l/min [not significant (NS)], respectively. In PET, infusion of ANP produced (basal vs. ANP) a natriuresis (UNa 0.14 +/- 0.02 vs. 0.28 +/- 0.04 mmol/min, P < 0.001) and an increase in GFR (97 +/- 7 vs. 106 +/- 8 ml/min, P < 0.05), with ERPF unchanged (609 +/- 24 vs. 634 +/- 29 ml/min, NS). In PP, ANP infusion also produced a natriuresis (UNa 0.20 +/- 0.02 vs. 0.25 +/- 0.02 mmol/min, P = 0.01), no significant change in GFR (109 +/- 7 vs. 102 +/- 4 ml/min), and a significant reduction in ERPF (514 +/- 22 vs. 409 +/- 18 ml/min, P < 0.0001). Analysis of variance demonstrated a greater natriuretic effect of ANP in PET compared with PP (P < 0.05), similarly a significant difference in the effect of ANP on ERPF (P < 0.01) and GFR (P < 0.05) was seen but not on filtration fraction (P = 0.35).

Objective: Our purpose was to determine whether human pregnancy alters the metabolic clearance and natriuretic effect of atrial natriuretic peptide., Study Design: The metabolic clearance rate of atrial natriuretic peptide (ANP 99-126) was measured serially in nine normotensive primigravid women studied in early and late pregnancy and again 4 months post partum (nonpregnant). Metabolic clearance of atrial natriuretic peptide was determined by use of a two-tier constant infusion technique (6 and 12 ng/kg/min, respectively). Sodium excretion was determined from 30-minute urine collections taken before and during infusion of atrial natriuretic peptide at both 6 and 12 ng/kg/min., Results: Basal plasma atrial natriuretic peptide levels increased with gestation: in early pregnancy 18.0 +/- 2.7 pg/ml, in late pregnancy 22.6 +/- 4.2 pg/ml, and post partum 19.5 +/- 3.6 pg/ml. Infusion of atrial natriuretic peptide at 6 and 12 ng/kg/min produced two distinct physiologic plasma levels of atrial natriuretic peptide. The metabolic clearance rates for nonpregnant women and those in early and late pregnancy at 6 and 12 ng/kg/min, respectively, were 3.4 +/- 0.4 and 2.9 +/- 0.4 L/min at plasma atrial natriuretic peptide levels of 86.2 +/- 13.2 and 179.8 +/- 42.5 pg/ml, respectively, 4.3 +/- 0.5 and 4.3 +/- 0.5 L/min at plasma atrial natriuretic peptide levels of 61.1 +/- 4.9 and 131 +/- 20.9 pg/ml (p < 0.01, nonpregnant vs early pregnancy), and 3.8 +/- 0.6 and 3.8 +/- 0.5 L/min at plasma atrial natriuretic peptide levels of 72 +/- 8.0 and 136 +/- 18.3 pg/ml (p < 0.05, nonpregnant vs late pregnancy), respectively. Infusion of atrial natriuretic peptide produced natriuresis in both pregnant and nonpregnant states; sodium excretion (basal to atrial natriuretic peptide infusion at 12 ng/kg/min) increased from 133 +/- 19 to 207 +/- 18 mumol/min, 129 +/- 21 to 374 +/- 35 mumol/min, and 128 +/- 20 to 221 +/- 33 mumol/min in nonpregnant women and those in early and late pregnancy, respectively., Conclusions: The metabolic clearance of atrial natriuretic peptide increased by 16 weeks' gestation and remained elevated thereafter. There appears to be no attenuation of the natriuretic effect of infused atrial natriuretic peptide in normotensive human pregnancy.

The effect of infused atrial natriuretic peptide (ANP) on sodium excretion (UNa), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF) was studied in 12 normotensive primigravidae at 32 wk gestation [late pregnancy (LP)] and again 4 mo postpartum [nonpregnant (NP)]. Three 20-min steady-state (renal) clearances of inulin and p-aminohippurate were used to measure GFR and ERPF, respectively, before and after infusion of ANP at 2 pmol.kg-1.min-1. Basal plasma ANP (pANP) was increased in LP compared with NP [7.8 +/- 0.6 vs. 3.3 +/- 0.4 pmol/l (P < 0.0001), respectively]. In LP, infusion of ANP increased pANP from 7.8 +/- 0.6 to 21.8 +/- 1.4 pmol/l (P < 0.00001), which produced a natriuresis [UNa of 0.18 +/- 0.02 vs. 0.25 +/- 0.03 mmol/min (P = 0.03), respectively], with no change in GFR (153 +/- 13 vs. 142 +/- 8 ml/min, P = 0.16) but a significant reduction in ERPF (766 +/- 52 vs. 660 +/- 31 ml/min, P = 0.002). In NP, ANP infusion increased pANP from 3.3 +/- 0.4 to 27.7 +/- 2.5 pmol/l (P < 0.00001), which produced no significant natriuresis [UNa of 0.22 +/- 0.07 vs. 0.26 +/- 0.09 mmol/min (P = 0.15), respectively] and no change in GFR (87 +/- 3 vs. 89 +/- 3 ml/min), but again a reduction in ERPF (486 +/- 17 vs. 414 +/- 9 ml/min, P < 0.001).

1. The effect of atrial natriuretic peptide on osmotically stimulated thirst appreciation and consequent fluid intake was investigated in healthy man. 2. Six seated male subjects were studied on two occasions: synthetic alpha-human atrial natriuretic peptide (99-126) (2 pmol min-1 kg-1) or placebo (saline, 150 mmol/l NaCl) was infused intravenously for 105 min; 30 min after the start of atrial natriuretic peptide/placebo infusion, hypertonic saline (855 mmol/l NaCl) was infused (0.06 ml min-1 kg-1) for 60 min. Subjects were then allowed free access to water for the next 2 h; infusion of atrial natriuretic peptide/placebo continued for the first 15 min of the drinking period. 3. The plasma atrial natriuretic peptide concentration did not alter significantly during infusion of hypertonic saline and placebo; it rose to a steady state of 12.7 +/- 1.1 pmol/l (mean +/- SEM) during the infusion of atrial natriuretic peptide and hypertonic saline, and remained at this level during the first 15 min of the drinking period. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, similar increases in plasma osmolality (P less than 0.001) and plasma vasopressin concentration (P less than 0.005) occurred. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, thirst increased significantly over the time course of both studies (P less than 0.01), but the effect of atrial natriuretic peptide infusion compared with placebo infusion was to significantly decrease thirst at 60 min. 4. Drinking rapidly abolished thirst and vasopressin secretion before changes in plasma osmolality occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: To assess whether drinking and oropharyngeal stimuli mediate the release of plasma atrial natriuretic peptide (ANP) in man., Design: Hypertonic saline was infused into male volunteers to stimulate thirst. In order to avoid any effect of volume change on ANP release, the studies were performed with the subject in the seated position., Subjects: Seated normal male volunteers (n = 6) were infused with hypertonic saline at a rate of 0.06 ml/kg/min for 90 min on two separate occasions. After a 15-min equilibrium period, subjects were allowed to drink for the following 45-min period on one occasion, but no drinking was permitted on the other occasion., Measurements: Aliquots of blood were withdrawn at 30-min intervals for 90 min during hypertonic saline infusion, and +3, 6, 9, 12, 15, 30 and 45 min during the drinking/control period for the measurement of plasma ANP, plasma vasopressin, plasma osmolality, serum sodium and haematocrit; thirst was assessed at the same time points using a visual analogue scale. Blood pressure was measured at 15-min intervals., Results: Hypertonic saline infusion induces increases in plasma vasopressin, plasma osmolality, serum sodium and thirst appreciation (P less than 0.005), and blood volume (P less than 0.05) on both study days; there was no increase in plasma ANP during hypertonic saline infusion. During the drinking period there was the expected decrease in plasma vasopressin (P less than 0.01), plasma osmolality (P less than 0.05), serum sodium (P less than 0.05) and thirst appreciation (P less than 0.01); no significant changes occurred in plasma atrial natriuretic peptide, mean arterial blood pressure or haematocrit during either the drinking or the control period., Conclusions: The drinking-mediated inhibition of thirst appreciation and plasma vasopressin is not associated with any change in plasma ANP concentrations; it does not appear that oropharyngeal stimuli contribute to the release of ANP in man.

We investigated the effect of human alpha-atrial natriuretic peptide (alpha-hANP) on osmotically stimulated arginine vasopressin (AVP) secretion and thirst appreciation. Seven normal male volunteers were studied on two occasions: synthetic alpha-hANP-(99-126) (2 pmol.kg-1.min-1) or control was infused intravenously for 30 min before and for the first 60 min of a 120-min hypertonic saline (855 mmol/l) infusion (0.06 ml.kg-1.min-1). Plasma ANP did not alter significantly during infusion of control and hypertonic saline (C+HS) but rose to steady-state concentrations of 17.4 +/- 3.2 pmol/l during infusion of ANP and hypertonic saline (ANP+HS). Plasma osmolality increased on both study days [ANP+HS: 284.4 +/- 0.6 to 299.7 +/- 1.1 mosmol/kgH2O (P less than 0.01)], C+HS: 283.6 +/- 1.2 to 299.1 +/- 1.6 mosmol/kgH2O (P less than 0.01)], as did plasma sodium [ANP+HS: 139.0 +/- 0.6 to 148.0 +/- 0.4 mmol/l (P less than 0.01), C+HS: 137.6 +/- 0.75 to 145.8 +/- 0.7 mmol/l (P less than 0.01)] and blood volume (ANP+HS: 7.7 +/- 0.6%, C+HS: 9.4 +/- 1.0%). The increase in plasma osmolality was accompanied by an increase in plasma AVP [ANP+HS: 1.4 +/- 0.3 to 8.3 +/- 1.2 pmol/l (P less than 0.01), C+HS: 1.6 +/- 0.4 to 7.8 +/- 1.5 pmol/l (P less than 0.01)].(ABSTRACT TRUNCATED AT 250 WORDS)

It is well known that atrial distension is an important stimulus for atrial natriuretic peptide (ANP) release, but conflicting evidence exists as to whether hyperosmolality also stimulates the release of atrial natriuretic peptide (ANP) in man. As infusion of hypertonic saline causes an increase in both blood volume and plasma osmolality, we have employed this stimulus to investigate: (i) whether hyperosmolality increases plasma ANP concentrations; (ii) the importance of posture in ANP release. Normal male volunteers (n = 6) were infused with hypertonic saline at a rate of 0.06 ml/kg/min for 2 h on two different occasions separated by 1 month. Infusion was performed with subjects in the seated and supine positions in random order. Hypertonic saline infusion induced increases in plasma osmolality (P less than 0.001), plasma sodium (P less than 0.01) and blood volume (P less than 0.001) in both seated and supine position. The increase in plasma osmolality was accompanied by an increase in plasma ANP during the supine infusion (2.7 +/- 1.0 to 9.0 +/- 2.4 pmol/l (mean +/- SEM; P less than 0.01] but no significant change in plasma ANP concentration occurred during the seated infusion. A positive linear correlation was obtained between increase in plasma osmolality and plasma ANP in the supine but not in the seated hypertonic saline infusion. There was a positive linear correlation between estimated increase in blood volume and plasma ANP in the supine but not the seated infusion of hypertonic saline. We suggest that the increase in ANP during hypertonic saline infusion reported by some workers was due to atrial distension, secondary to increased blood volume and is dependent on the position in which the subjects were studied.(ABSTRACT TRUNCATED AT 250 WORDS)

A new sensitive, specific radioimmunoassay for human alpha atrial natriuretic peptide (hANP) and a novel extraction method for hANP have been developed. Antiserum to hANP (Keq = 1.923 x 10(11) l/mol) showed no cross-reactivity with related analogues. Displacement of 50% bound 125I-hANP occurred at 4.7 +/- 0.1 fmol/tube (n = 15). The limit of detection of plasma hANP after extraction of 2 ml plasma with Florisil was 1.2 pmol hANP/litre plasma. The recovery of synthetic hANP from plasma over the range 6.5-162.5 pmol/l was 71.2 +/- 1.9%. Inter- and intra-assay coefficients of variation were 13.1% and 10.1% respectively. Extracted plasma was stored at -80 degrees C without loss in immunoreactivity. The radioimmunoassay was physiologically validated in man by measuring plasma hANP following central volume expansion - (a) plasma hANP rose from 2.5 +/- 0.5 to 4.1 +/- 0.6 pmol/l in 9 normal volunteers after postural change from seated to lying (b) infusion of normal saline (2 litre/2 hour) increased hANP from 1.6 to 4.3 pmol/l (n = 2). Infusion of hANP (2 pmol/kg/min) increased plasma hANP to 19.9 +/- 3.4 pmol/l (n = 6).

The anti-diuretic hormone, arginine vasopressin (AVP) stimulates the activity of Na+K+ATPase in the rat renal medullary thick ascending limb of Henle's loop (mTAL). Atrial natriuretic factor (ANF) has been suggested to exert a tubular effect on the mammalian nephron, perhaps in part, by interacting with other hormones. In the present study, we investigated the effect of rat ANF with and without AVP upon mTAL Na+K+ATPase activity using cytochemical methods. ANF alone failed to inhibit or stimulate Na+K+ATPase activity in mTAL at any of the concentrations tested (10 nmol-0.1 pmol l-1). Unlike the rat hypothalamic digitalis-like factor, ANF (10 nmol-10 fmol l-1) did not inhibit Na+K+ATPase activity after stimulation with AVP (1 fmol l-1) for either 4 or 10 min. The results suggest that ANF does not exert an effect on mTAL, either alone or in conjunction with AVP.

This two-site immunoradiometric assay (IRMA) for human atrial natriuretic factor (ANF)99-126 in plasma utilizes a mouse monoclonal antibody raised against rat (r) ANF103-125 with specificity directed towards the ring structure of ANF, and a rabbit antiserum to human (h) ANF99-126. The monoclonal antibody is radioiodinated, and the IgG fraction of the antiserum is coated onto wells of a microtiter plate. Plasma or standard hANF99-126 (150 microL) is incubated with the radioligand in coated wells for 24 h. The detection limit is 0.9 pg per well, corresponding to 2 pmol/L, with a working range (CV less than 10%) from 4.5 to 540 pmol/L. Intra- and interassay precision are 7% and 9%, respectively, and the assay is unaffected by plasma matrix. In humans, the IRMA is specific for hANF99-126, the major circulating form of ANF, and does not cross-react with metabolites having deletions at the carboxy terminus. Plasma IRMA values in normal seated subjects were 6.6 +/- 1.5 (SEM) pmol/L and results correlated with those of an extraction RIA (r = 0.81, P less than 0.001).

The changes in blood glucose, plasma oxytocin, plasma vasopressin, plasma atrial natriuretic peptide, serum osmolality, haematocrit and blood pressure were measured in response to acute insulin-induced hypoglycaemia in six normal male subjects. After the i.v. administration of insulin (0.15 U/kg), plasma concentrations of oxytocin and vasopressin increased rapidly in all subjects and were maximal 15 min after the acute hypoglycaemic reaction (R). Haematocrit increased at the time of the hypoglycaemic reaction, but there was no change in serum osmolality. Systolic blood pressure rose and diastolic blood pressure fell, but mean arterial blood pressure remained unchanged. No changes were demonstrated in plasma concentrations of atrial natriuretic peptide. The release of oxytocin and vasopressin in response to acute hypoglycaemia in man is probably caused by stimulation of the posterior pituitary gland via hypothalamic activation, and not by stimulation of osmoreceptors or baroreceptors.