Role of atrial natriuretic peptide in mineralocorticoid escape phenomenon in patients with primary aldosteronism

The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) in five patients with primary aldosteronism due to adenoma. The patients had been treated with spironolactone for 2-3 months before they were admitted. After admission, blood pressure, body weight, and urinary excretion of sodium were measured daily. Venous samples were obtained twice a week for measurements of plasma levels of ANP, plasma renin activity (PRA), and plasma concentrations of aldosterone (PAC), cortisol, and deoxycorticosterone. The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration. Plasma volume was determined two times, during the control period and on the 13th day after stopping spironolactone. Urinary sodium excretion decreased initially and returned to the control levels successively. Body weight and plasma volume increased, and blood pressure rose steadily. PRA and the plasma concentrations of cortisol and deoxycorticosterone decreased significantly (P less than 0.05); however, high levels of PAC did not alter significantly. Plasma ANP levels increased significantly (P less than 0.05) from 26 +/- 4 pg/ml during the control period to 195 +/- 47 pg/ml on the 13th day after stopping spironolactone. The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP. Furthermore, ANP might contribute to the decrease in cortisol and deoxycorticosterone in plasma because of the direct inhibitory action of ANP on steroidogenesis.     

A possible contribution of endogenous atrial natriuretic peptide to proteinuria in patients with chronic renal failure.

Plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) were measured with a specific radioimmunoassay in 19 undialysed patients with chronic renal failure. At the beginning, an extremely high level of plasma hANP (50 fmol/ml) seen in a patient was rejected with Smirnov's test and was excluded from further statistics. The plasma IR-ANP levels in these patients were significantly higher than those of 19 normal subjects matched with age and sex (10.9 +/- 1.6 vs 5.3 +/- 0.6 fmol/ml, mean +/- SEM, p less than 0.01), and positively correlated with mean blood pressure (r = 0.44, p less than 0.05) and the cardiothoracic ratio (r = 0.65, p less than 0.01), but did not correlate with creatinine clearance (r = -0.38, n.s.). Further, a significant correlation was observed between plasma IR-ANP and urinary protein output (r = 0.47, p less than 0.05). On the other hand, urinary protein output did not correlate significantly with variables such as mean blood pressure, the cardiothoracic ratio or creatinine clearance. Since it has been suggested that ANP enhances glomerular capillary permeability, increased ANP responding to volume overload in those patients may play an important role in increasing urinary protein excretion.     

Equimolar doses of atrial and brain natriuretic peptides and urodilatin have differential renal actions in overt experimental heart failure

A hallmark of overt congestive heart failure (CHF) is attenuated cGMP production by endogenous atrial natriuretic peptide (ANP) with renal resistance to ANP. ANP and brain natriuretic peptides (BNP) are of myocardial origin, whereas urodilatin (Uro) is thought to be derived from kidney. All three peptides are agonists to the natriuretic peptide-A receptor. Our objective was to compare the cardiorenal and humoral actions of ANP, BNP, and Uro in experimental overt CHF. We determined cardiorenal and humoral actions of 90 min of intravenous equimolar infusion of ANP, BNP, and Uro (2 and 10 pmol.kg-1.min-1) in three separate groups of anesthetized dogs with rapid ventricular pacing-induced overt CHF (240 beats/min for 10 days). BNP resulted in increases in urinary sodium excretion (U(Na)V) (2.2+/-0.7 to 164+/-76 microeq/min, P<0.05) and glomerular filtration rate (GFR) (27+/-4 to 52+/-11 ml/min, P<0.05) that were greater than those with Uro (P<0.05), whereas ANP did not result in increases in U(Na)V or GFR. Increases in plasma cGMP (25+/-2 to 38+/-2 pmol/ml, P<0.05) and urinary cGMP excretion with BNP (1,618+/-151 to 6,124+/-995 pmol/min, P<0.05) were similar to those with Uro; however, there was no change with ANP. Cardiac filling pressures were reduced in all three groups. These studies also support the conclusion that in experimental overt CHF, renal resistance to natriuretic peptides in increasing rank order is BNP相似文献   

Atrial and brain natriuretic peptide in adrenal steroidogenesis.

We elucidated the role of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in human and bovine adrenocortical steroidogenesis. The urinary volume, sodium excretion and cyclic GMP (cGMP) excretion and plasma cGMP were markedly increased by the synthetic alpha-human ANP (alpha-hANP) infusion in healthy volunteers. Plasma arginine vasopressin (AVP) and aldosterone levels were significantly suppressed. Both ANP and BNP inhibited aldosterone, 19-OH-androstenedione, cortisol and DHEA secretion dose-dependently and increased the accumulation of intracellular cGMP in cultured human and bovine adrenal cells. alpha-hANP significantly suppressed P450scc-mRNA in cultured bovine adrenal cells stimulated by ACTH. Autoradiography and affinity labeling of [125I]hANP, and Scatchard plot demonstrated a specific ANP receptor in bovine and human adrenal glands. Purified ANP receptor from bovine adrenal glands identified two distinct types of ANP receptors, one is biologically active, the other is silent. A specific BNP receptor was also identified on the human and bovine adrenocortical cell membranes. The binding sites were displaced by unlabelled ANP as well as BNP. BNP showed an effect possibly via a receptor which may be shared with ANP. The mean basal plasma alpha-hANP level was 25 +/- 5 pg/ml in young men. We confirmed the presence of ANP and BNP in bovine and porcine adrenal medulla. Plasma or medullary ANP or BNP may directly modulate the adrenocortical steroidogenesis. We demonstrated that the lack of inhibitory effect of alpha-hANP on cultured aldosterone-producing adenoma (APA) cells was due to the decrease of ANP-specific receptor, which caused the loss of suppression of aldosterone and an increase in intracellular cGMP.     

Significant increase in plasma immunoreactive atrial natriuretic polypeptide concentration during head-out water immersion

To investigate the physiological regulatory mechanism of human atrial natriuretic polypeptide (hANP) secretion, plasma hANP was measured by a direct radioimmunoassay during head-out total body water immersion (WI) in normal men. Five healthy men were immersed in water for 1 hr. Urine volume and Na excretion were significantly increased during WI. Plasma hANP increased significantly during WI peaking at 30 min. and returned toward the baseline after WI. Plasma renin activity and norepinephrine were suppressed occasionally during WI. Plasma ADH did not change throughout the study period. Maximal increments in plasma hANP correllated with that in urine output or urinary Na excretion during WI. These data suggest that acute central hypervolemia caused by WI increases hANP secretion and that this increase may participate in the diuretic response to WI.     

Effect of head-out immersion on plasma atrial natriuretic factor in man

This study was conducted to examine the role of atrial natriuretic factor (ANF) in the development of diuresis and natriuresis in response to the head-out immersion in 35 degrees C water. Six male subjects were hydrated (0.5% body wt), sat for 1 hr in air (preimmersion), were immersed in water to the neck for 3 hr, and then sat for 1 hr in air (postimmersion). In another series they were similarly hydrated and then sat for 5 hr in air for the time control. Urine and venous blood samples were collected hourly for creatinine and electrolyte measurements. In addition, the concentration of ANF was determined in unextracted plasma by a radioimmunoassay. The pattern of electrolyte excretion was evaluated on the basis of fractional excretion of filtered load. In the time control series, urine flow and fractional excretion of Na and K remained low throughout the 5-hr experimental period. On the other hand, urine flow increased significantly from the preimmersion level of approximately 2 to approximately 7 ml/min during the first hour of immersion (P less than 0.05), after which it decreased to approximately 5 ml/min during the second hour of immersion (P less than 0.05) and to approximately 2 ml/min during the third hour of immersion. Fractional excretion of Na increased continuously from preimmersion level of approximately 1.0 to approximately 1.8% during the second and third hours of immersion (P less than 0.05) and then decreased to 1.2% during the 1-hr postimmersion period. The plasma ANF remained low (approximately 75 pg/ml) during the 5-hr time control period. In the immersion series, plasma ANF increased significantly from the preimmersion level of approximately 80 to approximately 120 pg/ml during the entire 3-hr immersion period and then returned to the preimmersion level during 1 hr postimmersion. These results indicate that the immersion diuresis and natriuresis are indeed associated with the increased ANF release. However, it can not be ascertained from the present study if the increased ANF contributes directly to these renal responses to immersion or in concert with other mediators.     

Four-hour atrial natriuretic peptide infusion in conscious rats: effects on urinary volume, sodium, and cyclic GMP

Atrial natriuretic peptide (ANP) is released from the cardiac atria in response to acute volume loads; when infused acutely ANP causes diuresis and natriuresis. Cyclic GMP (cGMP) appears to be the second messenger for ANP in the kidney. The role that ANP plays in the long-term regulation of salt and water balance is unclear, however, since resistance to ANP's natriuretic and diuretic activity develops during prolonged administration. The purpose of the present study is to examine the relationship between the rate of cGMP excretion in response to ANP and the development of resistance to ANP's diuretic and natriuretic activity. Following a 30-min baseline period of infusion of Ringer's solution conscious rats received ANP at 15 micrograms/kg/hr (n = 6) or Ringer's alone (n = 5) for 240 min. ANP-infused rats had a significant diuresis and natriuresis during the first hour of infusion; urinary cGMP excretion also increased compared to baseline. By 120 min after initiating the infusion in ANP-rats urinary volume and sodium excretion had declined to values not significantly different from those of baseline or control. In contrast, urinary cGMP excretion remained elevated for the duration of the ANP infusion, whether compared to baseline values or the control group. Resistance to the diuretic and natriuretic activity of ANP is not a result of mechanisms that involve cGMP generation.     

Thiazolidinediones and the renal and hormonal response to water immersion-induced volume expansion in type 2 diabetes mellitus

Thiazolidinediones cause sodium retention and edema by a direct effect on the kidneys. The aim of this study was to use the technique of head-out water immersion to investigate the effects of rosiglitazone on sodium and volume homeostasis in subjects with type 2 diabetes mellitus. The volume expansion response to water immersion was compared with the response on a non-immersion control day in 12 nondiabetic male subjects and 8 diet-controlled male type 2 diabetic subjects with hourly blood and urine sampling over a 4-h period. This was repeated after both groups had taken 4 mg of rosiglitazone daily for 7 days. Immersion produced a natriuresis in both groups (P < 0.001). An impairment of this natriuresis was seen in the diabetic subjects (P = 0.006). However, when rosiglitazone was taken, there was no significant difference in immersion-induced natriuresis compared with nondiabetic controls (P = 0.2). There was an immersion-induced rise in atrial natriuretic peptide (ANP) and urinary cyclic guanosine monophosphate (cGMP), in the healthy subjects (ANP P = 0.001, cGMP P = 0.043), which was not seen in the diabetic subjects (ANP P = 0.51, cGMP P = 0.74). Rosiglitazone restored the immersion-induced increase in cGMP excretion and rise of ANP in the diabetic group (ANP P = 0.048, cGMP P = 0.009). This study confirms that type 2 diabetic subjects have an impaired natriuretic response to acute volume expansion, which appears to be enhanced rather than diminished by rosiglitazone. This may be related to its effects in increasing natriuretic peptides and restoring the impaired cGMP excretion to volume expansion.     

Vasopressin inhibits diuresis induced by water immersion in humans.

We tested the hypothesis that 1-desamino-8-D-arginine vasopressin (DDAVP), a V2-receptor agonist, could inhibit the diuresis induced by water immersion in humans. Water and electrolyte excretion, plasma atrial natriuretic factor concentration, and plasma aldosterone concentration were measured initially and after 3 h of water immersion in 13 healthy sodium-replete men given either placebo or 20 micrograms of intranasal DDAVP. Guanosine 3',5'-cyclic monophosphate and urea excretion and urine osmolality were also determined. DDAVP inhibited the diuresis induced by water immersion in men: 758 +/- 168 (SE) ml/3 h in the placebo group vs. 159 +/- 28 ml/3 h in the DDAVP group (P less than 0.05). After 3 h of water immersion, plasma atrial natriuretic factor concentrations were increased from 11 +/- 2 to 20 +/- 4 pg/ml in the placebo group and from 14 +/- 2 to 33 +/- 4 pg/ml in the DDAVP group (P less than 0.05). Plasma aldosterone concentrations were decreased from 98 +/- 18 to 45 +/- 6 pg/ml in the placebo group (P less than 0.05) and from 54 +/- 17 to 25 +/- 5 pg/ml in the DDAVP group (P less than 0.05). Despite these changes in aldosterone and atrial natriuretic factor concentrations, which should increase sodium excretion, DDAVP decreased the natriuresis induced by water immersion in humans: 56 +/- 8 meq Na+/3 h in the placebo group vs. 36 +/- 6 meq Na+/3 h in the DDAVP group (P less than 0.05). DDAVP may be used to prevent the diuresis associated with central redistribution of blood volumes that occur during water immersion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide--cyclic GMP coupling and urinary sodium excretion during acute volume expansion in man

The present study examines hormonal and renal responses to acute volume expansion in normal man, with particular emphasis on the atrial natriuretic peptide (ANP)--cyclic GMP coupling. Two liters of isotonic saline were infused into eight normotensive male subjects over a 1-h period. Plasma and urinary measurements were made before, during, and up to 300 min after the start of the saline infusion. With the initial increase in urinary sodium excretion there were increases in plasma ANP and plasma cyclic GMP, which reached maximum levels at 15 min after the end of the saline infusion. Urinary cyclic GMP increased gradually during saline infusion up to approximately 60 min after the end of the infusion. Plasma ANP and plasma and urinary cyclic GMP excretion gradually declined thereafter. By contrast, urinary sodium excretion remained elevated up to the end of the observation period. The saline infusion was associated with marked reductions in plasma renin activity and aldosterone, which persisted up to the end of the study. These results suggest a coupling between the increases in plasma ANP, the production of cyclic GMP, and urinary sodium excretion, in particular during the initial renal response to acute volume expansion. However, other mechanisms including the suppression of the renin--angiotensin--aldosterone system may become increasingly important in the later natriuretic response to acute volume expansion.     

Increased secretion of brain natriuretic peptide and atrial natriuretic peptide, but not sufficient to induce natriuresis in rats with nephrotic syndrome.

The levels of immunoreactive brain natriuretic peptide (ir-BNP) and immunoreactive atrial natriuretic peptide (ir-ANP) were evaluated by radioimmunoassay in both the atrium, ventricle and plasma of adriamycin-induced nephrotic rats and control rats. There was no difference in right and left atrial concentrations of ir-BNP, however, a higher right atrial concentration of ir-ANP was observed in nephrotic rats than in controls (p less than 0.01). The ventricular ir-BNP and ir-ANP were increased in nephrotic rats compared to controls (BNP: p less than 0.001, ANP: p less than 0.001). Cardiac BNPs were composed of pro-BNP (gamma-BNP) and its C-terminal 45-amino-acid peptide (BNP-45). The ratio of BNP-45/gamma-BNP in nephrotic rats was higher than that of controls in both atria and in the ventricle. Plasma ir-BNP and ir-ANP were significantly higher in nephrotic rats than in controls (BNP: p less than 0.001, ANP: p less than 0.001), and each level was negatively correlated with urinary sodium excretion in nephrotic rats (BNP: r = -0.84, p less than 0.001, ANP: r = -0.88, p less than 0.001). These results suggest that production and secretion of both BNP and ANP are concomitantly stimulated by a decreased renal ability to eliminate sodium and water, but this secretion is insufficient to induce effective natriuresis in nephrotic rats.     

Defective regulation and action of atrial natriuretic peptide in type 2 diabetes.

Increased plasma atrial natriuretic peptide (ANP) levels and impaired ANP action have been reported in patients with diabetes or insulin resistance. The aim of this study was to assess the interaction between insulin and ANP in type 2 diabetes. In 12 normotensive, normoalbuminuric type 2 diabetics, we infused insulin at a high (6.6 pmol/min/kg) or, on a different day, at a low rate (0.6 pmol/min/kg) during 4 hours of isoglycemia under isovolumic, isoosmolar conditions. The normal response was established in 12 healthy volunteers using an identical protocol. Despite higher baseline ANP levels (17.7 +/- 2.8 vs. 10.8 +/- 1.8 pg/ml, p = 0.04), urinary sodium excretion was similar in diabetics and controls (113 +/- 8.5 vs. 102 +/- 8.8 mEq/24 hours, p = ns). In both groups, hyperinsulinemia caused a decrease in blood volume (0.33 +/- 0.10 l, p < 0.01), diastolic blood pressure (6 %, p < 0.02), and natriuresis. However, plasma ANP decreased in controls (from 12.7 +/- 1.9 to 8.6 +/- 1.4 pg/ml, p = 0.01) but not in type 2 diabetics (15.1 +/- 2.7 vs. 17.2 +/- 3.8 pg/ml, p = ns). We conclude that ANP release is resistant to volume stimulation in type 2 diabetic patients, and natriuresis is resistant to ANP action. This dual disruption of ANP control may play a role in blood pressure regulation in diabetes.     

Plasma atrial natriuretic peptide levels in children with cardiac diseases: correlation with cGMP levels and haemodynamic parameters

In children with various forms of cardiac diseases (aged 2 months to 16 years) significantly higher plasma atrial natriuretic peptide (ANP; range 36-680, median 247 pg/ml) and cyclic 3'5'-guanosine monophosphate (cGMP; range 0.2-46, median 8.2 pmol/ml) levels were found than in control children (p less than 0.0001). In control children (aged 4 months to 17 years) plasma ANP and cGMP levels were measured in the range of 2.4-98 pg/ml and of 0.2-2.8 pmol/ml, respectively. There was a linear correlation between the two parameters in children with cardiac diseases (r = 0.62, p less than 0.01). Children with elevated mean right atrial pressure (i.e., greater than 6 mm Hg) showed significantly higher plasma ANP levels than children with normal atrial pressure (p less than 0.01). However, there was only a weak linear correlation between mean right atrial pressure and plasma ANP levels (r = 0.48, p less than 0.01). Plasma ANP levels from right atrium, pulmonary artery, left atrium and left ventricle were significantly higher than those from vena cava (p less than 0.05). Analysis of ANP-like immunoreactive material by high performance liquid chromatography suggested that alpha-ANP is the major form of circulating ANP in blood of children with cardiac diseases.     

Cardiorenal-endocrine responses to head-out immersion at night

Cardiorenal-endocrine responses to 3-h head-out immersion (HOI) (water temperature = 34.5 +/- 0.5 degrees C) were studied during day (0900-1400 h) and night (2300-0400 h) in six hydropenic male human subjects. Although HOI induced a reversible increase in urine flow in all subjects, the response was faster and greater in magnitude during the day compared with night (P less than 0.05). Na excretion and osmolal clearance (Cosm) also followed the identical response pattern as urine flow, and in fact, the HOI-induced diuresis was entirely accounted for by the increased Cosm. Endogenous creatinine clearance was not different between the day and the night and remained unchanged during HOI. Both plasma renin activity and aldosterone concentration and urinary aldosterone excretion were nearly twofold greater during the day compared with night before HOI but decreased to the same level during HOI in both daytime and the nighttime series (P less than 0.05). There was no correlation between the Na excretion rate and renin-aldosterone levels either before or during HOI. Plasma antidiuretic hormone (ADH) level was comparable between day and night before HOI and decreased to a similar level during HOI in both daytime and nighttime series (P less than 0.05 for nighttime HOI). Cardiac output increased from 3.3 1/min before HOI to 5-6 1/min during HOI without showing any significant circadian difference. Hematocrit, hemoglobin, and plasma concentrations remained unchanged under all conditions. It is concluded that the renal response to HOI is subject to nocturnal inhibition, which cannot be attributed to circadian differences in the degree of HOI-induced central blood pooling, renin-aldosterone, or ADH responses.     

Effects of clonidine and dihydralazine on atrial natriuretic factor and cGMP in humans

The effects of a 1-wk treatment with clonidine (75 micrograms/day twice a day) and dihydralazine (25 mg/day twice a day) on base-line levels of plasma atrial natriuretic factor (ANF) and plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and their changes by acute saline infusion (2 liters) in eight normal subjects were evaluated. Basal ANF was decreased to 65% in the clonidine group compared with both the control and dihydralazine groups. Volume loading increased plasma ANF levels by 30-40% of base-line values in the control and the dihydralazine groups and by 15% in the clonidine group. Basal plasma and urinary cGMP levels were raised by 30 and 90% in the dihydralazine group compared with both other groups. Volume loading increased plasma cGMP levels by 40% in the control and clonidine-treated groups and by 25% in the dihydralazine-treated group. It is concluded that ANF may contribute to hemodynamic effects of clonidine but not to those of dihydralazine. Dihydralazine increases plasma and urinary cGMP, supposedly by direct activation of the soluble guanylate cyclase.     

Suppression of ADH during water immersion in normal man.

Since previous studies from this laboratory have demonstrated that the redistribution of blood volume and concomitant relative central hypervolemia induced by water immersion to the neck causes a profound natriuresis and a suppression of the renin-aldosterone system, it was of interest to assess whether the diuresis induced by immersion was mediated by an analogous inhibition of ADH. The effects of water immersion on renal water handling and urinary ADH excretion were assessed in 10 normal male subjects studied following 14 h of overnight dehydration on two occasions, control and immersion. The conditions of seated posture and time of day were identical. During control ADH persisted at or above prestudy values. Immersion resulted in a progressive decrease in ADH excretion from 80.1 plus or minus 7 (SEM) to 37.3 plus or minus 6.3 muU/min (P smaller than 0.025). Cessation of immersion was associated with a marked increase in ADH from 37.3 +/- 6.3 muU/min to 176.6 +/- 72.6 muU/min during the recovery hour (P smaller than 0.05). Concomitant with these changes urine osmolality decreased significantly beginning as early as the initial hour of immersion from 1044 +/- 36 to 542 +/- 66 mosmol/kg H2O during the final hour of immersion (P smaller than 0.001). Recovery was associated with a significant mean increase in Uosm of 190 +/- 40 mosmol/kg H2O over the final hour of immersion (P smaller than 0.001). The suppression of ADH occurred without concomitant changes in plasma tonicity. These studies are consistent with the suggestion that in hydrated subjects undergoing immersion suppression of ADH release contributes to the enhanced free water clearance, which has been previously documented.     

Plasma atrial natriuretic peptide in conscious rats with reduced renal mass

The effect of salt intake and reduction of renal mass (RRM) on plasma immunoreactive atrial natriuretic peptide (iANP) levels in conscious rats was studied. Rats were divided into RRM and sham-operated groups, and then further subdivided into groups infused with 1 or 6 mEq of sodium per day. Plasma urea nitrogen increased in the groups with RRM. Plasma sodium, sodium balance, and heart rate did not differ between the sham and RRM groups. Rats with RRM maintained on 1 mEq of sodium per day did not have an elevation of water intake, arterial pressure, or plasma iANP. Rats with RRM maintained on 6 mEq of sodium per day had significantly (P less than 0.05) elevated water intake, arterial pressure, and plasma iANP. Arterial pressure and plasma iANP were correlated (r = 0.800) for rats with RRM on either 1 or 6 mEq of sodium per day. Increased plasma iANP in the RRM group on 6 mEq per day was not caused by either RRM or high sodium alone; it was an effect of RRM plus high salt intake. The increase in plasma iANP in the RRM group may be caused by the increase in arterial pressure, possibly due to an increase in extracellular fluid volume. ANP may not be responsible for the sustained increase in fractional sodium excretion observed in RRM.     

Reduced natriuresis after oral sodium load in cholestatic rats: role of compartment volumes and ANP

The purpose of this study was to assess the participation of the atrial natriuretic peptide (ANP)-cGMP system in electrolyte and volume handling of cholestatic rats submitted to an acute oral sodium load. Cholestasis was induced by ligation and section of the common bile duct (n = 51). Control rats were sham operated (n = 56). Three weeks after surgery, 24-hr urinary volume, sodium, potassium, cGMP and creatinine excretion were measured. Three days later, animals received 10 mmol/kg NaCl (1 M) by gavage, and urinary excretion was measured for 6 hr. In parallel groups of rats, plasma volume, electrolytes and ANP concentration, extracellular fluid volume (ECFV), and renal medullary ANP-induced cGMP production were determined in basal conditions or 1 hr after oral sodium overload. As compared with controls, cholestatic rats had a larger ECFV and higher plasma ANP (67.2 +/- 5.2 vs 39.7 +/- 3.5 pg/ml), but lower hematocrit and blood volume, and were hyponatremic. Cholestatic rats showed higher basal excretion of sodium, potassium, and volume than controls, but equal urinary cGMP. After the NaCl overload, cholestatic rats showed a reduced sodium excretion but equal urinary cGMP. One hr after sodium overload, both groups showed hypernatremia, but whereas in control rats ECFV and ANP increased (50.7 +/- 4.1 pg/ml), in cholestatic rats ECFV was unchanged, and plasma volume and ANP were reduced (37.5 +/- 5.8 pg/ml). ANP-induced cGMP production in renal medulla was similar in cholestatic and control nonloaded rats (14.2 +/- 5.2 vs 13.4 +/- 2.6 fmol/min/mg). One hr after the load, medullary cGMP production rose significantly in both groups, without difference between them (20.6 +/- 3.1 vs 22.7 +/- 1. 7 fmol/min/mg). We conclude that the blunted excretion of an acute oral sodium load in cholestatic rats is associated with lower plasma ANP due to differences in body fluid distribution and cannot be explained by renal refractoriness to ANP.     

Cyclic GMP down-regulates atrial natriuretic peptide receptors on cultured vascular endothelial cells.

Down-regulation of atrial natriuretic peptide (ANP) receptors was investigated using a cultured bovine pulmonary artery endothelial (CPAE) cell line. Endothelial cells have been shown to possess two subtypes of ANP receptors, a guanylate cyclase-coupled receptor (B-receptor) and a clearance receptor (C-receptor). The treatment with APIII, rat ANP (103-126), at concentrations of 10(-8) to 10(-6) M for 24 h, resulted in a significantly (p less than 0.01) greater decrease in maximum 125I-APIII binding to CPAE cells than the identical concentration of API, rat ANP (103-123). APIII at concentrations of 10(-8) to 10(-6) M stimulated cyclic GMP (cGMP) production 3.3-17.5-fold greater than similar concentrations of API. From these findings, we hypothesized that cGMP produced following ANP binding to the B-receptor participates in ANP receptor regulation. M&B 22948, a selective inhibitor of cGMP-specific phosphodiesterase, significantly (p less than 0.01) potentiated the effect of both API and APIII on 125I-APIII binding, while M&B 22948 itself had no significant effect on 125I-APIII binding. Treatment of the cells with 1 mM 8-bromo-cGMP also significantly (p less than 0.01) decreased 125I-APIII binding to the cells, and a potentiation of this effect was observed by M&B 22948. Scatchard analysis of binding data from 8-bromo-cGMP-treated cells showed a significant decrease in Bmax (1.79 +/- 0.15 to 1.20 +/- 0.07 fmol/mg protein, p less than 0.05) without a significant change in Kd. Affinity cross-linking of 125I-APIII to 8-bromo-cGMP-treated cells showed a decrease in the labeling of 60- and 70-kDa bands corresponding to the C-receptor. In addition, the APIII-stimulated cGMP response remained unchanged in the 8-bromo-cGMP-treated cells, indicating that the B-receptor was not down-regulated. We conclude that cGMP regulates ANP-binding sites on the endothelial cell and that the evidence indicates that the C-receptor may preferentially be down-regulated by cGMP in CPAE cells.     

Atrial natriuretic polypeptide in atria and plasma in experimental hyperthyroidism and hypothyroidism

To investigate the involvement of thyroid hormone on the release of atrial natriuretic polypeptide (ANP), we have measured immunoreactive ANP in the atria and plasma of experimental hyperthyroid and hypothyroid rats. Plasma ANP was higher (p less than 0.05) in hyperthyroid rats and was lower (p less than 0.05) in hypothyroid rats than in euthyroid rats. ANP content and concentration in the atria were lower (p less than 0.01) in hyperthyroid rats than in hypothyroid rats. An inverse correlation was found between the plasma ANP and ANP concentration in the atria (n = 15, r = 0.60, p less than 0.01). The results indicate an increased systemic release of ANP from the atria in hyperthyroidism and a decreased systemic release in hypothyroidism.