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Aldosterone stimulates the reabsorption of sodium across epithelial cells of various target tissues. The initial events in the molecular action of the mineralocorticoid are the following: (1) Diffusion of the steroid across the cellular (baso-lateral, serosal) plasma membrane into the cytoplasmic compartment. (2) Binding of the steroid to a receptor protein specific for the class of steroid and activation of this steroid-receptor-complex. (3) Translocation of the activated aldosterone-receptor complex to the nucleus and stimulation of RNA synthesis (including the synthesis of messenger RNA and ribosomal RNA). (4) Translation of the steroid-induced messenger RNAs at the ribosomal level into the aldosterone-induced proteins (AIP) within the cytoplasmic compartment. Whereas these induction steps are uniformly accepted, the mechanisms by which the AIPs increase the activity of a rate-limiting step in the sodium transport process are still object of debate. In this paper we discuss the initial events in the mode of action of aldosterone and the biochemical and physiological approaches to the aldosterone-induced proteins with special reference to the "sodium permease", the "energy", and the "sodium pump" theory. Our analysis shows that despite serious efforts by multiple laboratories, the first AIP with an established relationship to the mineralocorticoid actions of aldosterone is yet to be identified.

We have previously shown that a natriuretic factor which is present in a small molecular weight fraction (IV) of serum and urine from salt loaded animals and healthy subjects, respectively, inhibits the Na-K-ATPase enzyme in vitro and also binds to a specific digoxin antibody. In the present study digoxin-like immunoreacting activity (DLIA) was therefore determined in the serum of healthy volunteers during low (35 nmol/day) and high (greater than 400 mmol/day) sodium intake and of patients with chronic renal failure and serum creatinine concentrations ranging from 127 to 757 mumol/l. DLIA was determined with a radioimmunoassay for digoxin in native serum and in the salt (III) and post-salt (IV) serum fractions eluted from a Sephadex G-25 column. DLIA in native serum of healthy subjects was less than 0.125 ng/ml. After gel filtration DLIA eluted exclusively in the small molecular weight salt (F III) and post-salt (F IV) fractions. Whereas DLIA increased in F III and decreased in F IV, total DLIA in F III + IV slightly increased from 0.37 +/- 0.03 to 0.49 +/- 0.05 ng/ml (p less than 0.01) with the change from low to high sodium intake. DLIA in native serum of uremic patients ranged from 0 to 1.70 ng/ml and was detectable consistently only in patients with serum creatinine concentrations above 250 mumol/l. DLIA in F III which averaged 0.22 +/- 0.04 ng/ml and total activity which ranged from 0.11 to 0.88 ng/ml closely correlated with the degree of renal impairment (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the role of the intracellular calcium-calmodulin complex in the hydro-osmotic response to antidiuretic hormone (ADH), the effects of trifluoperazine (TFP), a well-established inhibitor of calmodulin-mediated functions, and of verapamil (V), a calcium entry blocker, were examined in the urinary bladder of the toad, a model for the late distal tubule and the collecting duct of the mammalian nephron. Preincubation of the hemibladders with TFP at serosal concentrations of 10(-5) and 10(-4) M was without effect on basal water flow but markedly reduced the maximal hydroosmotic response to ADH (50 mU/ml) in a dose-dependent manner as compared to control hemibladders (23.60 +/- 1.23 vs. 42.17 +/- 4.18 mg/min per hemibladder (10(-5) M TFP) and 5.43 +/- 0.59 vs. 52.50 +/- 4.67 mg/min per hemibladder (10(-4) M TFP). This inhibitory effect of TFP on the ADH-stimulated osmotic water flow persisted in the presence of naproxen (10(-5) M), a known inhibitor of prostaglandin synthesis. The hydro-osmotic response to cyclic adenosine 3',5' monophosphate (cAMP, 10(-3) M) was also significantly reduced in TFP-pretreated tissues (11.68 +/- 1.84 vs. 32.83 +/- 3.14 mg/min per hemibladder), suggesting a post-cAMP inhibitory effect of TFP. V (10(-4) M) had no effect on basal water flow but significantly reduced the hydro-osmotic effect of 50 mU/ml ADH (15.17 +/- 1.05 vs. 38.00 +/- 3.39 mg/min per hemibladder). In contrast, cAMP-stimulated osmotic water flow was significantly stimulated in V-treated tissues (48.07 +/- 1.95 vs. 27.13 +/- 1.50 mg/min per hemibladder).(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate a tubular action of atrial natriuretic peptide (ANP), in the present study the effects of rat atrial extract (AE) and of synthetic rat atriopeptin III (AP III) were assessed in conscious rats during hypotonic saline infusion. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were estimated by the clearances (C) of PAH and of endogenous creatinine, respectively. CPO4 was used as a marker of proximal tubular function. Distal delivery (DD) and distal fractional absorption of chloride (DFACl), a measure of solute absorption in the diluting segments, were calculated from CH2O and CCl. AE and AP III increased RPF in all groups of animals. Low doses of AP III (40 ng/100 g B.W.) significantly increased urine flow rate and CCl, whereas GFR, CNa, CPO4, and CK remained unaltered. The marked natriuresis at high doses of ANP was associated with a rise in GFR and in absolute and fractional CPO4 as well as an increase in DD and CK. AE and AP III (1 microgram/100 g B.W.) decreased DFACl from 0.94 +/- 0.03 and 0.87 +/- 0.03 to 0.80 +/- 0.07 (p less than 0.05) and 0.54 +/- 0.07 (p less than 0.01), respectively. Some of the effects on tubular reabsorptive capacity probably result from medullary wash-out which thereby contributes to the natriuresis by potentiating the rise in the filtered load of sodium at high ANP levels. In the absence of changes in GFR and CPO4, the tubular action of ANP is more accurately reflected by CCl which may result from decreased absorption in the medullary collecting tubule.

Recent experimental and clinical findings indicate that immunoreactive human Atrial Natriuretic Peptide (alpha-hANP) is involved in the regulation of blood volume and arterial blood pressure (BP). Whereas the potential regulatory role of alpha-hANP in acute changes of extracellular fluid volume (ECFV) and in the modulation of BP has been demonstrated in various studies, their involvement in the chronic maintenance of sodium and water homeostasis is still equivocal. Moreover the role of alpha-hANP is of particular interest in chronic renal failure, since in this pathological condition increased sodium and water retention plays a major pathogenetic role in the development of hypertension and altered secretion and/or metabolism of alpha-hANP may contribute to fluid volume and BP regulation. To evaluate the relationship between the degree of renal insufficiency, BP and circulating alpha hANP we determined plasma alpha-hANP concentrations in 16 nondialyzed patients with progressive chronic renal failure (CRF) of various degree. Serum creatinine concentrations ranged from 127 to 1187 (435 +/- 76) mumol/l, systolic BP from 135 to 200 (158 +/- 4) and diastolic BP from 80 to 110 (94 +/- 2) mm Hg respectively. Plasma alpha-hANP concentrations ranged from 49 to 753 with a mean of 228 +/- 42 pg/ml which was thus significantly higher as compared to 90.0 +/- 16.2 pg/ml found in healthy volunteers (p less than 0.05). A highly significant linear correlation between plasma alpha-hANP and serum creatinine concentrations (r = 0.92) was observed; a weaker correlation was found between mean arterial pressure and alpha-hANP (r = 0.66) and serum creatinine concentration (r = 0.59), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-circuit current (SCC) techniques were used to monitor the effects of various diuretic agents on Na+ transport in isolated frog skin, a model for the late distal tubule and the collecting duct of the mammalian kidney. Acetazolamide, hydrochlorothiazide, torasemide, and ethacrynic acid did not affect sodium transport (as indicated by the SCC) or transepithelial electrical resistance when added either to the apical (outer) or to the inner (basolateral, corial) bathing solution of the tissue. However, Na+ transport was sensitive to amiloride, the triamterene derivate dimethylamino-hydroxypropoxytriamterene (RPH 2823), and to furosemide. Whereas apical amiloride, and RPH 2823 induced a dose-dependent decrease in SCC and increase in transepithelial electrical resistance, apical furosemide resulted in a dose-dependent increase in SCC and a decrease in electrical resistance. None of the three diuretic agents caused a significant change in SCC when applied to the inner bathing Ringer's solution. The small furosemide-induced decrease in resistance compared with the huge increase in SCC suggests that furosemide affects Cl- permeability as well as Na+ permeability. Evidence for this notion was achieved by the following findings: The decrease in resistance after furosemide was more pronounced in tissues bathed in Cl(-)-free solutions compared with Cl(-)-containing solutions. n contrast, SCC stimulation by apical furosemide is Cl(-)-ion independent, but strongly Na+-ion dependent. SCC stimulation by furosemide is amiloride-sensitive. With respect to the onset, locus, and reversibility of action, it seems reasonable to assume that amiloride, RPH 2823, and furosemide all influence transepithelial Na+ transport by interacting with the Na+ channel or a regulator site of it within the apical membrane. The stoichiometry of the amiloride (RPH 2823)-receptor site interaction revealed Hill-coefficient(s) of less than 1, indicating a negative cooperativity among the receptor sites. The interaction between Na+ ions and amiloride or RPH 2823 displayed mixed competitive-noncompetitive inhibition. Taken together, these results support the hypothesis that amiloride and Na+ as well as RPH 2823 and Na+ may act at different loci on the apical entry mechanism in Rana esculenta skin.

The hepato-renal syndrome is defined as potentially reversible functional renal failure associated with acute fulminant hepatitis or, more often, with advanced chronic liver failure. It is characterized by oliguria, azotemia, retention of sodium and water with formation of ascites, and hyponatremia. While urinary sodium concentration of less than 10 mEq/l reflects intact tubular sodium absorption, the kidney lacks the ability for adequate free-water generation. This condition must be separated from specific renal diseases which may arise during the course of intra-or extrahepatic diseases and which must be classified accordingly. Pathophysiological aspects of the hepa-to-renal syndrome include hemodynamic factors, such as changes in intrarenal blood flow distribution in the presence of elevated intrarenal and reduced peripheral vascular resistance. The functional relationship of vasoconstrictor, sodium retaining, and anti-diuretic hormones (e.g., renin-angiotensin, aldosterone, and vasopressin) to vasodilator, diuretic, and natriuretic hormonal factors (e.g., prostaglandins, kinins, and natriuretic hormone) may be altered as well. Finally, a pre- and intrahepatic spillover resulting in decreased endotoxin clearance must be considered. Due to the lack of understanding of their complex interactions, so far pharmacological and therapeutic approaches remained ineffective to correct at least some of these factors. Today, recovery from hepato-renal syndrome will, therefore, mainly depend on the course of the underlying liver disease.