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Collecting duct (CD)-derived endothelin-1 (ET-1) acting via endothelin B (ETB) receptors promotes Na+ excretion. Compromise of ET-1 signaling or ETB receptors in the CD cause sodium retention and increase blood pressure. Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ reabsorption in the CD. To test for ETB receptor regulation of ENaC, we combined patch-clamp electrophysiology with CD-specific knockout (KO) of endothelin receptors. We also tested how ET-1 signaling via specific endothelin receptors influences ENaC activity under differing dietary Na+ regimens. ET-1 significantly decreased ENaC open probability in CD isolated from wild-type (WT) and CD ETA KO mice but not CD ETB KO and CD ETA/B KO mice. ENaC activity in WT and CD ETA but not CD ETB and CD ETA/B KO mice was inversely related to dietary Na+ intake. ENaC activity in CD ETB and CD ETA/B KO mice tended to be elevated under all dietary Na+ regimens compared with WT and CD ETA KO mice, reaching significance with high (2%) Na+ feeding. These results show that the bulk of ET-1 inhibition of ENaC activity is mediated by the ETB receptor. In addition, they could explain the Na+ retention and elevated blood pressure observed in CD ET-1 KO, CD ETB KO, and CD ETA/B KO mice consistent with ENaC regulation by ET-1 via ETB receptors contributing to the antihypertensive and natriuretic effects of the local endothelin system in the mammalian CD.

Insulin-mediated sodium retention is implicated as a mechanism for hypertension in metabolic syndrome and type II diabetes. However, there is no direct experimental evidence for a sustained antinatriuretic effect of insulin outside of rodents, and all previous studies in dogs have been negative. This study used a novel approach to test for a chronic sodium-retaining action of insulin in dogs, by testing the hypothesis that natriuresis in type I diabetes is dependent on the decrease in insulin, rather than being due solely to osmotic actions of hyperglycemia. Dogs were chronically instrumented and housed in metabolic cages. Fasting blood glucose in alloxan-treated dogs was maintained at ∼65 mg/dl by continuous intravenous insulin infusion. Then, a 6-day diabetic period was induced by either 1) decreasing the insulin infusion to induce type I diabetes (D; blood glucose = 449 ± 40 mg/dl) or 2) clamping the insulin infusion and infusing glucose continuously (DG; blood glucose = 470 ± 56 mg/dl). Control urinary sodium excretion (UnaV) averaged 70 ± 5 (D) and 69 ± 5 (DG) meq/day and increased on day 1 in both groups. UnaV remained elevated in the D group (115 ± 15 meq/day days 2– 6), but it returned to control in the DG group (69 ± 11 meq/day days 2– 6) and was accompanied by decreased lithium clearance. Thus, insulin had a sustained antinatriuretic action that was triggered by increased glucose, and it was powerful enough to completely block the natriuresis caused by hyperglycemia. These data may reveal an unrecognized physiologic function of insulin as a protector against hyperglycemia-induced salt wasting in diabetes.

We have previously shown that systemic treatment with the somatostatin analog octreotide has marked beneficial effects on renal function in rats with liver cirrhosis induced by common bile duct ligation (CBL; Jonassen TEN, Christensen S, Sørensen AM, Marcussen N, Flyvbjerg A, Andreasen F, and Petersen JS. Hepatology 29: 1387–1395, 1999). In the present study, we tested the hypothesis that octreotide has a direct effect on renal tubular function. Rats (CBL or Sham-CBL) were intrarenally treated with low-dose octreotide in a long-acting release formulation, which had no systemic actions (100 μg/kg body wt as a single dose). Rats receiving low-dose octreotide (sc) were used as controls. The rats were chronically instrumented, and renal function was examined 4 wk after CBL or Sham-CBL. Intrarenal octreotide administration (IROA) prevented sodium retention in CBL rats without changes in renal plasma flow, glomerular filtration rate, or circulating levels of aldosterone and vasopressin. Renal clearance studies revealed that IROA normalized the increased natriuretic efficacy of furosemide found in CBL rats. Furthermore, IROA protected against the development of hypertrophy of the inner stripe of the outer medulla and thereby the increased the volume of thick ascending limb of Henle's loop (TAL) epithelium found in CBL rats. Finally, Western blot analyses of outer medullary homogenates showed increased abundance of the furosemide-sensitive Na-K-2Cl (NKCC2) cotransporter. IROA did not affect the abundance of NCKK2 within the outer medulla. Together with the histological findings, these results indicate that IROA reduces the total number of NKCC2 within the outer medulla. In conclusion, the results indicate a direct intrarenal effect of octreotide on TAL function and morphology in cirrhotic rats.

Alterations in total body sodium (TBSodium) that covered the range from moderate deficit to large surplus were induced by 10 experimental protocols in 66 dogs to study whether large amounts of Na+are stored in an osmotically inactive form during Na+retention. Changes in TBSodium, total body potassium (TBPotassium), and total body water (TBWater) were determined by 4-day balance studies. A rather close correlation was found between individual changes in TBSodium and those in TBWater ( r2= 0.83). Changes in TBSodium were often accompanied by changes in TBPotassium. Taking changes of both TBSodium and TBPotassium into account, the correlation with TBWater changes became very close ( r2= 0.93). The sum of changes in TBSodium and TBPotassium was accompanied by osmotically adequate TBWater changes, and plasma osmolality remained unchanged. Calculations reveal that even moderate TBSodium changes often included substantial Na+/K+exchanges between extracellular and cellular space. The results support the theory that osmocontrol effectively adjusts TBWater to the body's present content of the major cations, Na+and K+, and do not support the notion that, during Na+retention, large portions of Na+are stored in an osmotically inactive form. Furthermore, the finding that TBSodium changes are often accompanied by TBPotassium changes and also include Na+/K+redistributions between fluid compartments suggests that cells may serve as readily available Na+store. This Na+storage, however, is osmotically active, since osmotical equilibration is achieved by opposite redistribution of K+.

Schmidt, W., A. Bub, M. Meyer, T. Weiss, D. Schneider, N. Maassen, and W. G. Forssmann. Is urodilatin the missing link in exercise-dependent renal sodium retention? J. Appl. Physiol. 84(1): 123–128, 1998.—The purpose of the present study was to investigate the behavior of plasma atrial natriuretic peptide [ANP-(99—126)] concentration ([ANP]) and renal urodilatin [Uro; ANP-(95—126)] excretion during and after exercise and their possible effects on renal Na+retention. Ten male subjects performed a cycle ergometer test for 60 min at 60% of maximum workload. Blood and urine samples were collected before, during, and up to 24 h after exercise. During exercise, plasma [ANP] and renal Uro excretion were oppositely affected: whereas [ANP] increased from 46.5 ± 5.1 to 124.1 ± 10.6 pg/ml, urinary Uro excretion decreased from 120.8 ± 16.0 to 49.5 ± 9.8 fmol/min and remained at a lower level until 1 h after exercise. Glomerular filtration rate showed lowest values during exercise (from 164.9 ± 15.3 to 75.8 ± 10.1 ml/min), and urine flow and the fractional excretion rate of Na+([Formula: see text]) and Cl−([Formula: see text]) had their nadir during the first hour after exercise. Positive relationships were observed between Uro excretion and[Formula: see text]( P < 0.05) and[Formula: see text], whereas a tendency toward a negative correlation was obtained between [ANP] and[Formula: see text]. It seems possible that Uro may be, among other factors, involved in the exercise-related regulation of renal Na+retention. The specific roles Uro and ANP play during exercise, however, remain to be investigated.

Once viewed as physiologically insignificant by no less an authority than Homer Smith, the renal nerves have emerged as a physiologically important regulator of renal tubular sodium reabsorption. Increased renal sympathetic nerve activity contributes significantly to the renal sodium retention in edema-forming states.

To define the role of renal nerves in renal Na retention of cirrhosis and congestive heart failure (CHF), experiments were done in rats with cirrhosis due to common bile duct ligation (CBDL) and CHF due to myocardial infarction from left coronary artery ligation. Two weeks after induction of CBDL or CHF, diseased and sham diseased (Sham) rats were subjected to bilateral renal denervation (DNX) or sham renal denervation (innervated, INN). Five days after DNX or INN, 26-day metabolic balance studies were carried out in all rats. Daily dietary Na intake averaged 2.0-3.0 meq/day on days 1-6 and 22-26 and averaged 0.120 meq/day on days 7-21. Cumulative Na balance was greater in CBDL and CHF rats, INN or DNX, than in Sham/CBDL or CHF rats throughout the study. On day 6 at the end of the normal dietary Na intake period (days 0-6), cumulative Na balance was not affected by renal denervation in Sham/CBDL or CHF rats (INN, 2.02 +/- 0.19 meq, n = 10; DNX, 2.04 +/- 0.17 meq, n = 11), CBDL rats (INN, 4.21 +/- 0.39 meq, n = 10; DNX, 3.78 +/- 0.37 meq, n = 10), or CHF rats (INN, 3.74 +/- 0.72 meq, n = 9; DNX, 3.22 +/- 0.55 meq, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

The following is the abstract of the article discussed in the subsequent letter: Seeliger, Erdmann, Mechthild Ladwig, and H. Wolfgang Reinhardt. Are large amounts of sodium stored in an osmotically inactive form during sodium retention? Balance studies in freely moving dogs. Am J Physiol Regul

Previous research suggests that hamsters 1) fail to retain sodium after mineralocorticoid injections, 2) retain sodium after adrenalectomy equal to controls, and 3) do not develop salt appetite after mineralocorticoid or adrenalectomy. The present studies demonstrate sodium retention, body weight gain, hypernatremia, plasma volume expansion, and reduced fecal sodium excretion after daily injections of deoxycorticosterone acetate (DOCA). Salt appetite appeared after the 3rd and 4th days. Adrenalectomy caused reductions of sodium balance, plasma volume, and food intake, which were reversed by DOCA administration. Mineralocorticoids therefore represent one control of sodium metabolism in hamsters.

Normal Long-Evans rats (LE) exhibited diurnal variations of plasma arginine vasopressin (AVP) concentrations with peak values at 10 A.M. and minimum values at 1 P.M. Brattleboro rats heterozygous for hypothalamic diabetes insipidus (DI) had significantly reduced plasma AVP concentrations and increased plasma osmolalities when compared with LE rats. By prolonged injection of 100 mU/day of vasopressin tannate (VPT) into Brattleboro rats homozygous for DI, plasma AVP concentrations close to those of LE rats were achieved. Potassium was retained for 7 days until escape of vasopressin-induced potassium retention occurred. When 500 mU VPT were injected into DI rats, high plasma AVP levels were induced. Potassium was retained for 2-3 days. After initial sodium retention, periods of natriuresis occurred. During treatment with 100 mU VPT/day most of the alterations present in DI rats were corrected, which included increased water turnover and external water loss, increased hematocrit and plasma sodium concentrations (but not increased plasma osmolalities), hypokalemia, increased activity of the renin-angiotensin system, and reduced adrenocortical function.

Experimental cirrhosis was produced in dogs by the sporadic feeding of dimethylnitrosamine for the purpose of studying the temporal relationships between urinary sodium retention, plasma volume expansion, and ascites formation. Sodium retention started about 16 days following the onset of cirrhosis and preceded ascites formation by about 10 days. Plasma volume increased by 9% (P less than 0.05) within 3–4 days of sodium retention and expanded further as ascites accumulated. Splanchnic plasma volume was greater by 161 ml in 10 cirrhotic dogs with ascites than in 14 normal dogs. Nonsplanchnic volume was greater by 96 ml (P less than 0.05). Thus, the “effective” as well as the splanchnic component of the vascular space was expanded. Paracentesis did not cause the re-formation of ascites in five dogs as long as dietary salt was denied. Refeeding permitted reaccumulation of ascites and further plasma volume expansion. Renal perfusion remained constant as dogs became progressively cirrhotic. We conclude that ascites formation depends on the prior retention of urinary sodium, and occurs as an “overflow” phenomenon. A contracted effective plasma volume does not appear to be necessary for continuing sodium retention.

The purpose of this study was to test whether the absence or inhibition of aldosterone would alter the Na retention of pregnancy in the rat. We performed metabolic balance studies during the last 2 wk of the 3-wk rat pregnancy in the following four groups of saline-drinking rats: nonpregnant, sham adrenalectomized; pregnant, sham adrenalectomized; nonpregnant, adrenalectomized; and pregnant, adrenalectomized. Significant net Na retention was not found during the 2nd wk in any of the groups. During the final week, however, both pregnant groups retained between 8 and 11 meq Na more than their respective control groups. In addition, we measured plasma aldosterone concentration in these rats at term. The mineralocorticoid was not detectable in the nonpregnant adrenalectomized rats but was present in the pregnant adrenalectomized rats at a concentration of about 50% of that found in the pregnant sham-adrenalectomized rats. Serial measurements revealed that aldosterone was measurable by day 18 and nondetectable by 2 days postpartum in these pregnant adrenalectomized rats. Comparable balance studies were also performed in three groups of water-drinking rats: nonpregnant, pregnant, and pregnant rats that received large daily doses of spironolactone. During the 3rd wk both pregnant groups were in significant positive Na balance. Net Na retention for untreated pregnant rats was 8.4 meq and for the spironolactone treated, 6.9 meq, values that were not significantly different. We conclude that is is unlikely that aldosterone plays a critical role in the Na retention found during rat pregnancy.

An attempt was made to ascertain the circumstances under which unilateral nephrectomy maximally sensitized rats to hypertensive cardiovascular disease induced by desoxycorticosterone acetate in the presence of augmented NACl intake. The experiments showed that animals in which hormone treatment was delayed until 2 weeks after uninephrectomy were much more sensitive than animals in which hormone treatment was begun on the day of kidney removal. This was indicated by earlier onset and greater severity of hypertension; by a larger percentage of animals in such groups being affected, and by a greater incidence and severity of cardiovascular lesions in the former as compared with the latter. The much greater kidney size of the former clearly makes it difficult to ascribe the greater sensitivity to a reduction in renal mass as such. It is thought that during active compensatory renal hypertrophy the renal tubules are probably less responsive to the action of the hormone and therefore less prone to develop sodium retention and hence hypertension.