Diuretic action of calcitonin: demonstration of an inhibiting effect on sodium reabsorption in the ascending limb of Henlé's loop]

It was found that calcitonin (porcine) at the dose: 4 I.U. MRC./kg/hr (i.v.), in the rabbit, increased the diuresis and oxmolal excretion, and simultaneously decreased free-water reabsorption and urinary osmolality. The results suggest that calcitonin acts by inhibiting sodium reabsorption in the ascending limb of Henl's loop. This hypothesis was confirmed by renal autoradiography study with 22Na.     

Studies on Compensatory Adaptation of Renal Functions

Changes in the excretion of water and electrolyte in one kidney after exclusion of its partner have been studied in anesthetized dogs and rabbits. Complete clamping of the contralateral kidney pedicle or ureter results in a rapid increase in the excretion of water, sodium, potassium, chloride, calcium, phosphate and bicarbonate. This response is also observed in denervated kidneys. Pretreatment with the loop inhibitor, furosemide, does not preclude adaptation which, however, is blunted by acetazolamide, an inhibitor of proximal sodium and bicarbonate reabsorption. Free-water reabsorption during hypertonic saline diuresis is normal in the remaining kidney. Compensatory adaptation, thus, appears to be located in the proximal tubule. The regulatory response to contralateral kidney exclusion is already fully developed in one-month-old rabbits. Compensatory adaptation of electrolyte excretion is not accounted for by changes in extracellular fluid volume, plasma composition, glomerular filtration rate, effective renal plasma flow, aldosterone or vasopressin.     

刺激脑内渗透压感受器对大鼠肾小管重吸收钠,氯,钾的影响

实验在麻醉大鼠上进行。用肾小管微穿刺技术观察到,脑室内注射高张盐水(icv.HS)后:(1)近曲小管末段钠残留分数从53.0±2.1％升高至66.0±2.9％(P<0.01);氯残留分数从65.4±3.4％升高至78.2±3.9％(P<0.05);钾残留分数和小管液渗透克分子浓度无显著变化。(2)远曲小管起始段钠残留分数从8.2±0.9％升高至13.6±1.8％(P<0.05);氯残留分数从5.4±0.8％升高至9.5±1.4％(P<0.05);小管液渗透克分子浓度从139.8±6.9mOsm/kg H_2O升高至181.3±15.6mOsm/kgH_2O(P<0.05);钾残留分数无显著变化。静脉注射速尿能消除icv.HS引起的尿钾增多反应,但不能消除icv.HS引起的利尿和尿钠增多反应。上述结果表明,刺激脑内渗透压感受器能抑制近曲小管中钠和氯的重吸收,并促进远曲小管及其以后部位的钠钾交换,导致尿钠排出增多和尿钾排出增多。     

Fluoride reabsorption by nonionic diffusion in the distal nephron of the dog

This study was done to test the hypothesis that fluoride reabsorption is extensive from the distal nephron, the major site for tubular fluid acidification, and to compare the distal nephron handling of fluoride and chloride. Ten stop-flow studies were done in five dogs anesthetized with pentobarbital. Urinary alkalinization was achieved by the intravenous infusion of sodium bicarbonate and acetazolamide or lithium chloride. Acidification was achieved by the infusion of sodium nitrate or sodium sulfate. The results indicate that the extent of fluoride reabsorption from the distal nephron is inversely correlated with urinary pH (P less than 0.001). When the urine was strongly acidified by the infusion of sodium sulfate, urine to plasma fluoride concentration ratios were less than 1.0, a finding not previously reported from studies of the renal handling of fluoride. The reabsorption of fluoride from the distal nephron was not correlated consistently with that of chloride. The results indicate that the distal nephron is an important site for the reabsorption of fluoride and they provide additional evidence that HF is the permeating moiety.     

A search for a defect of proximal transport in denervated kidneys of conscious dogs

The influence of renal nerves on proximal Na+ reabsorption was studied in clearance experiments with unilaterally renal-denervated conscious dogs prepared by surgical bladder division. Two types of experiments were made : A. maximal water diuresis, and B. Total blockade of distal NaCl reabsorption with ethacrynic acid and chlorothiazide. In maximal water diuresis CH2O + CNa was used as a measure of fluid delivery to the distal nephron. At similar GFR on both sides, the proximal reabsorption estimated as GFR--(CH2O + CNa) was 38.4 +/- 5.6 ml/min for the intact and 35.9 +/- 4.2 ml/min for the denervated kidney (n = 6, difference NS). After distal tubular blockade, proximal Na+ reabsorption calculated as filtered load minus urinary excretion was 3.84 +/- 0.43 mmol/min for the intact and 3.91 +/- 0.36 mmol/min for the denervated kidney (n = 6, difference NS). The fractional reabsorption of NA+ was 64.9 +/- 1.0% for the intact and 66.9 +/- 1.1% for the denervated kidney (difference NS). In contrast to data from renal denervation studies with anaesthetized animals, the present experiments did not show any difference in proximal reabsorption between the innervated- and denervated kidney. We conclude that in absence of anaesthesia renal efferent nerves have no major effect on NaCl transport in dog proximal tubule.     

Role of V1- and V2-receptors in mechanism of physiological paradox--an increase of reabsorption of the solute free water and simultaneous rise of diuresis

In experiments on non-anesthetized rats with administration into stomach of water (5 ml/100 g body mass) direct correlation has been found between an increase of diuresis and excretion of solute free water (r = 0.98, p < 0.01), while after injection to these animals of 5 x 10(-11) M arginine-vasotocin - between an increase of diuresis and simultaneous rise reabsorption of solute free water (r = 0.8, p < 0.01). The rise of diuresis after the vasotocin injection is due to inhibition of sodium re- absorption, with the solute excretion fraction increasing from 2.6 +/- 0.2 % to 11.9 +/- 1.2, p < 0.001. A similar physiological paradox - an increase of diuresis with the simultaneous increase of reabsorption of solute free water - has been revealed at night hours in children with tendency for nocturnal enuresis (r = 0.64, p < 0.01). Mechanism responsible for this phenomenon consists in a rise of diuresis due to a decrease of sodium ion reabsorption in the ascending Henle loop limb. A problem is discussed of the homeostatic significance of a decrease of sodium reabsorption combined with an increase of solute-free water reabsorption; it is suggested that this phenomenon is based on a redistribution of reabsorption inside the nephron - a decrease of ion and water reabsorption in the initial parts of the nephron distal segment and an increase of solute free water reabsorption with the antidiuretic hormone-stimulated high osmotic permeability of terminal parts of renal tubules. An intraperitoneal injection of V1-anatagonist (OPC-21268) decreased the natriuretic component of response to arginine-vasotocin, while injection of V2-antagonist (OPC-31260) eliminated the antidiuretic component.     

Effects of atrial natriuretic peptides and furosemide in conscious dogs

Effects of ANF(8-33) and Auriculin A on renal variables were investigated in conscious water-diuretic dogs. The two substances were injected intravenously (1.08 micrograms/kg in 3 min) or ANF(8-33) was infused (0.2 microgram/kg X min in 20 min). The effects were compared to those of an equinatriuretic dose of furosemide (1.0 microgram/kg X min). Injections caused increases in sodium excretion, diuresis, and osmolar clearance. No significant change in exogenous creatine clearance (CCREA) occurred. Infusion of ANF(8-33) decreased blood pressure by 14% (P less than 0.01) and increased sodium excretion by a factor of 10 (P less than 0.01). The natriuresis was a function of increases in diuresis and urinary sodium concentration, the latter by a factor of 6 (P less than 0.01). Diuresis and free-water clearance (CH2O) increased by 60% (P less than 0.01), but urine osmolality did not change significantly. After the infusion a significant decrease in PAH clearance (CPAH) (P less than 0.01) was observed. Filtration fraction (FF) did not change. The furosemide natriuresis appeared later than that of ANF without significant deviations in diuresis, CH2O, CCREA, CPAH, and FF; urine osmolality increased by 35% (P less than 0.01). The effects of ANF(8-33) differ from those of furosemide in several ways. First, the onset of natriuresis is faster, second, the natriuresis is associated by marked increases in diuresis and free-water clearance but not in urine osmolality; and third, natriuresis is followed by a reduction in renal blood flow. The rapid natriuresis of ANF can occur without changes in glomerular filtration rate.     

Acute effect of salmon calcitonin on renal magnesium transport in the magnesium-loaded rat

The present studies were undertaken to examine whether salmon calcitonin, by increasing magnesium reabsorption in the thick ascending limb, and presumably the tubulointerstitial magnesium concentration gradient, would lead to an increase in fractional magnesium delivery to the end-descending limb (magnesium secretion) in magnesium-loaded rats. Thyroparathyroidectomized, postprandial Munich--Wistar rats were prepared for micropuncture of papillary end-descending limbs and of superficial end-accessible proximal tubules. Group 1 served as clonidine-water diuresis time controls; group 2 was treated as group 1 but also received synthetic salmon calcitonin (10 mU/min); and group 3 was treated as group 2 but also received calcium chloride intravenously. Calcitonin, alone or with calcium, produced a significant fall in fractional magnesium excretion. A significant relationship was also observed between fractional magnesium excretion and urine flow rate (r = 0.56, p less than 0.01). Calcitonin did not modify fractional magnesium delivery to the end-descending limb. A highly significant relationship was observed between tubule fluid-to-ultrafiltrate magnesium ratio and tubule fluid-to-plasma inulin ratio (r = 0.88, p less than 0.001). Within each group, fractional magnesium delivery to the end-descending limb was similar to the corresponding value in the superficial end-accessible proximal tubule. Our results suggest that despite intense magnesium reabsorption, presumably in the thick ascending limb, magnesium secretion does not occur in the juxtamedullary pars recta and (or) thin descending limb.     

Contribution of angiotensin to the control of medullary hemodynamics

The unique architecture and organization of medullary vasculature permit regional regulation of medullary hemodynamics by vasoactive hormones and are conducive to the operation of the countercurrent multiplication system. Recent studies suggest that an increase in inner medullary blood flow causes medullary solute washout, which in turn decreases passive sodium transport in the thin ascending limb of Henle's loop. In canine models of chronic sodium retention accompanied by activation of the renin-angiotensin system, glomerular filtration rate (GFR), renal blood flow (RBF), and intracortical blood flow distribution were similar to those in normal dogs; however, papillary plasma flow (PPF) was markedly reduced and papillary tissue solute content was increased significantly both during hydropenia and after saline loading. During euvolemic diuresis with loop diuretics, there was an increased renin release associated with a marked reduction in PPF, despite an increase in total RBF. Direct intrarenal infusion of angiotensin II (AngII) (at a dose not affecting GFR and RBF) induced ipsilateral sodium retention, conservation of urinary concentration, and papillary ischemia. These studies provide evidence for regional regulation of medullary hemodynamics by AngII, possibly contributing to sodium retention in chronic salt-retaining states.     

Effects of atrial natriuretic factor on renal handling of water and electrolytes in rats

The intravenous injection of an extract of atrial myocardium into anesthetized rats during a hypotonic diuresis resulted in an increase in the renal excretion of water, sodium, potassium, calcium, magnesium, and phosphate. There was an increase in urine concentration which was probably a result of the secretion of vasopressin since it did not occur in Brattleboro (di/di) rats. A transient increase in glomerular filtration rate and renal plasma flow occurred during the first five minutes with a more sustained rise in filtration fraction. Injection of atrial extract also caused a partial inhibition of solute-free water formation in Brattleboro rats subjected to water diuresis and a partial inhibition of solute-free water reabsorption in rats subjected to maximal antidiuresis by infusing vasopressin. In neither case was the degree of inhibition as profound as that observed after injecting furosemide in a dose which caused a comparable natriuretic response. A large dose of furosemide blocked the natriuretic response to atrial extracts whereas, when a comparable level of sodium and water output was produced by massive infusions of saline, the natriuretic response to atrial extract was increased. It is suggested that atrial natriuretic factor might inhibit sodium transport in nephron segments beyond the medullary thick ascending limb. Furosemide might also act at the same tubular site or inhibit tubular secretion of the atrial natriuretic factor.     

Osmoregulating reactions following serotonin metabolism inhibition or activation

Effect of p-chlorphenilalanine and 5-hydroxytriptophan on the urine flow (V), glomerular filtration rate (GFR), free water reabsorption (TCH2O), and sodium fraction excretion (ENa.F%) in Wistar rats loaded with water or 2% sodium chloride solution, was studied. It was found that treatment of rats with inhibitor of serotonin biosynthesis, p-chlorphenilalanine (300 mg/kg, 48 hrs before the experiment) had no effect on the kidney response to the water loading in the experimental rats as compared to the control ones: changes in V, GFR, TCH2O and ENa.F% were the same. Treatment of rats with precursor of serotonin, 5-hydroxytriptophan which is known to increase the serotonin level in the brain (50 mg/kg) simultaneously with the water loading prevented the development of the diuretic reaction because of the high level of TCH2O reflected in the blood vasopressin concentration. Injection of 5-hydroxytriptophan at the maximum level of water diuresis resulted in the sharp increase in TCH2O and drop of the V. 5-hydroxytriptophan had no significant effect on the kidney response to the loading with the 2% sodium chloride solution. Under these conditions, increase in V was produced by suppression of the distal tubular sodium reabsorption, the TCH2O remaining at the high level. It is suggested that the brain serotonin manifested a significant stimulating effect on the vasopressin release from the neurohypophysis, but it is not involved in the mechanisms of suppression of its release into the blood. Serotonin seems not to interact with brain mechanisms regulating natriuretic function of the kidney.     

Renal blood flow, early distal sodium, and plasma renin concentrations during osmotic diuresis

Inconsistencies in previous reports regarding changes in early distal NaCl concentration (ED(NaCl)) and renin secretion during osmotic diuresis motivated our reinvestigation. After intravenous infusion of 10% mannitol, ED(NaCl) fell from 42.6 to 34.2 mM. Proximal tubular pressure increased by 12.6 mmHg. Urine flow increased 10-fold, and sodium excretion increased by 177%. Plasma renin concentration (PRC) increased by 58%. Renal blood flow and glomerular filtration rate decreased, however end-proximal flow remained unchanged. After a similar volume of hypotonic glucose (152 mM), ED(NaCl) increased by 3.6 mM, (P < 0.01) without changes in renal hemodynamics, urine flow, sodium excretion rate, or PRC. Infusion of 300 micromol NaCl in a smaller volume caused ED(NaCl) to increase by 6.4 mM without significant changes in PRC. Urine flow and sodium excretion increased significantly. There was a significant inverse relationship between superficial nephron ED(NaCl) and PRC. We conclude that ED(Na) decreases during osmotic diuresis, suggesting that the increase in PRC was mediated by the macula densa. The results suggest that the natriuresis during osmotic diuresis is a result of impaired sodium reabsorption in distal tubules and collecting ducts.     

Urinary-blood delta PCO2 in renal tubular acidosis (author's transl)

A state of renal tubular acidosis has been produced in rats by the administration of sodium maleate or acetazolamide (proximal tubular acidosis) and of lithium chloride of amiloride (distal tubular acidosis). During progressive alkaline diuresis, delta PCO2 (urine minus blood PCO2) increases significantly in rats presenting proximal tubular acidosis. Delta PCO2 is significantly depressed in rats presenting distal tubular acidosis. In well defined conditions of bicarbonate or phosphate excretion, delta PCO2 is a valuable index of distal ion secretion.     

Further research on the role of prostanoids in controlling renal function in humans in normal potassium balance and acute experimental potassium depletion. I: Studies of normal potassium balance. Effects of indomethacin

The renal function was studied by clearance (cl.) method during hypotonic polyuria (oral water load followed by 5% dextrose solution infusion) and successive relative antidiuresis induced by lysine-8-vasopressin (LVP) administration (5 microU in bolo followed by continuous infusion at a rate of 0.04 microU/min). Four 15 min and two 60 min clearance (cl.) periods were performed during hypotonic polyuria and antidiuresis, respectively. Glomerular filtration rate was estimated by creatinine cl.; the osmotic cl. (Cosm, CH2O), the absolute and fractional excretions of water, sodium, potassium and chloride were determined by usual methods. The urinary PGE2, 6-keto-PGF1 alpha and TxB2 concentrations were determined by RIA method. Fourteen healthy women submitted to a normal sodium and potassium daily intake were studied; in 6 of them paired studies in absence and in presence of indomethacin (100 mg, i.m.), respectively, were performed. LVP induced a significant reduction of creatinine cl., urinary flow rate and of prostanoid excretion. In hypotonic polyuria, indomethacin significantly reduced the creatinine cl. and the diuretic response to the water load; moreover the urinary PGE2 and 6-keto-PGF1 alpha excretions were significantly lower (85.6 +/- 1.9% and 37.7 +/- 3.2%) while the reduction of urinary TxB2 excretion was not significant (34.4 +/- 13%). Indomethacin did not affect significantly the LVP renal effects in normal potassium balance.     

Role of prostanoids in the control of renal function in normal potassium balance and in acute experimental potassium depletion. 4. Relation of extrarenal parameters, renal function parameters and urinary excretion of prostanoids

The renal function has been evaluated by clearance (cl.) method during hypotonic polyuria and successive moderate antidiuresis induced by a low dose of lysine-8-vasopressin; four 15 min and two 60 min cl. periods were performed, respectively. Glomerular filtration rate was estimated by creatinine cl.; the osmotic cl. (Cosm, CH2O), the absolute and fractional excretions of water, sodium, potassium and chloride were determined by usual methods. The urinary concentrations of PGE2, 6-keto-PGF1 alpha (6KPGF) and TxB2 were measured by RIA. The study protocol was applied in normal potassium balance and experimental potassium balance (KD), both in absence and presence of indomethacin. In KD groups with a potassium cumulative deficit of 198.4 +/- 22.2 meq (D3; n = 6) during polyuria significant correlations are consistent with the hypothesis that the lower the plasma potassium concentration is the higher the urinary chloride excretion and the inhibition of distal fractional chloride reabsorption. Moreover, by utilizing the polyuria and antidiuresis data pool, the effects of urine flow rate changes on PGE2 and 6KPGF urinary excretions are blunted as compared to normal potassium balance (n = 14). After indomethacin treatment (D3.I) the following functional relationships are disclosed: a) the lower the kaliemia is the lower the urinary chloride and potassium excretions and the higher the fractional isosmotic reabsorption; b) the lower the urinary potassium excretion is the lower the urinary chloride excretion. In both D3 and D3.I experimental groups the positive correlation between urinary chloride excretion and urinary potassium excretion is significant.     

Sulpiride (stereoisomers, racemic) and dopamine: actions and interactions on renal excretion of hydro-saline

Renal effects of Dopamine (DA, subpressor dosage 0.1 microgram X kg -1 X min -1) during hypotonic polyuria in moderate hydro-saline retention are variously modified by either d- or l-Sulpiride isomers. In the presence of d-Sulpiride, DA effects, such as an increase in diuresis, free water clearance (CH20) and kaliuresis are suppressed, while increases of saluresis and natriuresis are significantly blunted. In the presence of l-Sulpiride no changes are observed in both saluresis and natriuresis, while decreases occur in diuresis, CH20 and kaliuresis. The inhibitory DA effects on isosmotic sodium reabsorption as a percentage of sodium filtered load are prevented by either isomer as well. A possible role of ineffective renal vascular DA action can be involved in such defective tubular inhibition. However is also suggested a pharmacological blockade of proximal tubular specific DA receptors.     

Effect of severe normocapnic hypoxia on renal function in growth-restricted newborn piglets

To examine the effects of intrauterine growth restriction and acute severe oxygen deprivation on renal blood flow (RBF), renovascular resistance (RVR), and renal excretory functions in newborns, studies were conducted on 1-day-old anesthetized piglets divided into groups of normal weight (NW, n = 14) and intrauterine growth-restricted (IUGR, n = 14) animals. Physiological parameters, RBF, RVR, and urinary flow, were similar in NW and IUGR piglets, but glomerular filtration rate (GFR) and filtration fraction were significantly less in IUGR animals (P < 0.05). An induced 1-h severe hypoxia (arterial PO(2) = 19 +/- 4 mmHg) resulted in, for both groups, a pronounced metabolic acidosis, strongly reduced RBF, and increased fractional sodium excretion (FSE; P < 0.05) with a less-pronounced increase of RVR and arterial catecolamines in IUGR piglets. Of significance was a smaller decrease in RBF for IUGR piglets (P < 0.05). Early recovery showed a transient period of diuresis with increased osmotic clearance and elevated FSE in both groups (P < 0.05). However, GFR and renal O(2) delivery remained reduced in NW piglets (P < 0.05). We conclude that, in newborn IUGR piglets, RBF is maintained, although GFR is compromised. Severe hypoxemia induces similar alterations of renal excretion in newborn piglets. However, the less-pronounced RBF reduction during hypoxemia indicates an improved adaptation of newborn IUGR piglets on periods of severely disturbed oxygenation. Furthermore, newborn piglets reestablish the ability for urine concentration and adequate sodium reabsorption early after reoxygenation so that a sustained acute renal failure was prevented.     

Cell volume regulation in renal cortical cells

Both proximal renal tubule cells and cultured Madin-Darby canine kidney (MDCK) cells are capable of regulating their volume in hypotonic media. Regulatory cell volume decrease in proximal straight tubules is impaired by barium, amiloride and acetazolamide and depends on the presence of bicarbonate and of sodium, whereas it is unaffected by complete removal of extracellular chloride. The observations may point to parallel loss of potassium through potassium channels as well as of bicarbonate and sodium via a bicarbonate-sodium cotransport. Alternatively, potassium/hydrogen ion exchange or potassium bicarbonate cotransport could be involved. In MDCK cells, exposure to hypotonic media apparently leads to the activation of an anion channel, while potassium conductance is rather decreased. In both proximal tubules and MDCK cells, volume regulatory decrease is possibly triggered by leucotrienes, which may be released during cell swelling. Cell volume is altered in a variety of conditions even at isotonic extracellular fluid and cell volume-regulatory mechanisms are likely to participate in regulation of renal transepithelial transport.     

脑室内注射高张盐水抑制近曲小管对水和钠的重吸收

实验在麻醉大鼠上进行。用锂清除率为指标观察脑室内注射高张盐水对近曲小管重吸收水和钠的影响。在切断单侧肾神经的动物中,脑室内注射高张盐水后的锂清除率与肾小球滤过率比值在去神经侧肾脏从0.37±0.04增加至0.51±0.05(P<0.01);神经完好侧肾脏则从0.26±0.03增加至0.31±0.04(P<0.05);双侧肾脏的肾小球滤过率、尿量、尿钠和尿钾量均增加,且去肾神经肾脏的增加幅度高于肾神经完好肾脏。在肾小管微穿刺实验中,脑室内注射高张盐水后,近曲小管末段小管液流量从24.42±1.84nl/min增加至31.86±3.09nl/min(P<0.01),小管液的渗透压无显著变化。以上实验结果表明,脑室内注射高张盐水引起的利尿、尿钠增多反应与肾小球滤过率增加和近曲小管对水、钠重吸收减少有关,体液因素在该反应中可能起主要作用。