Stimulation of tubular reabsorption of magnesium and calcium by antidiuretic hormone in conscious rats

The effect of antidiuretic hormone on urinary electrolyte excretion was investigated by clearance techniques in conscious rats in metabolic cages. Brattleboro rats with hereditary diabetes insipidus (DI) (no ADH) were studied in the absence of exogenous ADH (control group = C,n=4), and after several weeks of continuous dDAVP infusion (period A) followed by discontinuation of dDAVP (period B) (experimental group = E,n=6). dDAVP, a non-pressor antidiuretic analogue to ADH, induced 1) a high urine concentration (2,645±44 (SEM) in group E vs 131±6 mosmol/kg H₂O in group C),P<0.001; 2) no significant change in plasma osmolality (288±2 vs 297±7 mosmol/kg H₂O respectively) and in plasma concentration of major electrolytes, Na, K, Cl, Mg, and Ca; 3) a large decrease in urinary excretion of calcium and magnesium and no change in other electrolyte or total osmolar excretion. Fractional excretions in rats of groups C and E during period A were, respectively, for Na: 0.59±0.03 (SEM) and 0.51±0.33% (NS), for Ca: 2.92±0.62 and 0.34±0.05% (P<0.001) and for Mg: 7.75±0.83 and 1.38±0.28% (P<0.001). After treatment discontinuation, plasma osmolality in group E rose to 304±2 mosmol/kg H₂O (P<0.01 compared to period A) with slight increases in plasma Na and Cl concentrations. Urine osmolality fell below, and urine flow rate rose above values observed in the control group. Fractional excretion of Ca and Mg rose to values seen in DI rats (3.30±0.37%, NS, for Ca) or above (26.95±0.65%,P<0.001, for Mg), with no change in other solute fractional excretion. Other works, from our and other's groups have shown that 1) long-term exposure to dDAVP induces a marked hypertrophy of the epithelium of the thick ascending limb of Henle's loop in its medullary part (MTAL) and 2) dDAVP induces an increase in Ca and Mg tubular reabsorption between end proximal and early distal sites of micropuncture. Taken together, these results suggest that the effects of ADH on divalent cation fractional excretion, seen in the present study, probably results from an increased Ca and Mg voltage-dependent reabsorption in the MTAL. This reabsorption is linked to the increased salt transport induced in this segment, both by a direct effect of ADH and by an indirect effect resulting from the increased solute delivery to the MTAL in the concentrating kidney.     

Effect of somatostatin on kidney function and vasoactive hormone systems in healthy subjects

Summary The acute effects of i.v. somatostatin (250 mcg bolus followed by 250 mcg/h continuous infusion for two hours) on renal hemodynamics, renal electrolyte and water handling, and urinary excretion of catecholamines and prostaglandins, as well as on plasma concentrations of arginine vasopressin, atrial natriuretic factor, norepinephrine, epinephrine, dopamine, glucagon, and plasma renin activity were studied in seven normal subjects. Somatostatin decreased effective renal plasma flow and glomerular filtration rate, osmotic and free water clearances, urine volume, and sodium and potassium excretion, while urinary osmolality, fractional excretion of sodium, and phosphate excretion increased significantly. Plasma concentrations of arginine vasopressin, atrial natriuretic factor, norepinephrine, epinephrine, and dopamine remained unchanged, while plasma renin activity (3.0±0.25 vs 2.4±0.2 ng AngI/ml/h;p}<0.01) and glucagon levels (40±11 vs 20±16 pg/ml;p}<0.01) decreased. Urinary excretion of norepinephrine, epinephrine, dopamine, PGE₂, and PGF_2alpha was suppressed under somatostatin. A significant positive correlation was found between urinary dopamine and sodium excretion (r=0.7;p}<0.001) and urinary postaglandin E₂ and glomerular filtration (r=0.52;p}<0.01). Without accompanying changes in plasma osmolality and vasopressin concentration significant antidiuresis occurred, suggesting a direct tubular effect of somatostatin. However, the hormone-induced changes are due mainly to the decrease in renal plasma flow. The results demonstrate that somatostatin at supraphysiological doses exerts significant effects on the kidney.Abbreviations PAH paraaminohippuric acid - ANF atrial natriuretic factor - AVP arginine vasopressin - PRA plasma renin activity - ERPF effective renal plasma flow - GFR glomerular filtration rate - TRP tubular reabsorption of phosphate - NE norepinephrine - E epinephrine - DA dopamine - GH growth hormone     

Responses of Reindeer to Water Loading,Water Restriction and ADH

Two female reindeer were hydrated by administration of (10% of b.wt.) water into the rumen. The diuretic response was very fast and strong but the urea and electrolyte excretion were little affected. Dehydration was carried out by not giving the reindeer water for 48 h. This water deprivation caused a loss of up to 20% of their body weight. The urine osmolality did not exceed 840 mosm/kg H₂O, although the plasma osmolality rose from 300 to 346 and 368 mosm/kg H₂O respectively. The plasma and urine urea concentrations were elevated during dehydration, while the urine urea excretion did not increase. Urine sodium concentration did not increase. When the urine flow rate, after two days of water deprivation, decreased to half of the original, the urine Na⁺ concentration, instead of increasing, went down to half of the original. So did the potassium excretion. When ADH was injected intravenously into hydrated animals a dose of 30 mU of ADH was needed to induce antidiuresis or increased excretion of potassium. The resistance to ADH and the low relative thickness of the medulla confirm the limited capacity of reindeer kidney to concentrate urine or to excrete a solute load. On the other hand, reindeer is able rapidly to excrete surplus water without affecting the electrolyte or nitrogen balance.     

Fluid balance and renal response following dehydrating exercise in well-trained men and women

We examined the recovery of plasma volume, plasma osmolality, renal water and sodium handling and fluid-regulating hormones to dehydrating exercise in well-trained women and compared them to men. Ten male and eight female athletes cycled at anaerobic threshold at an ambient temperature of 32°C until dehydration by 3 % of their body mass (Mb). After exercise, they drank water equal to 1 % Mb and rested for 240 min. Plasma renin activity (PRA), serum aldosterone [ALDO]_s, plasma arginine vasopressin [AVP]_pl, norepinephrine concentrations and plasma osmolality (Osm_pl) were determined at baseline, end of exercise, 30, 60, 120 and 240 min postexercise. Urine was collected at baseline, end of exercise, 60, 120 and 240 min postexercise. Renal free water and sodium handling were assessed. The recovery of OSM_pl and plasma volume occurred within the first 60 min of recovery and at similar rates between the groups. However, women had lower PRA at the end of exercise (P = 0.05), an earlier recovery of [ALDO]_s, and a slower [AVP]pl recovery. Overall fluid balance was similar between the men and women, as were the early recovery of renal free water clearance (C _{H 2}O). During the last 120 min of recovery C _{H 2}O was more negative (greater water reabsorption) and fractional sodium excretion was increased in the women compared to the men. Despite small differences in sodium and water reabsorption following dehydration, it appears from other study that recovery from dehydrating exercise in well-trained men and women is remarkably similar.     

Induction of chromosomal aberrations by hypotonic culture conditions is independent of the S-phase in V79 hamster cells

A deviation from physiological osmolality (300 mOsm/kg H₂O) can lead to genotoxic effects. A 30-min treatment of V79 hamster cells with hy-potonic sodium chloride of 60 mOsm/kg H₂O or with diluted culture medium of the same osmolality induces extraordinarily high frequencies of chromosomal aberrations. In this study, multiple fixation times over a 24-hr period were used to identify cells in various stages of the cell cycle at the time of treatment and to find out whether or not hypotonic conditions are able to induce aberrations in all cell cycle stages. Because of the aberration pattern observed, it is suggested that hypotonic treatment acts as an S-independent agent, like X-rays or restriction endonucleases. Whether the aberrations originate from directly induced DNA damage or from a release of DNase after lysosomal breakdown is discussed.     

Effects of osmolality and antidiuretic hormone on prostaglandin synthesis by renal papilla

Prostaglandin (PG) production by the kidney is known to be reduced both in vivo and in vitro in rats with hereditary diabetes insipidus (DI), totally lacking ADH. Exogenous ADH restores normal PG excretion in these rats. On the other hand, osmolality in vitro, and urine flow rate in vivo have been shown to influence PG synthesis rate. In order to determine whether the decreased PG synthesis of DI rats is due to the lack of antidiuretic hormone itself or to low tissue osmolality, we studied in vivo and in vitro PG production in DI rats in which urine osmolality had been raised either with ADG (infused by Alzet minipumps), or without ADH (by dehydratation) and in control DI rats.PGE₂ and PGF₂ were measured by radioimmunoassay in the urines and in supernatants of papillary homogenates incubated at 37°C for 15–120 min. ADH administration and dehydration led to similar urine osmolalities (900–1,000 mosmol/kg H₂O versus 150 in controls). However, only ADH administration but not dehydration increased PG urinary excretion (×5,P<0.001) and subsequent in vitro papillary synthesis (×1.6,P<0.01). These results show that antidiuretic hormone increases PG-synthesis of the renal papilla directly and not through its effects on papillary osmolality.     

Impaired ability to increase water excretion in mice lacking the taurine transporter gene TAUT

Summary Cellular taurine uptake or release counteracts alterations of cell volume. Na⁺-coupled taurine transporter TAUT mediates concentrative cellular uptake of taurine. Inhibition of vasopressin secretion by hypotonicity may involve taurine release from glial cells of supraoptic nucleus. We compared renal function of mice lacking TAUT (taut^–/–) and wild-type littermates (taut^+/+). We observed renal taurine loss and subsequent hypotaurinemia in taut^–/– mice. With free access to water, plasma and urine osmolality, urinary flow rate as well as urinary excretion and plasma concentrations of Na⁺ and K⁺ were similar in taut^–/– and taut^+/+ mice, whereas plasma concentrations of urea were enhanced in taut^–/– mice. An oral water load (1 ml/16 g body weight) induced a similar diuresis in both genotypes. Repeating the oral water load immediately after normalization of urine flow rate, however, resulted in delayed diuresis and higher urinary vasopressin/creatinine ratios in taut^–/– mice. In comparison, the repeated diuretic response to vasopressin V₂ receptor blockade was not different between genotypes. Water deprivation for 36 h led to similar antidiuresis and increases of urinary osmolality in both genotypes. Upon free access to water after deprivation, taut^–/– mice continued to concentrate urine up to 6 days, while taut^+/+ mice rapidly returned to normal urinary osmolality. Urinary vasopressin/creatinine ratios and plasma aldosterone concentrations were not different under basal conditions but were significantly higher in taut^–/– mice than in taut^+/+ mice at 6 days after water deprivation. In conclusion, taut^–/– mice suffer from renal taurine loss and impaired ability to lower urine osmolality and to increase urinary water excretion. The latter defect could reside extrarenally and result from a role of taurine in the suppression of vasopressin release which may be attenuated in taut^–/– mice.     

Effects of atrial natriuretic peptide on systemic and renal hemodynamics and renal excretory function in patients with chronic renal failure

Summary We examined the effects of 60 min-hANP infusion (24 ng/min/kg) on glomerular filtration rate (GFR), renal blood flow (RBF), cardiac index (CI) and blood pressure (BP) in 8 patients with chronic renal failure (CRF) with GFR ranging from 18 to 80 ml/min/1.73 m² and in 8 control (C) subjects with normal renal function. Basal plasma levels of ANP and cGMP were elevated in CRF (ANP: 60.6±9.1 vs 13.6±1.9 pmol/l,p<0.05; cGMP: 14.3±2.9 vs 6.6±1.1 pmol/ml,p<0.05). During ANP infusion, peak levels of cGMP were higher in CRF than in C (27.5±3.2 vs. 17.3±1.3 pmol/ml,p<0.05). During ANP infusion, GFR increased in CRF by 70.7±4.2% from 34.5±6.8 to 57.4±9.9 ml/min/1.73m² (p<0.001) as compared to 16.2±1.4% in C (p<0.001 vs CRF). RBF increased in CRF by 43.6±6.4% and in C by 3.1±1.2% (p<0.01). Basal urinary sodium excretion (U_NaV) was slightly lower in CRF than in C but rose to the same level in both groups during ANP infusion. In CRF, as opposed to C, U_NaV remained elevated above baseline after the end of the infusion. The effect of ANP on fractional sodium excretion (FE_Na), however, was more pronounced in C. Basal FE_Na was higher in CRF (12.8±2.5% vs 2.4±1.5% in C,p<0.001), FE_Na remained elevated at 180% over baseline in C sixty minutes after cessation of ANP infusion, while it had returned to baseline in CRF. During ANP infusion, CI increased in CRF after 30 min from 2.91±0.08 to 3.12±0.091/min/m² (p<0.001) and in C from 3.20±0.11 to 3.39±0.13 l/min/m² (p< 0.05). Mean arterial BP was higher in CRF and its decrease was greater than in C (21.1±2.7% vs 9.1±1.0%,p<0.001). In patients with CRF GFR, RPF, and CI remained significantly elevated and BP was still significantly decreased 60 min after ANP infusion. Total peripheral vascular resistance (TPR) was elevated in CRF and declined during ANP infusion in both CRF and C. The decline of TPR was sustained and more pronounced in CRF than in C. Renal vascular resistance (RVR) was high in CRF and dropped by nearly 50% during ANP infusion, whereas only a moderate decline in RVR during ANP application was observed in C. Thus, exogenous ANP had greater and prolonged effects on systemic hemodynamics and renal function in CRF than in C. They may be due to higher levels of ANP following ANP infusion and appear to be mediated by a more sustained formation of the second messenger cGMP.Abbreviations ANP atrial natriuretic peptide - CRF chronic renal failure; - GFR glomerular filtration rate - FF filtration fraction - ERPF effective renal plasma flow - ERBF effective renal blood flow - BP blood pressure - MAP mean arterial blood pressure - HR heart rate - SV stroke volume - CO cardiac output - CI cardiac index - TPR total peripheral resistance - RVR renal vascular resistance - U_NaV urinary sodium excretion - FE_Na fractional sodium excretion - PRA plasma renin activity - ECFV extracellular fluid volume - PAH paminohippuric acid Dedicated to Prof. Dr. med. F. Krück on the occasion of his 70th birthday     

Palatability and body fluid homeostasis

The results show that rats drink large volumes of a palatable saccharine solution and rely on the kidneys to eliminate excess water. Rats in fluid balance at the start of the experiment overdrink sodium saccharine (0.005 M) and go significantly into positive fluid balance. If the kidneys are functioning normally the maximum change in fluid balance occurs one half hour after the start of drinking (plasma osmolality is decreased by 9 m osm/kg H₂O). The production of a hypotonic urine rapidly restores the plasma to more normal levels. If rats are injected with antidiuretic hormone so that a hypotonic urine cannot be produced, drinking persists in spite of significant plasma dilution. After 3 hr plasma osmolality is reduced by 22 m osm/kg H₂O (p<0.001), plasma sodium is reduced by 8 m equiv/L (p<0.001) and plasma protein is reduced by 0.4 g% (p<0.05). At this point saccharine consumption decreases but does not stop. The rats showed signs of ill health and subsequent transitory aversion to saccharine. Thus if renal function is impaired, palatability can lead to severe overhydration and hyponatremia.     

Renal function changes during preoptic-anterior hypothalamic heating in the rabbit

Summary Thermoregulatory reactions evoked by selective preoptic-anterior hypothalamic (PO/AH) heating in conscious rabbits were associated with significant changes in renal function. Urine flow rate decreased from a control value of 0.92±(S.E.) 0.08 to 0.47±0.07 ml/min after 10–20 min of heating, urine osmolality increased from 273±34 to 417±46 Osm/kg H₂O, and free water clearance per 100 ml GFR decreased from 1.11±0.46 to –0.50±0.23 ml/min. These changes were followed by a gradual recovery despite continued heating. Clearances of exogenous creatinine and p-aminohippurate fell transiently during the first 10 min of heating and then returned to normal.Plasma antidiuretic activity (ADA) measured by rat bioassay increased regularly and markedly during PO/AH heating but was poorly correlated with changes in urine concentration. Moreover, a similar increase in plasma ADA observed with selective heating of a different brain area (supraoptic nucleus) never produced urine concentration or other renal changes. This suggests that a large and variable fraction of ADA appearing in rabbit blood in response to thermal stimuli was not identical with antidiuretic hormone. Therefore, the causal relationship of ADH release and antidiuresis associated with thermoregulatory reactions could not be clearly demonstrated. The physiological role of renal water conservation would be to compensate for extrarenal water loss related to thermal sweating or panting.     

Renal handling of norepinephrine and epinephrine in the pig

To investigate the renal handling of catecholamines in the pig, intravenous infusions of⁵¹Cr-EDTA and PAH were performed in 7 animals, and samples for simultaneous measurement of norepinephrine (NE), epinephrine (E),⁵¹Cr-EDTA and PAH were obtained through catheters placed into the aorta, left renal vein and both urethers. For both kidneys together,⁵¹Cr-EDTA clearance [GFR] averaged 48±14 (±SD) ml/min (2.23±0.66 ml/kg/min). In the left kidney, GFR averaged 22±9 ml/min, arteriovenous PAH extraction 0.87±0.09, and calculated total renal plasma flow 91±30 ml/min. Plasma NE and E were lower in renal venous than arterial blood (P<0.005), extraction ratios averaging 0.36 and 0.77, respectively. NE excretion rate in final urine (8.9±4.3 ng/min) exceeded transrenal NE extraction rate (5.2±3.9 ng/min) by 3.7±4.4 ng/min. In contrast, urinary E excretion rate (2.9±2.0 ng/min) was slightly lower than transrenal E extraction rate (3.6±3.8 ng/min). These observations suggest that in pig kidneys, plasma PAH extraction rate and GFR related to body weight are quite similar to values in man. Three quarters of circulating E are extracted for the most part by tubular secretion, and the slightly smaller amount appearing in urine is consistent with some intrarenal metabolism. NE, presumably originating from intrarenal neuronal release and/or de novo production, is secreted into the urine.This study was supported by the Swiss National Science Foundation     

Plasma immunoreactive atrial natriuretic peptide and vasopressin after ethanol intake in man

To study the mechanisms of alcohol-induced diuresis, the plasma concentration of immunoreactive atrial natriuretic peptide and arginine vasopressin, serum sodium and osmolality, plasma renin activity and aldosterone, urinary sodium and volume, free water clearance, blood pressure and heart rate were measured in seven healthy men after oral intake of ethanol (1.5 g kg^-1 in 6 h). Serum ethanol levels increased to 27 ± 4 mmol 1^-l (mean ± SD) in 30 min and remained detectable for 14 h. Serum osmolality rose from 280±10 to 340 ± 4 mosm kg^-1 in 2 hours (P < 0.01) and was 300 ± 4 at 14 h (P < 0.01). Formation of hypotonic urine began after the alcohol intake and resulted in a net loss of 0.9 ± 0.1 kg water in 2 h. Free water clearance increased from -3.4 ± 1.4 to 2.8 ± 1.5ml min^-l in 2 h (P < 0.01). Plasma immunoreactive arginine vasopressin decreased from 5.7 ± 2.1 to 3.3 ± 1.3 ng 1^-1 (P = 0.05) in 30 min and increased to 17 ± 25 and 12±10 ng 1^-1 at 6 and 12 h, respectively (P < 0.05 for both). Plasma immunoreactive atrial natriuretic peptide levels decreased from 17 ± 9 to the minimum of 11 ± 3 ng 1^-1 in 2 h (P < 0.01) and returned to the initial levels in 6 h. Serum sodium, plasma renin activity and plasma aldosterone increased maximally by 4 ± 2 , 165 ± 153 and 143 ± 101 % (P < 0.01 each) during 1–6 h. No changes in blood pressure were observed during the ingestion period, but the heart rate rose significantly from 70 min^-1 at 6 p.m. to 95 min^-1 at 12 p.m. We conclude that ethanol intake in relation to serum ethanol levels caused in the first phase a rapid increase in osmolality which was associated with a decrease in plasma immunoreactive arginine vasopressin. This caused hypotonic diuresis and increased free water clearance followed by volume contraction which evidently led to decreased plasma immunoreactive atrial natriuretic peptide. Serum osmolality was significantly elevated during the whole experiment and serum sodium 1–2 h after the ethanol intake. This was associated with the return of plasma immunoreactive atrial natriuretic peptide to initial levels after 6 h, the increase in plasma immunoreactive arginine vasopressin levels and reduced diuresis after 2 h. Our results suggest that ANP is not responsible for the diuresis seen after the alcohol intake.     

Urinary sodium excretion in renal stone formers

Summary In the present investigation 238 randomly selected male individuals of the general population (age 19–41 years) and 42 age-matched male patients with recurrent renal stone formation (calcium oxalate and/or calcium phosphate) were studied under outpatient conditions without dietary restrictions. Urinary Na excretion was 207 ± 82 mmol/24 h (range 55–570) in controls and 208 ± 100 (range 76–575) in recurrent renal stone formers. Both in controls (r=0.36;p < 0.01) and in stone formers (r=0.4;p < 0.01) a significant correlation was observed between urinary excretion of sodium and calcium.Urinary sodium excretion was unrelated to systolic or diastolic blood pressure in normotensive or hypertensive individuals. This finding indicates that factors other than sodium are involved in the maintenance of hypertension. Urinary sodium, presumably an index of intake of nutrients, was significantly correlated to several coronary risk factors, e.g. fasting glucose, cholesterol and overweight. There existed a significant inverse relationship between fasting plasma phosphate and urinary sodium, but not between fasting plasma phosphate and serum iPTH or urinary cAMP. This finding points to some function of sodium excretion as one determinant of plasma phosphate.

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Abbreviations UV_Ca rate of urinary calcium excretion (mmol/24 h) - UV_Na rate of urinary sodium excretion (mmol/24 h) - TMP/GFR tubular threshold for phosphate (mg/dl) - C_Cr endogenous creatinine clearance (ml/min × 1.73 m²) - 25(OH)D serum level of 25-hydroxy-vitamin D - ECV extracellar fluid volume     

Atrial pressure and postprandial volume regulation in conscious dogs

Conscious, chronically instrumented dogs (n=24; left and right atrial catheter, electromagnetic flow probe around the left renal artery, carotid loop) were used in 97 expts. to study mechanisms mediating postprandial (pp) excretion of sodium and water up to at least 180 min after food intake. The dogs were kept under standardized conditions and maintained on ahigh (14.5 mmol Na/kg b.w./day) or alow (0.5 mmol Na/kg b.w./day) sodium intake diet (HSI, LSI) which was given once daily in the morning.In HSI dogs left atrial pressure (LAP) increased from a fasting control value of 0.2 kPa (2 cm H₂O) to 0.7 kPa (7 cm H₂O) (120–180 min pp), right atrial pressure from 0.0 kPa (0 cm H₂O) to 0.3 kPa (3 cm H₂O). 25% of the sodium intake were excreted up to 180 min pp. There was a highly significant positive correlation between pp sodium excretion (U _Na V) and pp LAP.U _Na V was not related to pp increase in renal blood flow (RBF) and glomerular filtration rate (GFR). Fractional sodium excretion increased from a fasting control value of 0.6% to more than 4% in HSI dogs and from 3.3% to more than 7% in anadrenalectomized HSI dog. DOCA did not diminishU _NA V in HSI dogs.In LSI dogs, RBF and GFR increased pp, LAP did not change pp. No substantial increase inU _Na V was observed.The close correlation between ppU _Na V and pp LAP in HSI dogs supports the hypothesis that intrathoracic vascular receptors are involved in the mediation of volume regulation by stimulation of still unknown natriuretic mechanisms which operate on the tubular level in the presence of high mineralocorticoid activity.     

Effects of potassium bicarbonate on distal nephron Na−K-ATPase in adrenalectomized rabbits

Na–K-ATPase activity in the connecting tubule (CNT) and cortical collecting duct (CCD) has been shown to be influenced by KCl both in the presence and in the absence of aldosterone. To investigate if the aldosterone-independent effect of K⁺ on Na–K-ATPase can be produced by other K⁺ salts, we studied the effects of dietary KHCO₃ on Na–K-ATPase and ouabain-insensitive Mg-ATPase activities in four nephron segments of adrenalectomized (ADX) rabbits. The segments examined were: the distal convoluted tubule (DCT), CNT, CCD and medullary collecting duct (MCD). All diets were similar in composition except their KHCO₃ contents which were 100, 300, 500 and 700 meq/kg in groups 1 to 4 respectively. Increasing KHCO₃ in the diet increased K⁺ excretion (7×) and urine pH (6.6 to 8.3). Na–K-ATPase activity in the CCD increased >200% as dietary KHCO₃ was increased to 700 meq/kg. There was a linear relation between Na–K-ATPase activity in this segment and steady state plasma K⁺ as well as K⁺ excretion in the urine. However, Na–K-ATPase activity in the CCD was lower in KHCO₃-fed ADX rabbits than the KCl-fed animals studied previously under similar conditions. There were no significant differences in Na–K-ATPase activities in DCT, CNT and MCD among the four groups given different KHCO₃-diets. It is concluded that dietary intake of KHCO₃ can also influence Na–K-ATPase activity in the CCD independent of aldosterone.Abbreviations used ADX adrenalectomized - ATPase adenosine triphosphatase - CCD cortical collecting duct - CNT connecting tubule - DCT distal convoluted tubule - MCD medullary collecting duct     

Histamine release with intravenous narcotics: Protective effects of H1 and H2-receptor antagonists

Summary High dose narcotic anesthesia with fentanyl or morphine is not associated with significant direct myocardial depression. Morphine is reported to produce arteriolar dilatation and a decrease in SVR (probably due to histamine release) while fentanyl is not. Studies were undertaken to determine if morphine or fentanyl caused histamine release; if such a release correlated with hemodynamic changes, and if H₁ and H₂ antagonists could provide protection. In a randomized double blind study of 40 patients in 4 groups, patients who received morphine (1 mg/kg) demonstrated significant increases in plasma histamine (880±163 to 7,437±2,684 pg/ml–p<0.01) accompanied by an increase in CI (2.4±0.2 to 3.0±0.2 l/min/m²–p<0.01) and decreases in (88±4 to 61±4 torr–p<0.01) and SVR (15.5±1 to 9.0±1 torr-l-min^–1 p<0.01). The prior administration of H₁ (dyphenhydramine 1 mg/kg) and H₂ (cimetidine 4 mg/kg) antagonists provided significant protection (SVR 17.4±1 to 14.6±1 torr-l-min^–1–p<0.05) although histamine increased comparably (1,059±22 to 7,653±4,242 pg/ml–p<0.05). In a separate study, seven patients receiving fentanyl 50 µg/kg showed no histamine changes (935±51 to 685±51 pg/ml) and no significant hemodynamic response. Eight patients receiving morphine 1 mg/kg again showed significant increases in plasma histamine (880±163 to 7,480±2,230 pg/ml–p<0.05) which collelated with the decrease in SVR (r=0.81). These data demonstrate that morphine releases histamine in amounts which correlate with the hemodynamic changes seen. Prior administration of H₁ and H₂ histamine antagonists provide significant protection — more so than either alone. Fentanyl produced no histamine release which may account for much of the cardiovascular stability reported with this drug.     

Urinary excretion of prostaglandin F2α and 6-keto-prostaglandin F1α during volume expansion in man

Renal function and the urinary excretion of immunoreactive prostaglandin F_2α (PGF_2α) and 6-keto-prostaglandin F_1α (6-keto-PGF_1α) were investigated during volume expansion (VE) in 9 healthy young adults. The studies were started after at least 17 h of food and fluid deprivation. Volume expansion (3% of body weight) was achieved by a continuous infusion of Ringer's solution (0.22 ml/kg/min). This increased the urinary excretion of sodium from 195±25 to 714±55 μmol/min/1.73 m²(mean ± S.E.) and decreased the excretion of potassium by 24% and plasma renin activity by 60% (P<0.01). The clearance of inulin increased slightly (from 102.4±3.7 to 114.5±6.2 ml/min/1.73 m², P<0.025), whüe clearance of PAH did not change. The excretion of immunoreactive PGF_2α decreased in 8 out of 9 individuals during VE, from 1.58±0.15 to 0.97±0.10 ng/min/1.73 m²(P<0.01). In contrast, excretion of immunoreactive 6-keto-PGF_1α increased in 8 out of 9 subjects, from 2.32±0.20 to 3.47±0.48 ng/min/1.73 m²(P<0.05). Urinary excretion of PGF_2α and 6-keto-PGF_1α may reflect renal synthesis of prostaglandins (PGs) and prostacyclin (PGI₂), respectively. The results indicate that synthesis of PGs is decreased and that of PGI₂ is increased during VE in man. However, no simple relationship could be found between the prostaglandins and the renal functional parameters.     

Activation of luminal Na+/H+ exchange in distal nephron of frog kidney

Increased chronic intake of K⁺ induced H⁺ and K⁺ secretion in amphibian distal tubule, paralleled by an elevation of plasma aldosterone. The present experiments test whether the mineralocorticoid hormone is responsible for the alteration of ion transport. The blood capillaries of the isolated kidneys of NaCl-adapted (i.e. aldosterone-suppressed)Rana pipiens were perfused with HEPES-buffered amphibian Ringer solution (pH 7.8). Limiting intraluminal pH (pH_1u) was measured continuously with pH-sensitive microelectrodes while aldosterone (3·10^–7 to 3·10^–6 mol/l) was applied in the peritubular perfusate. Concomitant with a decrease of the lumen-positive transepithelial potential (V _te) from 8.5±1.1 mV to 4.0±0.6 mV pH_1u dropped from 7.73±0.02 to a new steady-state value of 7.17±0.05 within 60 to 180 min of aldosterone administration. Significant luminal acidification occurred already 20 min after application of aldosterone. Luminal addition of 10^–3 mol/l amiloride reversed luminal acidification to a pH_1u of 7.68±0.04; at the same timeV _te recovered partially. Pretreatment of the distal tubules with spironolactone prevented the aldosterone-induced acidification of the tubule fluid. We conclude that in early distal tubule of the amphibian kidney aldosterone — after interaction with cytoplasmic receptors — activates the luminal, amiloride-inhibitable Na⁺/H⁺ exchanger. This mechanism could explain enhanced H⁺ secretion found in the K⁺ adapted animal.     

Role of aldosterone in the mechanism of renal potassium adaptation

Chronic potassium loading results in an adaptive change in renal tubular epithelium which increases the capacity for potassium excretion. The present study was performed to evaluate the role of aldosterone in renal potassium adaptation, since hyperaldosteronism stimulates potassium secretion, and potassium loading increases the production of aldosterone. Experiments were performed in animals with intact adrenal glands, and in adrenalectomized animals (Adx) replaced with basal physiologic amounts of corticosterone, which 1) were not replaced with aldosterone, or 2) were chronically infused with aldosterone to achieve either basal plasma levels or elevated levels.Chronic potassium loading in adrenal intact animals was associated with a statistically significant higher rate of urinary potassium excretion (3.57±0.30 Eq/min/100 g BW) compared to the control rate (2.54±0.25 Eq/min/100 g BW, p<0.05), during acute infusion of KCl. In potassium loaded Adx animals, with selective replacement of adrenal hormones, the maximum rate of potassium excretion was blunted in the absence of aldosterone, compared to potassium loaded animals with intact adrenal glands. In contrast, when Adx animals were infused chronically with aldosterone, to achieve basal or elevated plasma levels, the maximum rate of potassium excretion was not blunted, although at basal aldosterone levels increased potassium excretion was due, at least in part, to hyperkalemia.These results indicate that the infuction of renal potassium adaptation after a week or more of chronic potassium loading is dependent on the action of hyperaldosteronism on renal tubular epithelium.     

Urinary prostaglandins in human neonates: Relationship to kidney function and blood pressure

Summary We studied the excretion of prostaglandin (PG) E₂ and of PGF₂ in 172 healthy newborns during the first week of life to detect possible biochemical markers for the individual susceptibility to hypertension. PG excretion was compared to urinary electrolytes, urinary osmolality, and blood pressure. In addition, blood pressure of the newborns was related to the blood pressure of the mothers and to the history of hypertension in parents and/or grandparents.PGE₂-excretion increased from 0.7 ng/mg creatinine on the third day to 1.5 ng on the fifth day of life (p<0.001) while PGF₂ excretion remained unchanged at 2 ng/mg creatinine. PGE₂ (but not PGF₂) was inversely correlated to urinary osmolality (p<0.001) while urinary potassium was positively correlated to PGF₂ (p<0.001). On the fifth day of life systolic blood pressure of the newborns was correlated to PGF₂-excretion and to systolic blood pressure of the mother (p<0.05). Blood pressure was significantly higher in newborns with a history of hypertension in parents or grandparents than in those without hypertension in relatives (p<0.02).The data suggest that renal PG:s are involved in the regulation of urinary osmolality and potassium excretion in the neonate. The positive correlation between PGF₂ excretion and blood pressure may indicate a genetically determined PG-related renal influence on the level of systemic blood pressure.Supported by the Deutsche Forschungsgemeinschaft (Sche 118/3–5)