Aluminium: gastrointestinal absorption and renal excretion.
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Adolescent↗
Biomedical subjects
C J Lote
Publications and source records attributed to C J Lote.
Effect of probenecid on the urinary excretion of TXB2 and PGE2 in the anaesthetised rat.
In the anaesthetised rat, probenecid (33 mg/kg) produced a 50% fall in urinary TXB2 excretion indicating that a component of the TXB2 excreted in the urine is secreted by the proximal tubule. At a higher dose of probenecid (100 mg/kg) this effect was overcome, a relative increase in urinary TXB2 excretion being produced. This may provide evidence for the proximal reabsorption or bi-directional transport of TXB2 in the rat. At 100 mg/kg probenecid also produced an 8-fold increase in urinary PGE2 excretion. Although the bi-directional transport of PGE2 is well known, this is the first time urinary PGE2 excretion rate has been shown to be modified by probenecid. The increase in PGE2 excretion could obscure the assessment of any inhibition by probenecid of proximal PGE2 secretion. It could also provide evidence for the proximal reabsorption of PGE2. However the interpretation of probenecid-induced changes in eicosanoid excretion in terms of modified tubular reabsorption must be treated with caution since urinary eicosanoid excretion could be increased by other properties of probenecid including inhibition of either protein binding or the uptake of eicosanoids into the lung.
Animals↗
Urinary prostaglandin F2 alpha excretion is not pH-dependent in the conscious rat: implications for the urinary prostaglandin E2/prostaglandin F2 alpha ratio.
1. The influence of urine pH on the urinary excretion of prostaglandin (PG) F2 alpha and the PGE2/PGF2 alpha ratio has been examined in the conscious rat. 2. The basal urinary PGF2 alpha excretion rate of 3.9 pmol/h (n = 23) did not vary with urine pH. In marked contrast, PGE2 excretion increased as the urine became more alkaline. The PGE2/PGF2 alpha ratio therefore progressively increased from 1.5 to 22 as the pH of the urine changed from pH 5.8 to pH 7.8. 3. The independence of PGF2 alpha excretion from urine pH: (a) excludes cyclo-oxygenase as a potential site of action for the pH-dependence of urinary PGE2 excretion; (b) suggests that the urinary PGE2/PGF2 alpha ratio measured in alkaline urine may be a more accurate reflection of the kidneys, ability to synthesize these two prostaglandins in vivo; (c) suggests that control of urine pH is required before the urinary PGE2/PGF2 alpha ratio can be employed as an index of PGE2 9-ketoreductase (EC 1.1.1.189) activity in vivo.
Animals↗
Diuresis and natriuresis after dihydropyridines: role of prostaglandin E.
It is known that calcium antagonists may produce a natriuresis and diuresis but the mechanisms are unknown and there have been few studies of the relative potencies of different drugs. This paper reports a study designed to measure the effect of nifedipine and nitrendipine on urine volume, sodium and potassium and the renal excretion of prostaglandin E2 (PGE2) in healthy, saline-loaded volunteers. Nifedipine and nitrendipine caused a significant natriuresis. Nifedipine also caused a significant diuresis but that produced by nitrendipine failed to reach statistical significance. Neither calcium antagonist altered PGE2 excretion. There was a small and insignificant fall in urinary potassium in all treatment groups. Blood pressure was not affected by the active treatments though heart rates tended to increase. We conclude that dihydropyridines have a potentially useful acute natriuretic effect which does not seem to be mediated by PGE2.
Adult↗
Eicosanoids in renal function.
The major role of renal eicosanoid synthesis appears to be a protective one. In the cortex, prostaglandin synthesis minimises potential anoxic and ischaemic damage by vasodilatation. In the medulla, prostaglandin synthesis appears to stabilise the corticomedullary solute gradient and may play a role in cell volume regulation. Mono-oxygenase production at this site, by modifying blood flow and cellular active transport processes could again serve a protective function against anoxia and ischaemia. The release of erythropoietin also appears to be prostaglandin dependent. It is likely that leukotrienes released from inflammatory cells within the kidney will affect renal haemodynamics and capillary permeability as in other tissues.
Animals↗
Vasopressin-induced natriuresis in the conscious rat: role of blood pressure, renal prostaglandin synthesis and the peptide ANF.
1. The response to arginine vasopressin (AVP) at doses of 5 and 10 pmol (100 g body weight)-1 h-1 was studied in conscious rats during the infusion of 1% (w/v) dextrose at 11.6 ml h-1 with and without pre-treatment with indomethacin. 2. In the absence of indomethacin AVP infusion induced dose-related increases in sodium output that were positively correlated with increases in mean arterial blood pressure (MAP) and plasma atrial natriuretic factor (ANF) immunoreactivity. Increases in renal prostaglandin E2 (PGE2) synthesis were also associated with AVP infusion. 3. Indomethacin pre-treatment abolished the AVP-induced increases in renal PGE2 synthesis and also the dose-related differences in ANF immunoreactivity. Increases in MAP and sodium output were unaffected at the 10 pmol (100 g body weight)-1 h-1 dose of AVP and only slightly attenuated for the 5 pmol (100 g body weight)-1 h-1 dose. 4. For both series AVP induced marked falls in glomerular filtration rate (GFR) but only small transient falls in effective renal plasma flow. The observed falls in GFR support the view that the natriuresis is due to changes in tubular handling and not in the filtered load of sodium. 5. It is concluded that the natriuresis elicited by AVP is closely related to the pressor action of the hormone but renal PGE2 synthesis and plasma ANF are not responsible for mediating this response.
Animals↗
Tubular mechanisms determining the urinary excretion of tritiated prostaglandin E2 in the anaesthetized rat.
1. The renal excretion of arterially injected tritiated prostaglandin E2 ([3H]PGE2) and its metabolites has been examined in the anaesthetized rat before and after the administration of probenecid (an inhibitor of proximal organic acid secretion). [14C]Inulin was employed as a freely filtered, non-reabsorbable marker, while [3H]p-aminohippurate was used to assess the inhibitory effect of probenecid. The experiments allowed us to quantify the tubular delivery, proximal secretion, intratubular metabolism, and tubular reabsorption of [3H]PGE2 by the whole kidney in vivo. 2. Following a single pass through the left kidney 25% of an injected dose of [3H]PGE2 was excreted, although only 1.7% of the injected 3H co-chromatogrammed with cold PGE2. The chemical content of PGE2 in the isotope employed, produced a slight but significant (P less than 0.05) fall (12%) in the single-pass excretion of [14C]inulin. 3. Intravenous probenecid (100 mg kg-1 + 100 mg kg-1 h-1) completely inhibited the proximal tubular secretion of [3H]p-aminohippurate, while the single-pass excretion of [14C]inulin remained unchanged. Probenecid also reduced the blood pressure and urine flow, and decreased the binding of [3H]PGE2 to plasma protein from 59 to 41%. 4. Probenecid administration reduced the single-pass excretion of 3H following an injection of [3H]PGE2 by 65% down to 8.5% of the injected dose. Due to the change in protein binding however, probenecid also increased the filtered load of [3H]PGE2 from 12 to 16% of the injected dose. 5. The following calculations were made concerning the tubular handling of [3H]PGE2 by the whole kidney in vivo. (i) Thirty-five per cent of the injected dose of [3H]PGE2 was secreted by the proximal tubules on a single pass through the kidney, in addition 12% was filtered while 59% was protein bound. (ii) The tubular reabsorption of [3H]PGE2 was 47% of the filtered load. (iii) [3H]PGE2 was subject to a high degree of intratubular metabolism which at a minimum value represented about 50% of the filtered load. The metabolism of [3H]PGE2 also occurred during proximal tubular secretion.
Animals↗
Renal response to vasopressin and indomethacin in cisplatin-treated rats.
1. Cisplatin [6 mg/kg body weight, in 0.9% (w/v) NaCl] was injected intraperitoneally as a single dose to two groups of rats (Fischer 344 strain). Two further groups of rats, injected intraperitoneally with an equivalent volume of 0.9% (w/v) NaCl, were used as controls. The cisplatin-treated rats developed a pronounced polyuria which did not recover during an 18 week observation period. 2. After 21 weeks, one group of the cisplatin-treated animals received a 6 h infusion of 2.5% D-glucose. Vasopressin (60 mu-units min-1 100 g-1 body weight) was incorporated into the infusate for the final 2 h. A control group of animals received an identical infusion. One week later the other group of cisplatin-treated rats received a 6 h infusion of 0.9% (w/v) NaCl. Indomethacin was incorporated into the infusate for 15 min, at 3 h 52.5 min, to deliver a dose of 10 mg/kg body weight. A control group again received an identical infusion. 3. Cisplatin did not impair the antidiuretic effect of vasopressin, but it reduced the natriuretic effect of vasopressin, and also impaired the ability of the animals to produce concentrated urine. 4. Cisplatin did not alter basal PGE2 excretion, or the reduction in PGE2 excretion induced by indomethacin. However, the urine flow in the cisplatin-treated group did not fall after indomethacin, whereas there was a fall in urine flow in the control group.
Animals↗
Renal haemodynamic actions of pressor doses of lysine vasopressin in the rat.
1. Dose-response effects of lysine vasopressin on renal haemodynamics were studied in conscious rats infused with 2.5% (w/v) dextrose solution at 5.8 ml/h. 2. Lysine vasopressin was maximally antidiuretic in the absence of a significant pressor effect at a dose of 2.5 pmol h-1 100 g body weight-1. Doses of vasopressin greater than this induced a dose-dependent increase in arterial blood pressure. 3. The clearance of p-aminohippurate (PAH) was not significantly changed by vasopressin, even at pressor doses. Rats pre-treated with indomethacin to inhibit prostaglandin synthesis showed a decrease in PAH clearance during the infusion of vasopressin at a dose of 30 pmol h-1 100 g body weight-1, and this suggests that the renal vasoconstrictor actions of vasopressin are attenuated by dilator prostaglandins. 4. Inulin clearance was unchanged by non-pressor doses of vasopressin but was decreased in a dose-dependent manner by pressor doses. A maximal effect was induced by a dose of 30 pmol h-1 100 g body weight-1 which decreased inulin clearance from 3.23 +/- 0.76 (mean +/- S.E. of mean) to 1.60 +/- 0.37 ml/min (P less than 0.02). A change in inulin clearance (from 3.42 +/- 0.46 to 2.17 +/- 0.33 ml/min, P less than 0.01) was also observed in rats pre-treated with indomethacin and infused with vasopressin at the same dose. The magnitude of the change was not significantly different from that observed in rats which were not treated with indomethacin. 5. Control rats infused with dextrose showed a slight but significant increase in sodium excretion during the course of the experiment. A similar natriuresis was observed in rats infused with non-pressor doses of vasopressin but was considerably enhanced in rats infused with pressor doses of the peptide. The antidiuresis induced by vasopressin remained maximal in rats infused with pressor doses. 6. Potassium and osmolal outputs were unchanged by non-pressor doses of vasopressin but significantly increased during administration of pressor doses. 7. It is concluded that pressor doses of lysine vasopressin do not alter total renal perfusion in conscious rats when the prostaglandin system is intact. Glomerular filtration is, however, decreased in a dose-dependent manner by these amounts but the mechanism is unclear.
Animals↗
Captopril reduces the renal response to intravenous atrial natriuretic peptide in normotensives.
The interaction between atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone (RAA) system was studied in 6 healthy volunteers using the angiotensin-converting-enzyme (ACE) inhibitor, captopril. Each volunteer received, on separate occasions in random order, 48 hours treatment with a) low-dose captopril (6.25 mg twice daily), b) 'high-dose' captopril (25 mg twice daily) and c) placebo prior to an infusion of synthetic human ANP (99-126). Resting plasma ANP levels were significantly (P less than 0.01) higher on treatment with 'high-dose' captopril when compared with low-dose captopril or placebo. 'High-dose' captopril reduced mean arterial blood pressure (BP) and significantly (P less than 0.01) reduced the natriuretic response to the human ANP infusion. These results support the hypothesis that ACE is involved in ANP metabolism. The reduced renal response to ANP during treatment with captopril may reflect the dependence of ANP on adequate renal perfusion pressure and angiotensin II levels to exert its natriuretic effect.
Adult↗
The effect of sodium bicarbonate on the flow-dependency of urinary prostaglandin excretion in man.
The influence of oral water loading on the excretion rate of prostaglandin (PG) E was investigated in healthy human subjects in a control study where the urine was acidic (pH 5.7) and after oral sodium bicarbonate, which made the urine mildly alkaline (pH 7.2). PGE was immediately extracted from urine and measured by a radioimmunoassay technique. After sodium bicarbonate (5 g) the urinary PGE excretion rate was some three-fold higher (P less than 0.01) than in the control study, in the absence of any significant difference in the urine flow (approximately 80 ml/h). In the control study (urine pH 5.7) the urinary PGE excretion rate increased significantly (P less than 0.01) as the urine flow rose in response to the oral fluid load. However, after sodium bicarbonate, PGE excretion did not alter after the fluid load despite a 10-fold increase in urine flow. Since after bicarbonate administration PGE excretion is independent of urine flow, mildly alkaline urine may represent a condition under which renal PGE synthesis can be effectively assessed from measurements of urinary PGE excretion, in the presence of changes in urine flow. In addition, the results are compatible with the hypothesis that, in man, PGE may be passively reabsorbed in the distal nephron, and a reduction in this reabsorption could contribute to or be responsible for the dependency of the excretion rate of PGE on urine flow.
Adult↗
Effects of sulindac on renal function and prostaglandin synthesis in patients with moderate chronic renal insufficiency.
The renal effects of therapeutic doses of sulindac were studied in nine patients with stable renal insufficiency, mean creatinine clearance 37.0 +/- 2.2 ml min-1 1.73 m-2 (range 24.7-54.6 ml min-1 1.73 m-2). Nine days' treatment with sulindac produced a small, but significant, reduction in the mean creatinine clearance (37.0 +/- 2.2 to 34.7 +/- 2.2 ml min-1 1.73 m-2; P less than 0.02) and 99mTc diethylenetriaminepenta-acetate (DTPA) clearance (35.5 +/- 3.4 to 31.4 +/- 3.6 ml min-1 1.73 m-2; P less than 0.02) without altering body weight, effective renal plasma flow [131I]hippuran clearance), plasma renin activity (PRA), 24 h urinary volume or electrolyte excretion. After discontinuation of sulindac, creatinine clearance returned to pretreatment values. In five female patients, pretreatment urinary excretion of the 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a stable breakdown product of prostacyclin (PGI2), was significantly reduced (P less than 0.02) when compared with four healthy controls, whereas prostaglandin E2 (PGE2) was unchanged. Administration of sulindac did not significantly alter the excretion rate of PGE2 or 6-ketoPGF1 alpha in this group of patients. In chronic renal disease with moderate renal impairment, reduced renal prostacyclin synthesis may be an important predisposing factor to the renal toxicity associated with the use of non-steroidal anti-inflammatory drugs (NSAID). Short term use of sulindac in therapeutic doses does not appear to influence the excretion of prostaglandins and produces only a minor reversible change in renal function; used cautiously it may have advantages over other NSAID in these patients.
6-Ketoprostaglandin F1 alpha↗
Change in plasma immunoreactive atrial natriuretic peptide during sequential ultrafiltration and haemodialysis.
Plasma immunoreactive human atrial natriuretic peptide (Ir-ANP) levels were measured in eight patients with chronic renal failure who were volume-expanded and during treatment by sequential ultrafiltration and haemodialysis. One patient was studied at two separate treatment sessions. Plasma Ir-ANP levels were raised in all patients (mean +/- SE 184 +/- 44 pmol/l, n = 9) compared with healthy controls (11 +/- 1.4 pmol/l), but showed considerable inter-patient variability. Plasma Ir-ANP levels fell with fluid removal during ultrafiltration (123 +/- 30 pmol/l, n = 9, P less than 0.02) and again as fluid was removed during haemodialysis (76 +/- 20 pmol/l, n = 9, P less than 0.02). Seven patients studied 48 h later, before their next dialysis treatment, had regained weight and showed a coincident rise in circulating plasma Ir-ANP (130 +/- 33 pmol/l, n = 7). Our data would support the hypothesis that the secretion of ANP is determined by volume or by a stimulus related to volume. However, it does not exclude the possibility that a factor other than extracellular fluid volume expansion contributes to the raised plasma Ir-ANP levels in chronic renal failure.
Adult↗
Urine pH and the relationship between urine flow and urinary prostaglandin E excretion in the rat.
The relationship between urine flow and urinary prostaglandin E (PGE) excretion was investigated at constant urine pH in the anaesthetized rat. The urine pH was maintained at approximately pH 6 or pH 8 by the intravenous infusion of either ammonium chloride or sodium bicarbonate respectively. Two distinct patterns in the relationship between PGE excretion and urine flow were observed. The first showed a fall in urinary PGE excretion as the urine flow increased over the low flow range of 2-5 ml/h, and was common to both experiments. The second relationship, however, showed a marked difference between the ammonium chloride and sodium bicarbonate experiments since: (a) in acidic urine (pH 6), PGE excretion increased (P less than 0.002) with the urine flow, attaining a rate of 87 +/- 6 pmol/h (n = 6) at the highest level of flow achieved (12 ml/h); (b) in alkaline urine (pH 8), PGE excretion was significantly (P less than 0.01) higher but did not increase with urine flow, remaining constant at approximately 90 pmol/h (n = 6). The lack of any additive effect on urinary PGE excretion between increasing the urine flow and making the urine alkaline may be explained by both stimuli acting through a common mechanism, a concept which is consistent with the hypothesis that PGE may be reabsorbed in the distal nephron. The flow-dependency of urinary PGE excretion could therefore result from a reduction in reabsorption rather than the increase in passive secretion proposed previously.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of vasopressin-glycine and vasopressin-glycine-lysine-arginine on renal function in the rat.
The peptides vasopressin-Gly and vasopressin-Gly-Lys-Arg occur as part of the sequence of the vasopressin-neurophysin precursor molecule and may be released from the hypothalamus and/or pituitary. [8-Lysine]-vasopressin-Gly (LVP-Gly) and [8-lysine]-vasopressin-Gly-Lys-Arg were administered i.v. to conscious, water-diuretic rats. The renal effects of the peptides were assessed by comparison with the actions of [8-lysine]-vasopressin (LVP) which was administered to separate groups of rats. LVP-Gly and LVP-Gly-Lys-Arg were weakly antidiuretic. LVP-Gly-Lys-Arg was the more potent of the two peptides, but on a molar basis it only had about 10% of the antidiuretic activity of LVP. LVP-Gly and LVP-Gly-Lys-Arg at 10 pmol/h per 100 g body weight (equivalent to the maximal antidiuretic dose of LVP) slightly decreased (P less than 0.001) urine flow without causing significant changes in urine osmolality. LVP (10 pmol/h per 100 g body weight) promoted a marked natriuresis (P less than 0.001) but LVP-Gly and LVP-Gly-Lys-Arg were not natriuretic, even at the dose which was markedly antidiuretic (100 pmol/h per 100 g body weight). Osmolal output decreased at all doses during administration of the extended peptides, but was not significantly changed in the control group or by LVP. Inulin clearance was decreased by about 30% during administration of both LVP and LVP-Gly-Lys-Arg at 100 pmol/h per 100 g body weight.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Is the urinary excretion of prostaglandin E in man dependent on urine pH?
The relationship between urine pH, modified by the oral administration of either ammonium chloride or sodium bicarbonate, and the urinary excretion of prostaglandin E (PGE) was studied in healthy female subjects. The urinary concentration of PGE, normally constant in man, was significantly higher (P less than 0.02) in alkaline than in acid urine. pH-dependent metabolism and flow-dependent excretion were identified as two factors liable to obscure the demonstration of the pH-dependency of the urinary excretion rate of PGE in man.
Adult↗
Effect of prolactin on short circuit current, potential and electrical resistance across isolated frog skin.
The effect of a range of ovine prolactin doses (10(-9)-10(-6)M) on the short circuit current (Isc), potential difference (E) and electrical resistance (R) of isolated frog skin has been studied. Prolactin produced a dose dependent stimulation of Isc and generally a fall in R, although the latter was only significant after 10(-9) and 10(-6)M prolactin. The effect of prolactin on E was found to be more dependent upon the initial E (at the time of hormone addition) than on the dose of hormone. 10(-9)M prolactin, in contrast to higher doses, produced a sustained fall in R without stimulating Isc. Thus the effect of prolactin on frog skin appears to be predominantly on passive permeability at low doses, and on active ion transport at higher doses.
Animals↗
Reduction of urinary excretion of PGE2 and 6 keto PGF1 alpha by tiaprofenic acid.
Tiaprofenic acid (Surgam, Cassenne) was administered intravenously to saline-diuretic conscious rats, at doses of 2, 10 and 25 mg kg-1 body weight. Tiaprofenic acid significantly reduced urinary prostaglandin E2 (PGE2) and 6 keto PGF1 alpha excretion, at all three doses employed. The extent of the reduction was similar for both PGE2 and 6 keto PGF1 alpha output; hence no evidence of 'selectivity' (i.e. sparing of PGI2 synthesis) was observed. Tiaprofenic acid was also administered to rats receiving an infusion of 5% dextrose. The dose employed (0.5 or 1 mg kg-1 body weight) was submaximal and elicited reductions in PGE2 output to values still more than 60% of the control period values. In this group of animals, the percentage change in 6 keto PGF1 alpha excretion was again not significantly different from that of PGE2. The maximal extent of reduction in urinary PGE2 excretion with tiaprofenic acid (25 mg kg-1 body weight) was not significantly different from that elicited by indomethacin (10 mg kg-1 body weight), although the time course of the reduction was different.
6-Ketoprostaglandin F1 alpha↗