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Anophthalmos with limb anomalies (Waardenburg Opththalmo-Acromelic Syndrome) is a very rare autosomal recessive multiple congenital anomaly syndrome, first described by Waardenburg et al. in 1961 (MIM 206920). It is characterized by mono or more often bilateral anophthalmia/microphthalmia and foot malformations, which can be observed in 91% of the patients. The most common anomaly of the feet is the presence of four toes. The hands are affected bilaterally in 77% of the cases. The most characteristic anomaly is the synostosis of the fourth and fifth metacarpals. To date, 33 cases from 19 families have been reported. We present an Italian case of anophthalmia with limb anomalies and a renal malformation, which has never been described in the literature.

Studies were carried out to evaluate the influence of variations in sodium balance on the renal response to low-dose infusion of 1-desamino-8- D -arginine vasopressin (dDAVP), and the functional interaction between dDAVP and renal prostanoids. The studies were performed on healthy women in conditions of extracellular fluid volume expansion (SR group, n =9) and depletion (SD2 group, n=6), respectively. The study protocol included hypotonic polyuria (induced by oral water load) and subsequent antidiuresis (induced by low-dose infusion of dDAVP). Three 60-min clearance (cl.) periods were performed during polyuria (cl. P), early (cl. A1) and late (cl. A2) antidiuresis. The urinary concentrations of prostaglandin (PG) E(2) and the stable metabolites of PGI(2) and thromboxane (Tx) A(2), 6-keto-PGF(1alpha) (6KPGF) and TxB(2), were estimated. Paired renal functional explorations were performed in salt retention and salt depletion both in absence and presence of indomethacin (SR.I and SD2.I groups). In both paired and unpaired studies, the early and late effects of dDAVP on the functional excretory variables and the excretion of prostanoids were assessed as percentage variations, (A1-P)% P and (A2-A1)% A1. (I) dDAVP in salt retention and depletion. During early infusion dDAVP produced in both conditions a significant reduction in urinary flow rate, creatinine cl., absolute and fractional excretions of sodium, chloride and potassium; during late infusion dDAVP was effective in inducing a further significant reduction in urinary flow rate. In salt retention compared to depletion the early reductions in sodium and chloride (absolute and fractional) excretions were significantly lower. (II) Indomethacin pretreatment. During early infusion the dDAVP-induced reductions in the urinary flow rate and 6KPGF excretion were enhanced in both conditions. In salt depletion the dDAVP effects in reduction of creatinine cl. and urinary electrolyte excretions were also enhanced. During late infusion the antidiuretic effect of dDAVP was suppressed in salt retention, while in salt depletion creatinine cl., the urinary excretions of electrolytes and both 6KPGF and TxB(2) showed increases significantly different from the dDAVP effects in the absence of indomethacin. In conclusion, (a) the salt-retaining effect of dDAVP was less effective in salt retention compared to depletion. (b) Indomethacin pretreatment affected the renal action of dDAVP in a time-dependent pattern. The early effects in both conditions were consistent with an inhibited synthesis of modulator PGs. On the contrary, the late effects were consistent with the occurrence, at least in salt depletion, of an escape from dDAVP renal action. This escape phenomenon probably depended on a partial regression of the pharmacological inhibition of the modulating PGs.

In healthy women submitted to a short-term expansion in extracellular fluid volume we have evaluated the urinary excretory profile of the stable metabolites of prostaglandin(PG) I2 and thromboxane(TX) A2, 6-keto-PGF1 alpha(6KPGF) and TXB2 respectively, and assessed the physiological role played by the prostanoids in this experimental condition. Salt retention (SR group, n=9) was induced by repeated i.v. infusion of saline solution (0.9% NaCl). At the end of the treatment the body weight had increased by 0.7+/-0.2 kg (mean+/-SEM) (P<0.05). Renal functional exploration [clearance (cl.) method] was performed during hypotonic polyuria (induced by oral water load) and subsequent moderate antidiuresis (induced by low-dose infusion of an antidiuretic hormone analogue). Urinary 6KPGF and TXB2 concentrations were estimated by RIA method during polyuria (P cl. period), early and late antidiuresis (A1 and A2 cl. periods). Paired functional explorations were performed in absence (control study) and presence of indomethacin. Basal values of plasma sodium and potassium concentrations, plasma renin activity (PRA) and urinary aldosterone excretion were determined just before the control study. The results in salt retention were compared to those previously obtained in healthy women submitted to a moderate salt depletion (SD2 group, n=6), in absence and presence of the drug. Women in salt retention received 100 mg i.m. of the drug, whereas salt-depleted women received only a halved dose as in previous studies in salt depletion the full dose produced prolonged anuria. (I) Salt retention vs salt depletion. The basal values of PRA and urinary aldosterone excretion were significantly lower. During polyuria, urinary excretion of 6KPGF, 6KPGF/TXB2 ratio, urinary flow rate, creatinine cl. and absolute and fractional excretions of sodium and chloride were significantly higher. In salt retention during polyuria, significant positive correlations were found between 6KPGF excretion and functional excretory parameters. (II) Indomethacin in salt retention. The following effects were significant: (a) a reduction in prostanoid excretions in P and A1 cl. periods only; (b) during polyuria, an increase in arterial pressure, a reduction in urinary flow rate and creatinine cl. (saluresis showed not significant reduction). During polyuria significant positive correlations occurred between the absolute effects of indomethacin on 6KPGF excretion and those on functional excretory parameters. (III) Comparative effects of indomethacin in salt retention and salt depletion. Despite the double dosage of the drug, the significant reductions in urinary metabolite excretions were not significantly different during P cl. period and significantly lower in A1 cl. period compared to the corresponding significant reductions in salt depletion. During polyuria, the significant increase in arterial pressure was significantly different from the not significant effect in salt depletion; the not significant effect on saluresis was significantly different from the significant reduction in salt depletion. The results suggest the following conclusions: (1) The present model showed the functional pattern of the volume-natriuresis; (2) In salt retention, in contrast with salt depletion, indomethacin induced an increase in arterial pressure consistent with the inhibition of a PG-dependent vasodilator mechanism active at the systemic level; (3) In salt retention, in contrast with salt depletion, indomethacin failed to induce a significant reduction in saluresis. This failure can be attributed to the drug's blunted effectiveness in inhibiting the renal synthesis of saluretic PGs, and probably to the interference of the concurrent increase in arterial pressure in the renal treatment of sodium and chloride.

It is accepted that the urinary excretions of the stable metabolites of prostaglandin (PG)I2 and thromboxane(Tx) A2, 6-keto-PGF1alpha (6KPGF) and TxB2 respectively, provide an accurate estimate of both basal and stimulated renal synthesis of their precursors. The excretory profile of these metabolites has been evaluated in healthy women submitted to a short-term expansion in extracellular fluid volume. Salt retention (SR group, n=6) was induced by physiological saline (0.9% NaCl) i.v. infusions (2 L per day) over a period of 2 days. On the third day the increase in body weight was 0.92 +/- 0.27 kg (P<0.05). The results of the study have been compared to those previously obtained in normal balance of sodium and potassium (N group, n=20) and in induced salt depletion (SD group, n=14). A common study protocol was used. Basal values of plasma renin activity (PRA) and urinary aldosterone excretion were determined. Renal functional exploration [clearance (cl.) method] was performed during hypotonic polyuria (induced by oral water load) and subsequent moderate antidiuresis (induced by low-dose infusion of an antidiuretic hormone analogue). Urinary 6KPGF and TxB2 concentrations were estimated by RIA method and their urinary excretions were determined at both high and low urinary flow rates. The linear regressions of the urinary metabolite excretions vs. urinary flow rate were estimated by using the data obtained in both hypotonic polyuria and antidiuresis. Salt retention (SR vs. N group) was effective in decreasing the basal values of plasma renin activity and urinary aldosterone excretion. Moreover, during hypotonic polyuria it was effective in increasing the absolute and fractional excretions of sodium and chloride, in the absence of significant variations in mean arterial pressure and creatinine cl. Regarding urinary prostanoid excretions the following results were obtained. 1. Comparative data for hypotonic polyuria. In the SR vs. N group, the urinary excretion of 6KPGF was significantly higher, whereas that of TxB2 was not significantly different. In the SR vs. SD group, the urinary excretion of 6KPGF was not significantly different, whereas that of TxB2 was significantly lower. 2. Comparative data for the regression lines of the urinary prostanoid excretions vs. diuresis. In the SR vs. N group, the regression line slope for 6KPGF excretion was significantly higher, whereas that for TxB2 excretion was not significantly different. In the SR vs. SD group, the regression line slope for 6KPGF excretion was not significantly different, whereas that for TxB2 excretion was significantly lower. 3. Correlative data in the SR group during hypotonic polyuria. The plasma chloride concentration was positively correlated with urinary flow rate, absolute and fractional chloride excretions, and 6KPGF excretion but not with TxB2 excretion. In conclusion, functionally effective salt retention in healthy women induces a selective stimulation of renal synthesis of prostacyclin, unlike salt depletion, in which the synthesis of both PGI2 and TxA2 is upregulated.

The acute effects on urinary prostanoid excretion and on renal function induced by pharmacological inhibition of either the angiotensin-converting enzyme or of the cyclooxygenase system, respectively, have been studied in healthy salt-depleted women. Two experimental groups were studied during salt depletion, SD1 (n=8) and SD2 (n=6). Salt depletion was obtained by combining a low sodium chloride dietary intake (< or =60 mmol per day) with natriuretic and potassium sparing treatment. Paired studies were performed in the absence and in the presence of enalapril (SD1 group) or indomethacin (SD2 group). In both paired studies renal function was estimated by the clearance (cl.) method and the urinary concentrations of PGE2, 6-keto-PGF1alpha and TXB2 were estimated by RIA during sustained hypotonic polyuria (induced by oral water load). Enalapril did not influence urinary excretion of prostanoids. Its main significant effects were: (a) a reduction in mean arterial pressure (MAP); (b) an increase in free-water cl. (C(H2O)) and a reduction in osmolar cl. (Cosm); (c) a reduction in the absolute and fractional urinary excretions of sodium and chloride; and (d) a reduction in both the plasma concentration and urinary excretion of potassium. The urinary flow rate and the creatinine cl. were not significantly affected. Indomethacin reduced urinary excretion of prostanoids and in addition it produced the following significant effects: (a) a reduction in urinary flow rate, C(H2O) and Cosm values, and in absolute and fractional urinary excretions of sodium and chloride; and (b) an increase in plasma potassium concentration. MAP, creatinine cl. and urinary potassium excretion were not significantly affected. With regard to the main parameters, both enalapril and indomethacin exerted similar effects on urinary sodium and chloride excretion but opposite effects on C(H2O) and plasma potassium concentration. In conclusion, after enalapril in a salt-depleted state, the functional expression of acute angiotensin II deprivation was partially masked by the activation of a homeostatic system responsible both for improvement in renal salt conservation and for facilitated cellular potassium uptake. After indomethacin in the same setting, the results were consistent with a differential role of prostanoids in modulating or mediating the activities of neuro-hormonal agonists.

The effective role played by prostanoids in the control of renal function has been investigated in healthy women with salt depletion. Salt depletion (SD2 group, n = 6) was induced by low sodium chloride dietary intake (< or = 60 mmol per day) and combined treatment with natriuretic and potassium-sparing drugs. At the end of the depletive treatment, the cumulative sodium deficit was 513 +/- 56 mmol. The renal function and urinary excretions of prostaglandin (PG) E2, 6-keto-PGF1 alpha (6KPGF) and thromboxane (Tx) B2 were evaluated during hypotonic polyuria. The basal values of plasma sodium and potassium concentrations, plasma renin activity (PRA) and urinary aldosterone excretion were determined before the induction of hypotonic polyuria. Paired studies were performed in the absence (control) and presence of indomethacin both in the SD2 group and in a previously studied group (N2, n = 6) of healthy women in normal sodium and potassium balance. Women in normal balance received 100 mg i.m. of indomethacin, salt-depleted women received only 50 mg (because 100 mg of the drug produced a prolonged anuria). In the SD2 vs. N2 group in the absence of treatment the following significant differences were found: (a) higher basal values of PRA and urinary aldosterone excretion; (b) higher urinary excretions of 6KPGF and TxB2 but not of PGE2; (c) lower values of urinary flow rate, creatinine clearance, absolute and fractional excretions of sodium and chloride, plasma osmolality and plasma electrolyte concentrations. The effects of the indomethacin have been assessed as percentage variations by using paired data for each experimental group. In the SD2 vs. N2 group the reduction in urinary excretions of 6KPGF, TxB2 and potassium as well as in creatinine clearance were not significantly different. On the other hand, the following were significantly different: (a) the lower reduction in PGE2 excretion; (b) the higher reduction in urinary flow rate and in CH2O; (c) the reductions in absolute and fractional excretions of sodium and chloride, and the increase in plasma potassium concentration, significant in the SD2 group but not in the N2 group. The data suggest that: (1) when stimulated by salt depletion the renal biosynthetic pathways of PGI2 and TxA2 showed greater sensitivity to indomethacin inhibition; (2) the effects of the neurohormonal systems activated by salt depletion were either modulated or mediated by renal prostanoids.

The short-term effects of extracellular fluid volume depletion on the generation of some bioregulators of the renal function have been studied in healthy women. Eight subjects (SD group) were submitted to a low NaCl dietary intake and natriuretic treatment. At the end of the treatment (6 days) a cumulative sodium deficit of 381 +/- 55 mmol (mean +/- SEM) and a body weight variation of -2.1 +/- 0.28 kg were estimated. The renal function was explored by clearance method during hypotonic polyuria induced by oral water load and subsequent antidiuresis induced by low-dose infusion of lysine-8-vasopressin. The basal values of plasma renin activity were determined just before the water load as well as the urinary aldosterone excretion of the foregoing 24 hours was. During the renal functional exploration the urinary concentrations of PGE2, 6-keto-PGF1 alpha (6KPGF) and TxB2 were determined by RIA method. We report also, as comparison terms, the results obtained either in potassium depletion (KD group, n = 12) or in normal sodium and potassium balance (N group, n = 20). 1) In the SD vs N group-besides the increase in renin and aldosterone secretion-the behaviour of urinary prostanoids is consistent with a stimulation of the renal synthesis of PGI2 and TxA2 as well as of PGE2, at least as a trend. 2) In the KD vs N group an increase in renin secretion occurred while the urinary aldosterone was not significantly decreased. The urinary prostanoid data suggest an inhibition of the renal synthesis of PGE2 and PGI2. All three urinary prostanoids were significantly lower in the KD as compared to the SD group. Thus, in salt depletion the renal prostanoid synthesis was enhanced while it was depressed in potassium depletion, despite the increased renin secretion.

The acute effects of angiotensin converting enzyme inhibition on the renal function and urinary prostanoids were studied. Healthy women were studied in both sodium depletion (n = 8) and normal balance of sodium and potassium (n = 6). Each woman underwent paired renal functional explorations (by the clearance method during hypotonic polyuria and subsequent antidiuresis) in the absence and in the presence of enalapril. In both experimental conditions enalapril failed to affect urinary prostanoid excretions. Only in the presence of hyperreninemia induced by salt depletion, enalapril was effective in inducing renal tubular effects only partly consistent with a depressed activity of angiotensin-aldosterone system. Specifically, in sodium depletion enalapril treatment promoted a decreasing trend in urinary salt excretion, dependent in turn on selective stimulation of the distal tubule NaCl transport. Furthermore, plasma potassium concentration was reduced despite the concomitant decrease in urinary potassium excretion.

The interaction between moderate salt depletion and urinary excretions of prostanoids (PGE2,6-keto-PGF1 alpha and TxB2), as well as the effective role of the activated renin-angiotensin system (RAS), in the control of renal function and urinary prostanoid excretions have been investigated in healthy women. Salt depletion (SD, n = 8) was induced by low sodium chloride dietary intake (< or = 60 mmol per day) and combined treatment with natriuretic and potassium sparing drugs. The cumulative sodium deficit was 381 +/- 55 mmol. The renal function and urinary excretion of prostanoids were evaluated during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis (lysine-8-vasopressin (LVP) low-dose infusion). Basal plasma renin activity (PRA) and urinary aldosterone excretion were determined, before the water load, in both the SD group and control studies in normal balance of sodium and potassium (N, n = 20). Paired studies were performed in the absence and in the presence of enalapril in the same SD group, as well as in a subgroup, with normal sodium and potassium balance, previously studied (N3, n = 6). In the SD vs. N group, significantly higher values of PRA and urinary aldosterone excretion were found. The renal antinatriuretic mechanism was activated and the diuretic response to water load depressed. During polyuria, the urinary 6-keto-PGF1 alpha and TxB2 excretions were significantly higher, probably reflecting an increase in the renal synthesis of their precursors. During the late LVP infusion, the urinary PGE2 excretion was also significantly increased, in absence of significant differences in urinary flow rate. In both SD and N3 groups, enalapril decreased the mean arterial pressure (MAP). Despite the decrease in MAP, not significantly different in SD vs. N3 group, the drug did not significantly affect the creatinine clearance. Also, the urinary prostanoid excretions were not significantly affected by enalapril. However, in the SD group, but not in the N3 group, the drug was effective in significantly decreasing the absolute and fractional excretions of sodium and chloride. Moreover, the plasma potassium concentration significantly decreased, despite the concurrent decrease in urinary potassium excretion. The data suggest that: (1) in salt depletion, the prostanoid release from the renal cortical structures was stimulated; (2) the renal prostanoid synthesis, either activated (sodium depletion) or not (normal sodium and potassium balance), was not affected by the RAS pharmacological blockade in the short-term; (3) in salt depletion, the RAS blockade recruited a homeostatic mechanism responsible for the improved renal salt conservation, as well as for the redistribution of potassium between the extra- and intra-cellular compartments.

In situ hybridization histochemistry of transverse sections from male rat kidney showed that the mRNA of the regulatory enzyme of polyamine degradation, spermidine/spermine N1-acetyltransferase, has a spotty distribution in the cortex, is low and diffused in the outer stripe and high and diffused in the inner stripe of the outer medulla. At the cellular level, this mRNA is solely expressed by the epithelium of the distal straight and convoluted nephron tubules. Since biosynthetic ornithine decarboxylase mRNA is solely found in the proximal straight tubules, it is proposed that polyamine biosynthesis and degradation occur at separate sites along the nephron.

Plasma renin activity (PRA) and urinary aldosterone excretion were determined in healthy women with normal potassium balance (N, n = 20) or experimental potassium depletion (KD). KD was induced by natriuretic treatment--associated with replacement of net NaCl and water losses--and low dietary potassium intake (< or = 10 mmol/d). By using different depletion patterns, three groups were obtained with cumulative potassium deficits (mean +/- SEM) of 160 +/- 43 (KD1, n = 8), 198 +/- 22 (KD2, n = 6) and 215 +/- 54 mmol (KD3, n = 6). The renal function by the clearance (cl.) method and urinary concentrations of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha (6KPGF), and thromboxane B2 (TXB2) by the RIA method were estimated during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis induced by low-dose infusion of lysine-8-vasopressin (LVP). 1. In all KD groups the depletion treatment significantly reduced both potassium plasma concentration (PK) and urinary potassium excretion while it increased basal PRA; the basal urinary aldosterone excretion was not significantly different from normokalemic controls. In the KD3 vs KD1 group the P kappa value was significantly lower. 2. In both KD2 and KD3 groups as compared to the N group, several hypokalemic-like renal dysfunctions--absent in the KD1 group--occurred. Particularly, in the KD2 + KD3 vs N group the renal ability in both urine diluting (water load) and concentrating (LVP infusion) was significantly impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

By using two similar dietary and pharmacological patterns of potassium depletive treatment, two experimental groups--KD2 (n = 6) and KD3 (n = 6)--with cumulative potassium deficit not significantly different, were obtained. The basal values of plasma potassium concentration and PRA, as well as the expression of renal hypokalemic dysfunction were not significantly different. Paired studies in the absence and presence of indomethacin (KD2 group) or enalapril (KD3 group) were performed. The aim of the research was evaluation of the effective roles of prostanoid and angiotensin (AT) II systems in renal hypokalemic dysfunction. The results show that: 1) AT II and cortical vasodilating prostanoids exerted opposite effects on the preglomerular arteriolar tone; 2) medullary prostanoids antagonized the vasopressin effects. Therefore, in potassium depletion the decreased synthesis of cortical and medullary prostanoids, in the face of the increased generation of AT II, contributed to reducing the glomerular filtration rate and facilitate the expression of vasopressin action. These components of the renal hypokalemic dysfunction probably exert a protective role with regard to the urinary chloride and potassium losses.

In order to investigate the renal functional effects of potassium depletion (KD) we have submitted 20 healthy women to different potassium depletive treatments by dietary and pharmacological means. By changing these treatments we have obtained three KD groups with cumulative potassium deficit of 160 +/- 43 (KD1, n = 8), 198 +/- 22 (KD2, n = 6) and 214 +/- 54 mmol (KD3, n = 6). Another 20 subjects were also studied as controls in normal potassium balance (N group). In all subjects the renal function has been evaluated by clearance (cl.) technique both during induced hypotonic polyuria and subsequent moderate antidiuresis induced by low dose infusion of lysine-8-vasopressin (LVP). A renal dysfunction occurred in differences between these two groups, they have been pooled in a single KD2 + KD3 group. In this group as compared to N the following renal dysfunctions were observed during hypotonic polyuria: a) reduction in creatinine cl. (in absence of significant differences in mean arterial pressure); b) inhibition of the fractional reabsorption of chloride by diluting segments; c) depression of the diuretic response to water load. Moreover in KD the LVP was less effective in reducing the creatinine cl. while it became effective in reducing the fractional excretions of NaCl. These findings indicate that the degree of KD reached in the KD2 + KD3 group was adequate to induce a renal dysfunction similar to that occurring in conditions of chronic hypokalemia. It is probable that hypokalemia by itself along with changes of both prostaglandin and angiotensin renal systems are involved in this renal dysfunction.

In healthy women we have studied the effects of potassium depletions of different degrees on the generation of some bioregulators of hydro-saline balance. The study has been performed on 20 women in normal potassium balance (N group) and 20 women submitted to potassium depletive treatment by dietary and pharmacological means. On the basis of different patterns of treatment we have obtained three groups i.e. KD1 (n = 8), KD2 (n = 6) and KD3 (n = 6) with potassium cumulative deficit of 160 +/- 43, 198 +/- 22 and 214 +/- 54 mmol, respectively. The renal function was assessed by the clearance method during induced hypotonic polyuria and subsequent moderate antidiuresis induced by low dose infusion of lysine-8-vasopressin. The urinary PGE2, 6-keto-PGF1 (6KPGF) and TxB2 were determined by the RIA method. Moreover, the basal PRA and urinary aldosterone were determined before the renal functional exploration. The data obtained in both KD2 and KD3 groups where renal hypokalemic dysfunctions occurred--indicate that hypokalemia stimulated renin secretion and inhibited the reactivity of renal prostanoid production to the polyuric stimulus. However, in the KD3 group--where the circulating levels of renin, and probably of angiotensin II were the highest--the hypokalemic depression of the synthesis of 6KPGF and TxB2 precursors was attenuated while the synthesis of PGE2 was still inhibited.

We have investigated the relative roles of angiotensin II on the renal function and urinary excretion of some prostanoids in healthy women submitted to different conditions of potassium balance. To this aim we have evaluated the effects of an acute inhibition of angiotensin converting enzyme by enalapril (E). The renal function was explored by clearance (cl.) method during induced hypotonic polyuria (oral water load followed by 5% dextrose solution infusion). During 60 min cl. period the urinary PGE2, 6-keto-PGF1 alpha and TxB2 were determined by RIA method. Each subject received paired studies, in absence and presence of E (10 mg administered per os 1 hour before the water load). Basal values of plasma renin activity (PRA) and urinary aldosterone (excreted during the 24 hours before the water load) were also determined by RIA method. This study protocol was applied in normal potassium balance (n = 6) and induced moderate potassium depletion (n = 6). This paper concerns the group in potassium depletion in both absence (D4) and presence of E (D4.E). Potassium depletion was induced by adaptation to a normal sodium (150 mmol/d) and low potassium (< or = 10 mmol/d) dietary intake combined to natriuretic treatment. The water and NaCl net losses were restored by 0.9% NaCl solution infusion. The cumulative potassium deficit achieved at the end of the depletive treatment was 214 +/- 54 mmol. This treatment induced significant decrease in basal plasma potassium concentration and increase in PRA without affecting urinary aldosterone and plasma sodium concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the relative roles of some renal prostanoids and angiotensin II in the hypokalemic renal dysfunction. To this aim we have evaluated the renal function in healthy women in induced potassium depletion of moderate degree before and after acute inhibition of cyclooxygenase (indomethacin, I) or angiotensin converting enzyme (enalapril, E). The renal function was explored by clearance (cl.) method during hypotonic polyuria induced by oral water load followed by 5% dextrose solution infusion; the urinary PGE2, 6-keto-PGF1 alpha and TxB2 were determined by RIA method. Potassium depletion was induced in 12 subjects by adaptation to low potassium (< or = 10 mmol/d) and normal sodium (150 mmol/d) dietary intake combined to natriuretic treatment. The water and NaCl net losses were restored by 0.9% NaCl solution infusion. In 6 subjects paired functional studies were performed in absence (D3) and presence of I (D3.I), 100 mg administered i.m. immediately before the water load. In other 6 subjects, paired studies were performed in absence (D4) and presence of E (D4.E), 10 mg administered per os 1 hour before the water load. No significant difference between D3 and D4 was observed as regards the potassium cumulative deficit as well as the basal values of plasma potassium concentration and plasma renin activity.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the effective role of angiotensin II on the renal function and urinary excretion of some prostanoids in healthy women submitted to different conditions of potassium balance. To this aim we have evaluated the effects of an acute inhibition of angiotensin converting enzyme by enalapril (E). The renal function was explored by clearance (cl.) method during induced hypotonic polyuria (oral water load followed by 5% dextrose solution infusion). During 60 min cl. period the urinary PGE2, 6-keto-PGF1 alpha and TxB2 were determined by RIA method. Each subject received paired studies, in absence and presence of E (10 mg administered per os 1 hour before the water load). Basal values of plasma renin activity (PRA) and urinary aldosterone (excreted during the 24 hours before the water load) were also determined by RIA method. This study protocol was applied in normal potassium balance (n = 6) and induced moderate potassium depletion (n = 6). This paper concerns the group in normal potassium balance in both absence (N3) and presence of E (N3.E). All subjects were submitted to normal dietary intake of sodium (150 mmol/d) and potassium (50 mmol/d). The basal values of PRA, urinary aldosterone and plasma electrolytes were in the normal range. The only significant effect produced by E was a reduction in mean arterial pressure, without significant changes in creatinine cl., urinary hydro-electrolyte excretions as well as urinary excretions of prostanoids.(ABSTRACT TRUNCATED AT 250 WORDS)

The hypothesis that potassium depletion (KD) might play a role in stimulating the renal synthesis of prostanoids, and that these materials can contribute to hypokalaemic renal dysfunction, has been tested. Healthy women were studied either in normal potassium balance (N,n = 14), or in experimental KD. KD was induced by low dietary potassium intake (less than or equal to 10 mmol day-1) and natriuretic treatment, associated with replacement of net NaCl and water loss. By using different depletive patterns, two groups with estimated cumulative potassium deficits of 160 +/- 43 mmol (KD1, n = 8) and 198 +/- 22 mmol (KD2, n = 6), respectively, were obtained. Renal function by the clearance (cl.) method and urinary PGE2, 6-keto-PGF1 alpha, TxB2 concentrations by the RIA method were measured during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis induced by the infusion of low-dose lysine-8-vasopressin (LVP). Compared to the N group, only in the KD2 group do glomerular and tubular dysfunctions typical of hypokalaemia and reduced prostanoid excretions (significant for 6-keto-PGF1 alpha and TxB2 but not for PGE2) appear during polyuria besides the significant reductions of plasma potassium concentration, urinary potassium excretion and the significant increase in plasma renin activity. During LVP infusion the urinary prostanoid excretions were all significantly lower in absence of significant differences in urinary flow rate. Concerning its renal effects, LVP lost its ability to reduce the creatinine cl., while expressing a trend towards reduction in fractional chloride excretion. Indomethacin pretreatment restored the LVP effect on creatinine cl. and increased the antichloruretic LVP effect (although not significantly). To the extent that urinary prostanoid excretions reflect their intrarenal synthesis, our data demonstrate that KD inhibits this biosynthesis. A depressed production of prostanoids endowed with vasodilating and chloruretic activity probably played a role in attenuating the renal vascular hyporeactivity and the urinary chloride dispersion induced by KD.

During hypotonic polyuria renal function studies by the clearance (cl.) method, and urinary PGE2, 6-keto-PGF1 alpha and TxB2 determinations were performed on 14 healthy women in normal potassium balance (N) and 14 healthy women in sustained potassium depletion (KD) induced by low dietary potassium intake (less than or equal to 10 mmol day-1) and natriuretic treatment. By using different depletive patterns, two groups with estimated cumulative potassium deficits of 160 +/- 43 mmol (KD1, n = 8) and 198 +/- 22 mmol (KD2, n = 6), respectively, were obtained. (1) In both the KD1 and KD2 groups as compared to normal potassium balance (N), plasma potassium concentration and urinary potassium excretion were significantly lower; plasma renin activity was significantly higher. (2) Only in KD2 did significant changes appear in renal function and urinary prostanoid excretions. Besides a decrease in creatinine cl. and the urinary flow rate, an increase in fractional chloride excretion and a reduction in distal fractional chloride reabsorption were manifest. The plasma chloride concentration was reduced too. Urinary prostanoid excretions were significantly (6-keto-PGF1 alpha, TxB2) or tendentially (PGE2) lower. (3) Indomethacin treatment resulted in changes in mean arterial pressure (increase) and creatinine cl. (decrease) which were not significantly different in normal potassium balance and KD groups. Only in KD2 did the drug significantly reduce the fractional salt and water excretions and the fractional sodium and chloride deliveries to the diluting segments. However, indomethacin was unable to correct the inhibition of distal fractional chloride reabsorption. Therefore, the potassium depletion attained in the KD2 group was efficacious in depressing renal prostanoid synthesis. This fact, in the presence of high levels of angiotensin II, induced a reduction of the glomerular filtration rate thus contributing to renal ability to retain chloride and potassium.

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.

The renal function was evaluated by clearance (cl.) method during hypotonic polyuria and successive relative antidiuresis induced by lysine-8-vasopressin (LVP) administration. Four 15 min and two 60 min 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. The study protocol was applied on 22 healthy women in acute potassium depletion obtained by natriuretic treatment combined with replacement on quantitative basis of net salt and water urinary losses either in normal potassium diet intake (50 meq/d) or in a low one (less than or equal to 10 meq/d). In Group D3 (n = 6) in the presence of a greater potassium cumulative deficit (198.4 +/- 22.2 meq), as compared to normal potassium balance, a significant reduction of kaliemia and a significant increase of PRA were present. During hypotonic poliuria, besides a marked renal potassium conservation, a significant decrease of creatinine cl., fractional chloride reabsorption (apparently at the diluting segments) and of urinary 6KPGF and TxB2 excretions, were observed. Urinary PGE2 excretion was n.s. reduced.

Renal function has been studied by the clearance (cl.) method during hypotonic polyuria--four 15-min cl. periods--and successive antidiuresis--two 60-min cl. periods (A1, A2)--induced by lysine-8-vasopressin (LVP), 5 mU in bolus followed by infusion at a rate of 0.04 mU/min. The endogenous creatinine cl. (Cc) and the osmotic cls. (Cosm, CH2O) were determined by the usual methods as well as the absolute and fractional urinary excretions of water, sodium, chloride and potassium. The urinary concentrations of PGE2, 6-keto-PGF1 alpha and TxB2 were determined by the RIA method. This study protocol has been applied to 28 healthy women either in normal potassium balance (N, n = 14) or after potassium depletion (KD) induced by low potassium dietary intake (less than or equal to 10 meq/d) plus natriuretic treatment according to two different time patterns: two KD groups were obtained with potassium cumulative deficit of 160 +/- 43 (D2, n = 8) and 198 +/- 22 meq (D3, n = 6). The early % effects of LVP, i.e. (A1-P)% of P (mean polyuria), were significantly different only in D3 as compared to N. Precisely, the LVP-effect to reduce Cc was blunted; moreover a LVP-effect to reduce renal sodium and chloride fractional excretions and a tendentiously enhanced LVP-effect to reduce water fractional excretion were observed. These tubular effects are likely related to the inhibited renal synthesis of prostanoids in the D3 group.

The renal function was evaluated by clearance (cl.) method during hypotonic polyuria and successive relative antidiuresis induced by lysine-8-vasopressin administration. Four 15 min and two 60 min cl. periods were performed in 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 excretions were determined by RIA method. The study protocol was applied on 14 healthy women in acute potassium depletion, treated with indomethacin (100 mg i.m. at the end of the oral water load). In Group D3 (n = 6) in the presence of a greater potassium cumulative deficit (198.4 +/- 22.2 meq), in hypotonic polyuria, indomethacin induces significant effects as an increase of fractional hydro-electrolytic reabsorptions and as a decrease of urinary prostanoid excretion. The indomethacin tubular action in potassium depletion differs significantly from that observed in normal potassium balance.

Renal function has been studied by the clearance (cl.) method during hypotonic polyuria--four 15-min cl. periods--and successive antidiuresis--two 60-min cl. periods (A1, A2)--induced by lysine-8-vasopressin (LVP), 5 mU in bolus followed by infusion at a rate of 0.04 mU/min. The endogenous creatinine cl. (Cc) and the osmotic cls. (Cosm, CH2O) were determined by the usual methods as well as the absolute and fractional urinary excretions of water, sodium, chloride and potassium. The urinary concentrations of PGE2, 6-keto-PGF1 alpha and TxB2 were determined by the RIA method. This study protocol has been applied to 20 healthy women submitted to paired functional explorations in both the absence and presence of indomethacin (100 mg i.m.); the drug effects have been evaluated in both normal potassium balance (N2, n = 6) and in two groups of potassium depletion (KD) with potassium cumulative deficit of 160 +/- 43 (D2, n = 8) and 198 +/- 22 meq (D3, n = 6), respectively. As regards the early % effects of LVP, i.e. (A1-P)% of P (mean polyuria), the inhibition of prostanoid synthesis with indomethacin produced significant changes: 1) an enhanced reduction in renal chloride excretion in all experimental groups; 2) a reduction in renal sodium and chloride fractional excretions in both KD groups; 3) an enhanced antidiuretic effect in D3 only, i.e. in the experimental condition with inhibition of prostanoid renal synthesis present during the control study.