Urinary prostanoid excretion in healthy women with different degrees of induced potassium depletion.

Plasma renin activity (PRA), urinary excretions of PGE2, 6-keto-PGF1 alpha (6KPGF), TXB2 and renal function were determined in healthy women both in normal potassium balance (N, n = 14) and in experimental potassium depletion (KD). KD was induced by natriuretic treatment--associated to replacement of net NaCl and water losses--in the presence of either normal (congruent to 50 mmol/d) or low (less than or equal to 10 mmol/d) dietary potassium intake. By using different depletive patterns, three groups with estimated cumulative potassium deficit (mean +/- SEM) of 124 +/- 38 (KD0, n = 8), 160 +/- 43 (KD1, n = 8) and 198 +/- 22 mmol (KD2, n = 6), respectively, were obtained. Renal function by the clearance (cl.) method and urinary prostanoid concentrations by the RIA method were estimated during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis induced by a low-dose infusion of lysine-8-vasopressin. 1. In KD0 group the potassium depletive treatment was inefficacious in significantly reducing either the plasma potassium concentration (PK) or the urinary potassium excretion (UKV). The reductions of PK and UKV as well as the enhancement of PRA became significant in KD1 and KD2 groups. 2. The urinary prostanoid excretions were not significantly changed in the KD0 and KD1 groups while in the KD2 group they were reduced, mainly concerning the urinary 6KPGF excretion. 3. Furthermore in the KD2 group, with larger potassium depletion, some of the typical hypokalemic renal dysfunctions appeared. The data suggest that a pathophysiologically critical degree of potassium depletion is associated with an inhibited renal prostanoid synthesis as well as an increased renin secretion.     

Renal synthesis of prostacyclin and thromboxane in healthy women: differential effects of a short-term saline loading

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.     

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

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

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

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.     

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

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.     

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

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

Low-dose desmopressin infusion: renal action in healthy women in moderate salt retention and depletion,and interactions with prostanoids

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.     

Volume-induced natriuresis in healthy women: renal metabolism of prostacyclin and thromboxane, and physiological role of prostanoids

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.     

Renal function in experimental potassium depletion. II. Indomethacin and effects of lysine-8-vasopressin in hypotonic polyuria

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.     

Renal effects of the acute inhibition of angiotensin-converting enzyme. I. 1) Studies during normal sodium and potassium balance]

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)     

Renal function in experimental potassium depletion. I. Effects of lysine-8-vasopressin in hypotonic polyuria

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.     

Renal effects of the acute inhibition of angiotensin-converting enzyme. I. 2) Studies during moderate potassium depletion]

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)     

Renal function and urinary prostanoid excretions in salt-depleted women: comparative effects of enalapril and indomethacin treatments.

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.     

Excretion of primary prostanoids and their metabolites during acute volume expansion

Simultaneous determination of urinary excretion rates of primary unmetabolized prostanoids and their enzymatic metabolites were performed by gas chromatography-mass spectrometry (GC/MS) or tandem mass spectrometry (GC/MS/MS). Changes in kidney function were induced by acute (4 h) volume expansion. Despite marked changes in urine flow, GFR, urinary pH, osmolality, sodium and potassium excretion, only a insignificant or transient rise in the enzymatic prostanoid metabolites (2,3-dinor-6-keto-PGF1 alpha, PGE-M, 2,3-dinor-TxB2 and 11-dehydro-TxB2) was observed. The excretion rates of the primary prostanoids were elevated in parallel with the rise in urine flow: PGE2 rose (p less than 0.05) from 14.2 +/- 4.0 to 86.2 +/- 20.7, PGF2 alpha from 60.0 +/- 4.9 to 119.8 +/- 24.0, 6-keto-PGF2 alpha from 7.2 +/- 1.3 to 51.5 +/- 17.0, and TxB2 from 11.2 +/- 3.3 to 13.6 +/- 3.6 ng/h/1.73 m2 (means +/- SEM) at the maximal urine flow. Except for 6-keto-PGF1 alpha and TxB2, this rise in urinary prostanoid levels was only transient despite a sustained fourfold elevated urine flow. We conclude that urine flow rate acutely affect urine prostanoid excretion rates, however, over a prolonged period of time these effects are not maintained. The present data support the concept that urinary levels of primary prostanoids mainly reflect renal concentrations whereas those of enzymatic metabolites reflect systemic prostanoid activity. From the excretion pattern of TxB2 one can assume that this prostanoid represents renal as well as systemic TxA2 activity.     

Renal effects of the acute inhibition of angiotensin-converting enzyme. I. 3) Relative roles of angiotensin II and prostanoids in early hypokalemic dysfunction]

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)     

Differential effects of various vasoactive drugs on basal and stimulated levels of TXB2 and 6-keto-PGF1 alpha in rat brain

Thromboxane B2 and 6-keto-PGF1 alpha (6KPGF1 alpha), the major stable metabolites of thromboxane and prostacyclin, are present in the CNS, where they appear to be mainly produced within and/or acting upon the vascular district. Their concentrations are of few pg/mg protein in rat brain cortex of animals sacrificed by microwave (MW) radiation, procedure which inactivates tissue enzymes and allows the determination of endogenous "basal" levels of eicosanoids. Levels of 6KPGF1 alpha and especially those of TxB2 increase several fold over the basal values in brain cortex of animals sacrificed by decapitation followed by a few minute interval before analysis (post-decapitation ischemia, PDI). Pretreatment of animals with the vasoactive drug papaverine, resulted in elevation of brain basal levels of 6KPGF1 alpha and with the carbochromene derivative AD6 in reduction of basal levels of TxB2, whereas the calcium antagonist nifedipine and dipyridamole did not modify basal levels of the two eicosanoids. Treatments with papaverine and AD6 reduced the accumulation of TxB2 and enhanced that of 6KPGF1 alpha occurring after PDI, to different extents, both resulting, however, in reduction of the TxB2/6KPGF1 alpha ratio. Nifedipine instead, decreased the release of both eicosanoids and resulted in elevation of the TxB2/6KPGF1 alpha ratio, whereas dipyridamole had no effect. In conclusion, the evaluation of the overall effects of drug treatments on the TxB2/6KPGF1 alpha ratio in cerebral tissue, provided useful informations on the pharmacological modulation of vascular eicosanoids in this district.     

Relationship of urinary kallikrein excretion to urinary potassium excretion during furosemide administration with and without amiloride

The relationship of urinary kallikrein excretion to urine volume, and to urinary sodium and potassium excretions was studied in normal rats during furosemide diuresis and superimposed injection of amiloride, a K+-sparing diuretic. Continuous infusion of furosemide increased urinary kallikrein, sodium and potassium excretions and the urine volume. Amiloride injection during furosemide diuresis caused further increase in diuresis and natriuresis, but a prompt decrease in urinary kallikrein excretion to basal level, and potassium excretion to below the basal level. The significant correlation of urinary kallikrein excretion to urinary potassium excretion, but not to urine volume and urinary sodium excretion after amiloride injection suggests that the major determinant of urinary kallikrein excretion is renal potassium secretion through a mechanism that is affected by amiloride.     

Relation between acute changes in diuresis and renal prostaglandins. I: Induced hypotonic polyuria

We have evaluated the effects of indomethacin (I) and of a rich in linoleic acid phosphatidylcholine (E) on the renal function and on the PGE urinary excretion during steady hypotonic polyuria. 5 normal subjects have been studied in the absence of treatment (TA) and after treatment with I, E, E + I. The renal function has been estimated by clearance (cl.) method during hypotonic polyuria induced by oral water loading and i.v. infusion of 5% dextrose solution. The glomerular filtration rate has been estimated by cl. of endogenous creatinine; moreover have been measured the osmotic clearances (Cosm, CH2O), the sodium and potassium clearances (CNa, CK), the mean arterial pressure (PA) and the urinary prostaglandins of E series (PGE) by RIA method. In I condition is observed: a) a trend to a glomerular filtration rate decrement; b) a significant decline of the urinary flow rate, CH2O, UPGV and a significant increment of the urinary osmolarity; c) a trend to an increment of potassium and a decrement of sodium urinary excretions; d) a significant increase of PA. It is possible that the contrary effects observed during the hypotonic polyuria in E condition depend on the stimulating effects of this material on the PG intrarenal synthesis.     

Neonatal urinary prostanoid excretion

Urinary excretion of prostanoids prostaglandin E2 (PGE2), PGE-M (7alpha-hydroxy-5,11-diketo-2,3,4,5,20-penta-19-carboxyprostano ic acid), 6-keto-PGF1alpha, 2,3-dinor-6-keto-PGF1alpha, thromboxane B2 (TxB2) 2,3-dinor-TxB2 and 11-dehydro-TxB2 was determined by gas chromatography/mass spectrometry in preterm and term infants to show that there is an age-dependent excretion rate of the above prostanoids in infants this young. Group I included premature children with normal postnatal development, Groups II and III included term children who were admitted in the neonatal period for observation because of feeding problems but who were subsequently found to be completely healthy. We present normal data of three primary prostanoids and four prostanoid metabolites. In Group I, excretion rates of 2,3-dinor-TxB2 were significantly lower than in Group II (P = 0.04) and in Group III (P = 0.05). Furthermore, the excretion rate of 11-dehydro-TxB2 in group I was significantly lower than in Group II (P = 0.05). We found no significant age-dependent differences between the three groups in excretion rates of PGE2, PGE-M, 6-keto-PGF1alpha, 2,3-dinor-6-keto-PGF1alpha, and TxB2.     

Urinary prostaglandin excretion in pregnancy: the effect of dietary sodium restriction

INTRODUCTION: Dietary sodium restriction results in activation of the renin-angiotensin-aldosterone-system. In the non-pregnant situation renin release in response to a low sodium diet is mediated by prostaglandins. We studied the effect of dietary sodium restriction on urinary prostaglandin metabolism in pregnancy. PATIENTS AND METHODS: In a randomized, longitudinal study the excretion of urinary metabolites of prostacyclin (6-keto-PGF(1 alpha)and 2,3-dinor-6-keto-PGF(1 alpha)) and thromboxane A(2)(TxB(2)and 2,3-dinor-TxB(2)) was determined throughout pregnancy and post partum in 12 women on a low sodium diet and in 12 controls. RESULTS: In pregnancy the excretion of all urinary prostaglandins is increased. The 6-keto-PGF(1 alpha)/ TxB(2)-ratio as well as the 2, 3-dinor-6-keto-PGF(1 alpha)/ 2,3-dinor-TxB(2)-ratio did not significantly change in pregnancy. CONCLUISION Prostacyclin and thromboxane do not seem to play an important role in sodium balance during pregnancy.