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

Abstract

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) I2and thromboxane(TX) A2, 6-keto-PGF1 α(6KPGF) and TXB2respectively, 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 TXB2concentrations 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/TXB2ratio, 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.