Increased Renal Sodium Absorption by Inhibition of Prostaglandin Synthesis During Fasting in Healthy Man. A Possible Role of the Epithelial Sodium Channels

Thomas G Lauridsen; Henrik Vase; Jørn Starklint; Carolina C Graffe; Jesper N Bech; Søren Nielsen; Erling B Pedersen

Disclosures

BMC Nephrology. 2010;11 

In This Article

Results

Demographics

Twenty subjects were allocated to the study. Three participants were excluded. The first was not able to fast for 24 hours, the second needed acute medication due to an intercurrent disease, and in the third blood sampling could not be performed. Seventeen participants were included in the study, 7 women and 10 men with a mean age of 33 ± 8 years. Blood pressure was 124/72 ± 14/9 mmHg. Blood samples showed: B-Hemoglobin 8.8 ± 0.79 mmol/L, P-Sodium 139 ± 2.4 mmol/L, P-Potassium 3.8 ± 0.3 mmol/l, P-Albumin 42 ± 1.5 g/L, P-Creatininium 78 ± 15 μmol/L, P-Bilirubin 8 ± 3 μmol/L, P-Alanintransaminase 23 ± 9 U/L, P-Glucose 5.2 ± 0.8 mmol/L, P-Cholesterol 4.4 ± 0.7 mmol/L.

Effect of Ibuprofen During Fasting on u-AQP2, u-ENaCβ, u-PGE2, u-c-AMP, CH2O, and p-AVP

Table 2 shows the effect of fasting during a 24 hours period and during 2½ hours immediately after 24 hours fasting. During fasting ibuprofen reduced u-PGE2 by 50% (P < 0.03), u-AQP2 by 17% (P < 0.01), and u-AQP2/u-Crea by 18% (P < 0.01). U-ENaCβ was increased by 170% (P < 0.0001). We found no statistically significant changes in urine volume, CH2O and u-c-AMP despite a tendency to lower values during ibuprofen treatment.

After fasting ibuprofen reduced u-PGE2 by 44% (P < 0.02), u-AQP2/u-Crea by 27% (P < 0.03), and u-ENaCβ was increased by 210% (P < 0.0001) in 2½ hours urine collection immediately after the 24 hours fasting period. We measured no statistically significant changes in urine output, CH2O and u-c-AMP despite a tendency to lower values during ibuprofen treatment.

Effect of Ibuprofen on the Response to Hypertonic Saline Infusion

Table 3 shows the effect variables before, during and after hypertonic saline infusion. U-AQP2, p-AVP, u-Osm and p-Osm increased significantly during infusion of 3% saline. After 120 min. U-AQP2 increased by 29% (p < 0.01) during ibuprofen treatment and by 51% (p < 0.001) during placebo. The level of u-AQP2 was significantly lower during ibuprofen treatment at three of four measurements after 3% saline infusion. During ibuprofen treatment we found that ENaCβ was increased significantly and approximately 3 fold at all times during the hypertonic saline infusion (figure 1). After 60 min we found a modest, but significant reduction in ENaCβ by 12% (p < 0.001), and this reduction remained unchanged during the study. During placebo ENaCβ levels were reduced significantly at 30 min and again 120 after hypertonic saline infusion. P-AVP increased by 108% (p < 0.001) immediately after 3% saline infusion in the ibuprofen group and by 118% (P < 0.001) in the placebo group. U-Osm increased by164% (p < 0.001) immediately after 3% saline infusion in the ibuprofen group and by 157% (P < 0.001) in the placebo group. S-Osm increased 3% (p < 0.001) immediately after 3% saline infusion in the ibuprofen group and by 2.5% (P < 0.001) in the placebo group. The levels of P-AVP, u-Osm and s-Osm did not differ between ibuprofen and placebo. Urine volume and CH2O decreased by 55% (p < 0.001) and 105% (p < 0.001), respectively, during ibuprofen administration and by 57% (p < 0.001) and 109% (p < 0.001) during placebo. Urine volume and CH2O did not differ significantly between the two groups. U-PGE2 did not change significantly during 3% saline infusion. The initial reduction in u-PGE2 persisted during ibuprofen treatment both during and after 3% saline infusion. GFR and u-c-AMP did not change significantly during 3% saline infusion and did not differ between ibuprofen and placebo treatment.

Figure 1.

Effect hypertonic saline infusion on ENaCb/crea in a randomized placebo-controlled, cross-over study of 17 healthy subjects.

Effect of Ibuprofen on FENa and Total Sodium Excretion

During 24 hours of fasting the total sodium excretion was reduced by 37% (p < 0.001) during Ibuprofen treatment, and FENa was reduced by 35% (p < 0.001). figure 2 shows that ibuprofen reduced FENa significantly at baseline, during and after hypertonic saline infusion. The changes after 3% saline infusion were the same in the two groups, but at different levels. FENa at baseline was 36% (p = 0.006) higher during placebo treatment compared with ibuprofen, and this difference remaind after infusion of hypertonic saline. Urinary sodium excretion increased significantly from baseline (Placebo: 1129 ± 509 μmol/min; Ibuprofen 827 ± 541 μmol/min) to the level during infusion (Placebo: 2856 ± 1068 μmol/min; Ibuprofen 3305 ± 941 μmol/min) and in the period after infusion (Placebo: 5603 ± 1907 μmol/min; Ibuprofen 5978 ± 1793 μmol/min).

Figure 2.

Effect hypertonic saline infusion on fractional sodium excretion (FENa) in a randomized placebo-controlled, cross-over study of 17 healthy subjects.

Effect of Ibuprofen on Vasoactive Hormones After 24 Hours Fasting and After Hypertonic Saline Infusion

Ibuprofen treatment increased p-BNP significantly during all periods of the study, except for 60 min after infusion ( Table 4 ). P-BNP increased by 61% (p < 0.03) immediately after 24 hours of fasting by ibuprofen. At baseline (before saline infusion) p-BNP was increased by 60% (p < 0.01). No significant increase in p-BNP values there observed 6o min after hypertonic saline infusion, but a clearer tendency was seen to a higher levels during ibuprofen (p < 0.08). The increase in p-BNP was 42% 120 min after hypertonic saline infusion (p < 0.02). P-ANP tended to increase using A General Linear Model With Repeated Measurements (p < 0.055). At baseline, P-ANP increased by 29% (p < 0.03), and 60 min after hypertonic saline infusion the increase was 20% (p < 0.03). No significant difference was observed 120 min after hypertonic saline infusion. Both p-Ang II and p-aldo tended to fall during ibuprofen treatment.

Effect of Ibuprofen on Blood Pressure

At baseline blood pressure was 115/64 ± 9/8 mmHg and pulse rate was 57 ± 8 beats/min during Ibuprofen treatment. The corresponding values during placebo did not deviate significantly, blood pressure was114/65 ± 11/7 mmHg and pulse rate 56 ± 7 beats/min.

The response to 3% saline infusion was measured 30 min after infusion. Systolic blood pressure was unchanged during ibuprofen treatment and increased by 4 mmHg (p < 0.01) during placebo. Pulse rate increased by 11 beats/min (p < 0.01) during ibuprofen treatment and 9 beats/min (p < 0.01) during placebo. Diastolic blood pressure decreased by 2 mmHg (p < 0.05) during ibuprofen treatment and were unchanged during placebo.

The response to 3% saline infusion was measured 60 min after infusion. Systolic blood pressure was unchanged during both ibuprofen and placebo treatment. Pulse rate was significantly increased in both groups by 7 Beats/min (p < 0.01) during ibuprofen and 6 beat/min (p < 0.01) during placebo. Diastolic blood pressure was decreased in both groups (p < 0.05). There were no statistical differences in blood pressure and pulse rate between ibuprofen and placebo at baseline, during and after 3% saline infusion.

Effect of Ibuprofen and Fasting on Body Weight and p-albumin

Body weight were 77.6 kg in the placebo group and 78.1 kg in the ibuprofen group (P < 0.07) after the study day, at the same time there was a decrease in p-albumin from 41 g/l at baseline to 37 g/l (p < 0.001) at the end of the study. None of the subjects had edema after infusion of 3% sodium chloride.

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