Background
Methods
Subjects
Inclusion criteria
Exclusion criteria
Study design
Number of subjects
Recruitment
Ethics
Effect variables
Diet
Experimental procedure
Measurements
Renal function
Urinary excretion of AQP2 and ENaC γ
Vasoactive hormones in plasma
Brachial and central blood pressure
Routine analyses
Statistics
Results
Demographics
Urine collection before the examination day
Before each examination day | p (pairedt-test) | ||
---|---|---|---|
Placebo | Tolvaptan | ||
UO (ml/24 h)
| 1969 ± 448 | 2025 ± 514 | 0.51 |
C
H2O
(ml/min)
| -0.46 ± 0.61 | -0.47 ± 0.57 | 0.99 |
U-AQP2 (ng/min)
| 1.10 ± 0.32 | 1.12 ± 0.27 | 0.57 |
U-ENaCγ (pg/min)
| 716 ± 374 | 705 ± 376 | 0.87 |
U-Na (mmol/24 h)
| 103 ± 11 | 101 ± 8 | 0.652 |
U-K (mmol/24 h)
| 55 ± 19 | 51 ± 14 | 0.472 |
GFR
Periods | Baseline | L-NMMA | Post infusion | P (GLM-within) | ||
---|---|---|---|---|---|---|
90-120 min | 120-150 min | 150-180 min | 180-210 min | |||
51
Cr-EDTA-clearance (ml/min/1.73 m2)
| ||||||
Placebo | 99 ± 5 | 93 ± 10***
| 92 ± 8***
| 94 ± 8***
| 97 ± 9 | 0.522 |
Tolvaptan | 97 ± 9 | 91 ± 12***
| 93 ± 9***
| 90 ± 12***
| 94 ± 12 | |
p (GLM between) 0.527 | ||||||
p (paired t-test, between) | 0.403 | 0.533 | 0.583 | 0.118 | 0.197 | |
UO (ml/min)
| ||||||
Placebo | 7.4 ± 1.3 | 3.0 ± 1.2***
| 4.2 ± 1.3***
| 4.9 ± 1.2***
| 6.3 ± 1.1 | <0.0001 |
Tolvaptan | 8.9 ± 1.7 | 4.3 ± 1.8***
| 4.2 ± 1.8***
| 4.9 ± 1.3***
| 5.7 ± 1.6 | |
p (GLM between) 0.230 | ||||||
p (paired t-test, between) | 0.009 | 0.026 | 0.965 | 0.861 | 0.124 | |
C
H2O
(ml/min)
| ||||||
Placebo | 4.6 ± 1.1 | 2.9 ± 1.0***
| 3.9 ± 1.2***
| 4.6 ± 1.0***
| 5.9 ± 1.0 | <0.0001 |
Tolvaptan | 5.8 ± 1.1 | 4.4 ± 1.8*
| 4.0 ± 1.6*
| 3.9 ± 1.2 | 5.2 ± 1.4 | |
p(GLM between) 0.185 | ||||||
p (paired t-test, between) | 0.002 | 0.009 | 0.756 | 0.063 | 0.097 | |
u-AQP2 (ng/min)
| ||||||
Placebo | 1.30 ± 0.27 | 1.04 ± 0.36*
| 0.99 ± 0.19***
| 1.06 ± 0.24***
| 1.11 ± 0.20 | 0.444 |
Tolvaptan | 1.32 ± 0.28 | 1.08 ± 0.39 | 1.04 ± 0.23***
| 1.17 ± 0.32***
| 1.10 ± 0.21 | |
p (GLM between) 0.614 | ||||||
p (paired t-test, between) | 0.771 | 0.427 | 0.382 | 0.044 | 0.665 | |
u-ENaC
γ
(pg/min)
| ||||||
Placebo | 476 | - | 367 | - | 442**
| |
(398; 640) | (296; 756) | (308; 605) | ||||
Tolvaptan | 320 | - | 430 ***
| - | 567***
| |
(281; 379) | (361; 492) | (322; 537) | ||||
p (Wilcoxon’s signed rank test, between) | <0.001 | 0.355 | 0.227 | |||
FE
Na
| ||||||
Placebo | 1.17 ± 0.62 | 0.77 ± 0.35*
| 0.78 ± 0.37*
| 1.12 ± 0.41 | 1.07 ± 0.35 | 0.945 |
Tolvaptan | 1.29 ± 0.45 | 0.89 ± 0.34*
| 0.87 ± 0.32*
| 1.22 ± 0.30 | 1.18 ± 0.30 | |
p (GLM between) 0.328 | ||||||
p (paired t-test, between) | 0.326 | 0.073 | 0.073 | 0.198 | 0.200 |
Tubular handling of water and sodium
U-AQP2 and U-ENaC
Plasma sodium, plasma osmolarity and plasma potassium
Periods | Baseline | L-NMMA | Post infusion | p (GLM-within) | ||
---|---|---|---|---|---|---|
0-90 min | 90-120 min | 120-150 min | 150-180 min | 180-210 min | ||
p-sodium (mmol/l)
| ||||||
Placebo | 140 ± 2 | 139 ± 1 | 139 ± 2**
| 139. ± 2 | 138 ± 2**
| 0.272 |
Tolvaptan | 143 ± 2 | 143 ± 2 | 141 ± 3**
| 141 ± 2 | 141 ± 2*
| |
P (Wilcoxon’s signed rank test) | 0.001 | 0.001 | 0.002 | 0.001 | 0.001 | |
p- osm (mosm/kg)
| ||||||
Placebo | 285 ± 3 | 285 ± 4 | 283 ± 4**
| 284 ± 4**
| 283 ± 4***
| 0.352 |
Tolvaptan | 291 ± 3 | 291 ± 3 | 291 ± 3 | 291 ± 3 | 290 ± 3 | |
p (GLM between) <0.0001 | ||||||
p (paired t-test) | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | |
p-potassium (mmol/l)
| ||||||
Placebo | 3.8 ± 0.2 | 3.8 ± 0.3 | 3.9 ± 0.3 | 3.9 ± 0.2 | 3.8 ± 0.1 | 0.325 |
Tolvaptan | 3.9 ± 0.2 | 3.9 ± 0.2 | 4.0 ± 0.2 | 4.0 ± 0.1 | 4.0 ± 0.1 | |
p (Wilcoxon’s signed rank test) | 0.028 | 0.117 | 0.272 | 0.929 | 0.430 |
Vasoactive hormones
Periods | Baseline | L-NMMA | Post infusion | P (GLM-within) |
---|---|---|---|---|
11:00 AM | 12:00 AM | 1:00 PM | ||
PRC(pg/ml)
| ||||
Placebo | 8.1 ± 4.3 | 6.1 ± 3.2**
| 5.9 ± 3.2**
| 0.670 |
Tolvaptan | 9.9 ± 6.8 | 7.5 ± 4.6**
| 7.5 ± 5.4**
| |
p (GLM between) 0.305 | ||||
p (paired t-test, between) | 0.101 | 0.050 | 0.038 | |
P-AngII (pg/ml)
| ||||
Placebo | 9.5 ± 4 | 8.6 ± 3.7 | 8.0 ± 3.3*
| 0.156 |
Tolvaptan | 11.9 ± 6.2 | 9.4 ± 4.6*
| 9.5 ± 5.1*
| |
p (GLM between) 0.686 | ||||
p (paired t-test, between) | 0.094 | 0.403 | 0.117 | |
P- Aldo (pmol/L)
| ||||
Placebo | 70 ± 2 | 75 ± 2 | 64 ± 2 | 0.949 |
Tolvaptan | 71 ± 2 | 78 ± 2 | 66 ± 1 | |
p (GLM between) 0.899 | ||||
p (paired t-test, between) | 0.962 | 0.785 | 0.840 | |
P- AVP (pg/ml)
| ||||
Placebo | 0.20 ± 0.15 | 0.20 ± 0.15 | 0.20 ± 0.20 | |
Tolvaptan | 0.70 ± 0.45 | 0.70 ± 0.55 | 0.70 ± 0.60 | |
p (Wilcoxon’s signed rank test, between) | <0.001 | <0.001 | <0.001 |
Effects of L-NMMA on brachial bloodpressure
Effects of tolvaptan on brachial blood pressure
Periods | Baseline | L-NMMA | Post infusion | p (GLM-within) | ||
---|---|---|---|---|---|---|
0-90 min | 90-120 min | 120-150 min | 150-180 min | 180-210 min | ||
SBP (mmHG)
| ||||||
Placebo | 112 ± 8 | 113 ± 9 | 115 ± 8*
| 115 ± 9*
| 116 ± 10*
| 0.170 |
Tolvaptan | 112 ± 11 | 115 ± 9*
| 116 ± 9*
| 116 ± 10*
| 114 ± 9 | |
p (GLM between) 0.876 | ||||||
p (paired t-test, between) | 0.833 | 0.117 | 0.272 | 0.929 | 0.430 | |
DBP (mmHg)
| ||||||
Placebo | 61 ± 5 | 68 ± 6***
| 67 ± 6***
| 67 ± 5*
| 65 ± 7 | 0.688 |
Tolvaptan | 63 ± 5 | 69 ± 7***
| 68 ± 6***
| 67 ± 6 | 66 ± 7 | |
p(GLM between) 0.606 | ||||||
p (paired t-test, between) | 0.049 | 0.467 | 0.259 | 0.907 | 0.454 | |
Pulse rate (BPM)
| ||||||
Placebo | 57 ± 10 | 52 ± 9***
| 53 ± 9***
| 55. ± 11***
| 58 ± 12***
| 0.889 |
Tolvaptan | 55 ± 10 | 50 ± 9***
| 51 ± 9***
| 53 ± 10***
| 56 ± 11*
| |
p (GLM between) 0.527 | ||||||
p (paired t-test, between) | 0.016 | 0.022 | 0.007 | 0.013 | 0.003 |
Central blood pressure
Periods | Baseline | L-NMMA |
---|---|---|
PWV(m/s)
| ||
Placebo | 5.3 ± 0.7 | 5.5 ± 0.5 |
Tolvaptan | 5.3 ± 0.6 | 5.6 ± 0.7*
|
p (paired t-test, between) | 0.652 | 0.929 |
AI
| ||
Placebo | 0.0 ± 18.7 | 3.7 ± 18.7 |
Tolvaptan | 1.2 ± 18.3 | 7.2 ± 17.5*
|
p (paired t-test, between) | 0.646 | 0.064 |
CSBP
| ||
Placebo | 100 ± 7 | 105 ± 4 |
Tolvaptan | 100 ± 4 | 107 ± 7*
|
p (paired t-test, between) | 0.871 | 0.351 |
CDBP
| ||
Placebo | 66 ± 12 | 70 ± 8*
|
Tolvaptan | 64 ± 5 | 68 ± 8*
|
p (Wilcoxon signed rank test, between) | 0.440 | 0.622 |