Background
Methods
Subjects
Inclusion criteria
Exclusion criteria
Study design
Medications
Number of subjects
Recruitment
Effect variables
Antihypertensive medications
Diet
Experimental procedure
Measurements
Renal function
Urinary excretion of AQP2
Urinary excretion of ENaCγ
Vasoactive hormones in plasma
Other biochemical measurements
Brachial and central blood pressure
Statistics
Results
Demographics
Urine collection before the examination day
Before each examination day | p (paired t-test) | ||
---|---|---|---|
Placebo | Tolvaptan 60 mg | ||
Urine Output (ml/24 h) | 2504 ± 518 | 2446 ± 615 | 0.57 |
CH2O (ml/min) | −0.22 ± 0.55 | −0.19 ± 0.57 | 0.72 |
u-AQP2 (ng/min) | 1.10 ± 0.26 | 1.09 ± 0.28 | 0.88 |
u-Na (mmol/24 h) | 117 ± 34 | 111 ± 28 | 0.46 |
u-K (mmol/24 h) | 66 ± 17 | 65 ± 18 | 0.77 |
Body weight during the examination day
51Cr-EDTA clearance
Periods | Baseline | L-NMMA | Post infusion |
p (GLM-within) | ||
---|---|---|---|---|---|---|
0–90 min | 90–120 min | 120–150 min | 150–180 min | 180–210 min | ||
51Cr-EDTA-clearance (ml/min/ 1.73 m2) | ||||||
Placebo | 73 ± 20 | 66 ± 22 | 72 ± 24 | 76 ± 17 | 73 ± 19 | 0.154 |
Tolvaptan 60 mg | 72 ± 19 | 67 ± 19 | 70 ± 19 | 68 ± 19 | 67 ± 19 | |
p (GLM between) | 0.684 | |||||
p (paired t-test, between) | 0.740 | 0.758 | 0.643 | 0.005 | 0.016 | |
UO (ml/min) | ||||||
Placebo | 5.6 ± 1.4 | 2.9 ± 1.2*** | 2.8 ± 1.2*** | 3.6 ± 1.4*** | 5.1 ± 1.7 | < 0.0001 |
Tolvaptan 60 mg | 11.1 ± 1.8 | 7.0 ± 2.2*** | 6.3 ± 1.9*** | 7.1 ± 1.7*** | 7.0 ± 2.0*** | |
p (GLM between) | < 0.0001 | |||||
p (paired t-test, between) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | 0.009 | |
CH2O (ml/min) | ||||||
Placebo | 3.0 ± 1.2 | 1.2 ± 0.8*** | 1.1 ± 0.7*** | 1.8 ± 0.9* | 2.9 ± 1.4 | < 0.0001 |
Tolvaptan 60 mg | 8.4 ± 1.7 | 4.8 ± 1.6*** | 4.3 ± 1.4*** | 4.8 ± 1.0*** | 4.7 ± 1.2*** | |
p (GLM between) | < 0.0001 | |||||
p (paired t-test, between) | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | 0.012 | |
u-AQP2 (ng/min) | ||||||
Placebo | 1.28 ± 0.37 | 0.87 ± 0.25*** | 0.85 ± 0.28*** | 0.94 ± 0.35* | 1.12 ± 0.40 | < 0.0001 |
Tolavptan 60 mg | 1.15 ± 0.32 | 0.87 ± 0.23* | 0.82 ± 0.22*** | 0.93 ± 0.23* | 0.89 ± 0.26* | |
p (GLM between) | < 0.0001 | |||||
p (paired t-test, between) | 0.075 | 0.931 | 0.702 | 0.887 | 0.015 | |
FENa (%) | ||||||
Placebo | 1.39 (1.18; 2.33) | 0.91* (0.84; 1.50) | 0.78* (0.56; 0.97) | 0.51*** (0.28; 0.78) | 1.10 (0.88; 1.50) | |
Tolvaptan 60 mg | 1.18 (0.83; 1.6) | 0.86 (0.69; 1.11) | 0.75 (0.45; 1.12) | 0.44* (0.30; 0.81) | 1.21 (0.81; 1.74) | |
p (Wilcoxon’s signed rank test, between) | 0.122 | 0.948 | 0.777 | 0.948 | 0.267 | |
ENaCγ (ng/min) | ||||||
Placebo | 0.78 (0.67; 0.79) | 0.61 (0.45; 0.70) | 0.60 (0.43; 0.76) | 0.65 (0.37; 0.70) | 0.73 (0.63; 0.91) | |
Tolvaptan 60 mg | 0.75 (0.65; 1.0) | 0.59 (0.52; 0.93) | 0.66 (0.51; 0.81) | 0.68 (0.56; 0.77) | 0.69 (0.59; 0.86) | |
p (Wilcoxon’s signed rank test, between) | 0.711 | 0.112 | 0.306 | 0.248 | 0.744 |
Tubular water excretion
Tubular sodium excretion
U-AQP2 and u-ENaCγ
Plasma sodium and plasma osmolarity
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 | 139 ± 2 | 138 ± 2 | 138 ± 2 | 138 ± 1 | 137 ± 2 | < 0.0001 |
Tolvaptan 60 mg | 141 ± 2 | 141 ± 2 | 141 ± 2 | 142 ± 2 | 141 ± 2 | |
p (GLM between) | < 0.0001 | |||||
p (aired t-test, between) | 0.001 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 | |
p- osm (mosm/kg) | ||||||
Placebo | 285 ± 5 | 283 ± 4 | 282 ± 5 | 283 ± 4 | 281 ± 4 | < 0.0001 |
Tolvaptan 60 mg | 288 ± 5 | 290 ± 5 | 289 ± 5 | 290 ± 5 | 289 ± 5 | |
p (GLM between) | < 0.0001 | |||||
p (paired t-test, between) | 0.024 | < 0.0001 | < 0.0001 | < 0.0001 | < 0.0001 |
Urinary excretion rate of nitrate
Vasoactive hormones
Periods | Prior to L-NMMA infusion period | At the end of L-NMMA infusion period | 1 h after L-NMMA infusion period | P (GLM-within) |
---|---|---|---|---|
PRC(pg/ml) | ||||
Placebo | 8.8 ± 5.3 | 7.4 ± 4.0 | 7.7 ± 4.3 | 0.610 |
Tolvaptan 60 mg | 10.1 ± 5.8 | 8.9 ± 6.1 | 8.4 ± 4.9 | |
p (GLM between) | 0.489 | |||
p (paired t-test, between) | 0.481 | 0.312 | 0.523 | |
P-AngII (pg/ml) | ||||
Placebo | 7.8 ± 3.8 | 7.4 ± 3.8 | 7.1 ± 3.1 | 0.801 |
Tolvaptan 60 mg | 9.1 ± 5.9 | 8.9 ± 4.7 | 8.6 ± 4.3 | |
p (GLM between) | 0.327 | |||
p (paired t-test, between) | 0.377 | 0.151 | 0.261 | |
P- Aldo (pmol/L) | ||||
Placebo | 125 (68; 168) | 127 (99; 224) | 119 (87; 224) | |
Tolvaptan 60 mg | 115 (87; 180) | 147 (115; 205) | 178 (108; 264) | |
p (Wilcoxon’s signed rank test, between) | 0.420 | 0.433 | 0.170 |
Brachial and central blood pressure
Periods | Baseline | L-NMMA | Post infusion | p (GLM-within) | ||
---|---|---|---|---|---|---|
Prior to L-NMMA infusion | At the beginning of infusion | At the end of infusion | 30 min after the end of L-NMMA infusion | 60 min after the end of L-NMMA infusion | ||
SBP (mmHG) | ||||||
Placebo | 137 ± 12 | 146 ± 17 | 149 ± 16 | 147 ± 16 | 146 ± 13 | 0.407 |
Tolvaptan 60 mg | 135 ± 9 | 144 ± 15 | 144 ± 14 | 142 ± 15 | 144 ± 13 | |
p (GLM between) | 0.305 | |||||
p (paired t-test, between) | 0.276 | 0.623 | 0.107 | 0.134 | 0.332 | |
DBP (mmHg) | ||||||
Placebo | 82 ± 10 | 88 ± 11 | 90 ± 10 | 87 ± 9 | 87 ± 9 | 0.502 |
Tolvaptan 60 mg | 81 ± 8 | 88 ± 9 | 87 ± 9 | 85 ± 8 | 85 ± 8 | |
p (GLM between) | 0.659 | |||||
p (paired t-test, between) | 0.410 | 0.762 | 0.094 | 0.101 | 0.190 | |
Pulse rate (BPM) | ||||||
Placebo | 58 ± 9 | 55 ± 8 | 55 ± 9 | 56 ± 9 | 6 0 ± 10 | 0.319 |
Tolvaptan 60 mg | 58 ± 9 | 54 ± 9 | 54 ± 9 | 57 ± 10 | 60 ± 11 | |
p (GLM between) | 0.991 | |||||
p (paired t-test, between) | 0.699 | 0.431 | 0.502 | 0.873 | 0.966 |
Prior to L-NMMA infusion (at 70 min) | During L-NMMA infusion (at 130 min) | |
---|---|---|
PWV(m/s) | ||
Placebo | 7.5 ± 1.1 | 8.0 ± 1.3* |
Tolvaptan 60 mg | 7.6 ± 1.3 | 8.2 ± 1.4*** |
p (paired t-test, between) | 0.598 | 0.501 |
AI (n = 16) | ||
Placebo | 21.1 ± 7.8 | 23.5 ± 7.3* |
Tolvaptan 60 mg | 21.1 ± 8.9 | 21.9 ± 9.1 |
p (paired t-test, between) | 0.949 | 0.130 |
CSBP | ||
Placebo | 132 ± 11 | 144 ± 18*** |
Tolvaptan 60 mg | 128 ± 9 | 139 ± 16*** |
p (paired t-test, between) | 0.084 | 0.124 |
CDBP (n = 17) | ||
Placebo | 85 ± 9 | 93 ± 10*** |
Tolvaptan 60 mg | 83 ± 8 | 88 ± 9*** |
p (paired t-test, between) | 0.142 | 0.004 |