Table 2.
Compound A demonstrated significant effects on renal potassium handling
| Treatment | Baseline 1 | Baseline 2 | Dose 1 | Dose 2 | Dose 3 | WO 0–20′ | WO 20–40′ | WO 40–60′ | |
|---|---|---|---|---|---|---|---|---|---|
| Blood Na+, mM | Vehicle | 137 ± 1 | 138 ± 1 | 138 ± 2 | 138 ± 2 | 138 ± 2 | 138 ± 1 | 137 ± 2 | |
| Blood Na+, mM | Cmpd A | 138 ± 1 | 139 ± 2 | 139 ± 2 | 138 ± 3 | 137 ± 2 | 137 ± 1 | 137 ± 2 | |
| Blood K+, mM | Vehicle | 4.2 ± 0.2 | 4.1 ± 0.3 | 4.1 ± 0.4 | 3.9 ± 0.2 | 3.9 ± 0.2 | 3.8 ± 0.2 | 3.9 ± 0.2 | |
| Blood K+, mM | Cmpd A* | 4.0 ± 0.3 | 3.9 ± 0.2 | 3.9 ± 0.4 | 3.9 ± 0.4 | 4.3 ± 0.3 | 4.3 ± 0.2 | 4.3 ± 0.4 | |
| Blood Cl−, mM | Vehicle | 102 ± 1 | 103 ± 0 | 104 ± 2 | 103 ± 2 | 104 ± 2 | 103 ± 2 | 103 ± 2 | |
| Blood Cl−, mM | Cmpd A | 103 ± 3 | 103 ± 3 | 104 ± 3 | 104 ± 5 | 105 ± 2 | 104 ± 2 | 106 ± 4 | |
| Plasma concentration, nM | Cmpd A | 0.7 ± 0.3 | 8.6 ± 2.1 | 0.6 ± 0.3 | 0.3 | 0.3 | |||
| UNaV, μmol/20′ | Vehicle | 20 ± 14 | 20 ± 13 | 38 ± 50 | 54 ± 51 | 84 ± 36 | 93 ± 16 | 114 ± 21 | 108 ± 74 |
| UNaV, μmol/20′ | Cmpd A | 27 ± 10 | 31 ± 26 | 53 ± 43 | 97 ± 68 | 180 ± 119 | 194 ± 131 | 184 ± 90 | 172 ± 37 |
| UKV, μmol/20′ | Vehicle | 27 ± 14 | 26 ± 17 | 24 ± 12 | 27 ± 22 | 36 ± 21 | 31 ± 12 | 31 ± 11 | 24 ± 11 |
| UKV, μmol/20′ | Cmpd A† | 45 ± 15 | 35 ± 10 | 43 ± 20 | 34 ± 18 | 9.6 ± 9.3 | 3.0 ± 3.6 | 3.9 ± 5.2 | 3.8 ± 4.5 |
| UClV, μmol/20′ | Vehicle | 44 ± 28 | 46 ± 29 | 58 ± 37 | 75 ± 44 | 115 ± 27 | 115 ± 22 | 136 ± 30 | 123 ± 66 |
| UClV, μmol/20′ | Cmpd A | 65 ± 22 | 58 ± 27 | 83 ± 22 | 112 ± 37 | 154 ± 99 | 163 ± 119 | 154 ± 75 | 153 ± 40 |
| UV, μl/20′ | Vehicle | 125 ± 23 | 124 ± 23 | 167 ± 52 | 226 ± 45 | 370 ± 44 | 526 ± 115 | 593 ± 96 | 488 ± 139 |
| UV, μl/20′ | Cmpd A | 176 ± 45 | 157 ± 80 | 228 ± 58 | 516 ± 464 | 607 ± 498 | 782 ± 653 | 906 ± 721 | 662 ± 319 |
| Urine concentration, nM | Cmpd A | 6.5 ± 3.2 | 10.3 ± 7.9 | 11.8 ± 6.4 | 7.6 ± 4.8 |
Values are means ± SD, n = 6. Compound A (Cmpd A) demonstrated significant effects on renal potassium handling at plasma concentrations (Cp) approaching 10 nM in the anaesthetized rat, i.e., below Cp after full efficacy on mucociliary clearance in sheep. The effect of Compound A on blood potassium was significantly increased and interacted with time (*P = 0.010) because of the decreased urinary excretion of potassium (†P = 0.028).
UNaV, urinary sodium excretion; UKV, urinary potassium excretion; UClV, urinary chloride excretion; UV, urine excretion; WO, washout.