Changes in urinary excretion of water and sodium transporters during amiloride and bendroflumethiazide treatment

doi:10.5527/wjn.v4.i3.423

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World Journal of Nephrology

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Randomized Controlled Trial

World J Nephrol. Jul 6, 2015; 4(3): 423-437
Published online Jul 6, 2015. doi: 10.5527/wjn.v4.i3.423

Table 1 Experimental procedures

	Before the study day				On the study day
	Day-4	Day-3	Day-2	Day-1	6:00-8:00	8:00-08:30	8:30-09:00	9:00-9:30	9:30-10:00	10:00-10:30	10:30-11:00	11:00-11:30	11:30-12:00	12:00-12:30	12:30-13:00	13:00-13:30
Periods										Baseline		Infusion			Post Infusion
Time								0	30	60	90	120	150	180	210	240
Diet	x	x	x	x
Study drug	xx	xx	xx	xx	x
24-h BP				x------	-----x
24-h urine				x------	-----x
IV access						x
Weight						x					x		x			x
Water load						x--------------------------------------------------------------------------- 175 mL every 30 min ----------------------------------------------------------------------------------------------- x
Urine sample							(x)	x	x	x	x		x	x	x	x
Blood samples								x	x	x	x		x	x	x	x
Blood pressure						x		x	x	x	x		x	x	x	x
⁵¹Cr-EDTA								x ------------------------------------------------------------------------------------------------------------------------------------------------------------------ x
IV. fluid												x-----------------x
App.Ton											x		x
BIS						x					x		x			x

24-h BP: 24-h ambulatory blood pressure measurements; 24-h urine: 24-h urine collection; App.Ton: Applanation tonometry; BIS: Bioimpedance spectroscopy.

Table 2 Twenty-four hours brachial blood pressure and urine collection with fluid deprivation (12 PM to 8.00 AM) in 23 healthy subjects

	Examination day			P (ANOVA)
	Thiazide	Amilorid	Placebo	P (ANOVA)
Urine output (mL/24 h)	2527 ± 728	2418 ± 469	2316 ± 700	0.481
u-osm (mosm/24 h)	865 ± 158	835 ± 176	761 ± 187	0.087
C_H2O (mL/min)	-0.40 ± 0.33	-0.37 ± 0.47	-0.24 ± 0.53	0.534
Cr.Cl (mL/min per m²)	113 ± 25	118 ± 32	110 ± 26	0.549
u-NKCC (ng/mmol)	0.35 ± 0.07	0.30 ± 0.05	0.32 ± 0.06	0.025
u-AQP2 (ng/mmol)	113.2 ± 39.2	103.3 ± 25.5	98.5 ± 17.4	0.244
u-ENaCγ (ng/mmol)	37.8 ± 26.7	30.8 ± 17.3	32.7 ± 15.6	0.867
u-Na (mmol/24 h)	108 ± 34	121 ± 27	106 ± 37	0.263
u-K (mmol/24 h)	80 ± 20	64 ± 21	60 ± 19	0.002
bSBP (mmHg)	119 ± 6	114 ± 7	116 ± 7	0.213
bDBP (mmHg)	72 ± 4	69 ± 3	70 ± 4	0.034

Values are means ± SD. One-way ANOVA was used for comparison between groups. P-values represent the possibility of a difference between groups. u-osm: Urine output, urine osmolality; C_H2O: Free water clearance; Cr.Cl: Creatinin clearance; u-NKCC2: Urinary NKCC2; u-AQP2: Urinary excretion of AQP2; u-ENaCγ: ENaCγ excretion adjusted for creatinin; u-Na: Urinary excretion of sodium; u-K: Potassium; bSBP: Brachial systolic blood pressure; bDBP: Brachial diastolic blood pressure.

Table 3 Effect of 3% hypertonic saline on urinary parameters in 22 healthy subjects treated with bendroflumethiazide or amiloride

Periods	Baseline	Infusion	Post infusion			P_{GLM RM}
Periods	0-90 min	90-150 min	150-180 min	180-210 min	210-240 min	P_{GLM RM}
C_H2O < 0.001
BFTZ	3.1 ± 1.6^a	-0.2 ± 0.5^d	-1.6 ± 0.6^d	-1.6 ± 0.7^d	-0.6 ± 1.6^d
Amiloride	3.7 ± 0.9	-0.6 ± 0.7^d	-2.1 ± 0.6^d	-2.4 ± 0.8^d	-1.4 ± 1.7^d
Placebo	4.4 ± 1.1	-0.6 ± 0.6^d	1.8 ± 0.7^d	-2.5 ± 1.0^d	-2.0 ± 0.5^d
P_{GLM between subjects} 0.061
P_ANOVA	0.006	NS	NS	0.001	0.007
UO (mL/min) 0.029
BFTZ	6.1 ± 1.6	2.6 ± 0.6^d	1.4 ± 0.5^d	1.7 ± 1.0^d	2.7 ± 1.9^d
Amiloride	6.8 ± 1.3	2.5 ± 0.6^d	1.6 ± 0.5^d	2.0 ± 0.7^d	3.2 ± 1.2^d
Placebo	7.3 ± 1.2	2.3 ± 0.9^d	1.7 ± 0.8^d	2.2 ± 1.2^d	2.4 ± 1.1^d
P_{GLM between subjects} 0.245
P_ANOVA	0.019	NS	NS	NS	NS
u-Na (mmol/min) 0.001
BFTZ	1.4 ± 0.4	1.7 ± 0.4^b	1.9 ± 0.7^b	2.1 ± 0.6^d	2.0 ± 0.6^b
Amiloride	1.6 ± 0.5	2.0 ± 0.7	2.5 ± 1.0^b	2.9 ± 1.2^d	3.0 ± 1.0^d
Placebo	1.3 ± 0.3	1.9 ± 1.1^a	2.5 ± 1.3^b	3.3 ± 1.7^d	3.0 ± 1.0^d
P_{GLM between subjects} 0.020
P_ANOVA	0.028	NS	NS	0.007	<0.001
FENa (%) < 0.001
BFTZ	1.5 ± 0.4	1.8 ± 0.5^a	2.0 ± 0.6^b	2.2 ±0.6^d	2.1 ± 0.6^d
Amiloride	1.8 ± 0.6	2.1 ± 0.6^a	2.6 ± 1.0^b	2.9 ± 1.2^d	3.0 ± 1.1^d
Placebo	1.4 ± 0.4	2.1 ± 1.0^b	2.7 ± 1.2^d	3.0 ± 1.1^d	3.1 ± 1.1^d
P_{GLM between subjects} 0.036
P_ANOVA	0.022	NS	NS	0.019	0.001
u-K (mmol/min)
BFTZ	20.3 ± 6.7	17.7 ± 5.3	15.8 ± 4.4^b	14.2 ± 5.6^b	13.3 ± 6.3^b	< 0.001
Amiloride	18.5 ± 8.4	15.7 ± 9.3	18.6 ± 11.1	22.4 ± 12.0	23.3 ± 10.2^a
Placebo	22.3 ± 9.3	15.6 ± 6.9^d	16.4 ± 8.5^a	22.3 ± 12.3	20.4 ± 7.9
P_{GLM between subjects} 0.255
P_ANOVA	NS	NS	NS	0.015	0.001
FEK (%)
BFTZ	21.7 ± 7.4	20.0 ± 6.6	16.1 ± 4.8^b	15.0 ± 5.9^b	14.4 ± 6.9^b	< 0.001
Amiloride	20.8 ± 9.8	18.7 ± 10.8	20.5 ± 12.0	23.6 ± 12.4	25.0 ± 11.0^a
Placebo	23.7 ± 9.3	18.1 ± 8.2^b	17.5 ± 8.9^a	20.6 ± 9.9	21.4 ± 8.8
P_{GLM between subjects} 0.254
P_ANOVA	NS	NS	NS	0.018	0.001
⁵¹Cr-EDTA (mL/min per 1.73m²) 0.271
BFTZ	92.1 ± 10.8	91.3 ± 11.9	96.0 ± 16.7	96.9 ± 16.8	96.5 ± 21.2
Amiloride	92.7 ± 13.7	93.2 ± 12.8	94.1 ± 12.1	96.7 ± 14.1	100.2 ± 15.6
Placebo	96.5 ± 9.5	90.0 ± 13.3	94.7 ± 15.1	102.4 ± 14.3	98.1 ± 15.9
P_{GLM between subjects} 0.887

Free water clearance (C_H2O), urinary output (OU), excretion of sodium (u-Na) and fractional excretion of sodium (FENa), urinary excretion of potassium (u-K) and fractional excretion of potassium (FEK) and

⁵¹Cr-EDTA clearance in a randomized, placebo-controlled, crossover study of 23 healthy subjects. Values are mean ± SD. General linear model (GLM) with repeated measures was performed for comparison within the group and intervention as between subjects factor. One-way ANOVA was performed when differences were found between interventions. Post hoc Bonferroni correction was used for multiple comparisons of post infusion periods to baseline within each treatment group.

^aP < 0.05;

^bP < 0.01;

^dP <0.001.

Table 4 Effect of 3% hypertonic saline on plasma in 23 healthy subjects treated with bendroflumethiazide or amiloride

Time	Baseline	Infusion	Post infusion			P_GLM-RM
	0-90 min	150 min	180 min	210 min	240 min
p-Na						0.281
BFTZ	137 ± 2	141 ± 2^d	141 ± 2^d	139 ± 2^d	139 ± 2^d
Amilorid	137 ± 2	141 ± 2^d	141 ± 2^d	140 ± 2^d	139 ± 2^d
Placebo	139 ± 1	43 ± 2^d	142 ± 1^d	141 ± 1^d	140 ± 1^d
P_{GLM between subjects} 0.003
P_ANOVA	0.001	0.019	0.004	0.007	0.005
p-K						0.001
BFTZ	3.35 ± 0.22	3.32 ± 0.23	3.43 ± 0.26	3.42 ± 0.21	3.40 ± 0.20
Amilorid	4.32 ± 0.30	4.17 ± 0.23^d	4.26 ± 0.27	4.27 ± 0.25	4.20 ± 0.20^a
Placebo	3.89 ± 0.18	3.83 ± 0.22	3.97 ± 0.23	3.94 ± 0.22	3.92 ± 0.20
P_{GLM between subjects} < 0.0001
P_ANOVA	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
p-Osm						0.600
BFTZ	281 ± 5	288 ± 4^d	288 ± 6^d	286 ± 5^d	284 ± 4^d
Amilorid	283 ± 4	290 ± 4^d	290 ± 3^d	287 ± 3^d	285 ± 3^a
Placebo	286 ± 3	294 ± 4^d	292 ± 4^d	290 ± 4^d	289 ± 3^b
P_{GLM between subjects} < 0.0001
P_ANOVA	< 0.001	< 0.001	0.005	0.002	< 0.001
p-Alb (g/L)						0.007
BFTZ	40.7 ± 3.1	35.5 ± 2.2^d	35.9 ± 2.7^d	36.0 ± 2.8^d	36.0 ± 2.7^d
Amilorid	40.9 ± 2.9	35.5 ± 2.3^d	36.4 ± 2.6^d	36.4 ± 2.7^d	36.3 ± 2.5^d
Placebo	39.0 ± 2.4	34.5 ± 2.0^d	35.1 ± 2.2^d	35.1 ± 2.3^d	35.3 ± 2.4^d
P_{GLM between subjects} 0.203

Plasma concentrations of sodium (p-Na), potassium (p-K) and albumin (p-Alb) and plasma osmolality (p-osm). Values are mean ± SD. General linear model (GLM) with repeated measures was performed for comparison within the group and intervention as between subjects factor. One-way ANOVA was performed when differences were found between interventions. Bonferroni correction was used for multiple comparisons between study-periods vs baseline.

^aP < 0.05;

^bP < 0.01;

^dP < 0.001.

Table 5 Effect of 3% hypertonic saline on brachial blood pressure, central blood pressure and pulse wave velocity in 23 healthy subjects treated with bendroflumethiazide or amiloride

Periods	Baseline	Infusion	Post infusion			P_{GLM RM}
	0-90 min	150 min	180 min	210 min	240 min
bSBP
BFTZ	112 ± 9	118 ± 9^d	116 ± 10	116 ± 11	117 ± 13	0.825
Amilorid	110 ± 8	115 ± 9^d	114 ± 10^d	114 ± 10^b	114 ± 10^b
Placebo	113 ± 10	117 ± 10^d	115 ± 9	115 ± 8	115 ± 10
P_{GLM between subjects}			0.679
bDBP
BFTZ	66 ± 7	63 ± 7^b	62 ± 6^d	62 ± 7^d	62 ± 7^b	0.055
Amilorid	64 ± 4	62 ± 5	60 ± 5^b	61 ± 5	62 ± 6
Placebo	64 ± 6	63 ± 5	63 ± 5	62 ± 6	63 ± 6
P_{GLM between subjects}			0.695
Pulse Rate
BFTZ	58 ± 10	61 ± 11^a	61 ± 11^b	62 ± 10^b	62 ± 10^b	0.782
Amilorid	57 ± 10	61 ± 11^d	60 ± 10^d	61 ± 11^d	61 ± 11^d
Placebo	55 ± 10	59 ± 12^a	59 ± 12^b	59 ± 12^b	59 ± 13^a
P_{GLM between subjects}			0.712
cSBP
BFTZ	99 ± 7	98 ± 7				NS
Amilorid	96 ± 5	97 ± 7				NS
Placebo	98 ± 6	98 ± 8				NS
P_ANOVA	NS	NS
cDBP
BFTZ	67 ± 5	63 ± 6				< 0.001
Amilorid	65 ± 5	65 ± 6				NS
Placebo	65 ± 5	64 ± 5				NS
P_ANOVA	NS	NS
PWV
BFTZ	5.5 ± 0.6	5.3 ± 0.4				0.055
Amilorid	5.3 ± 0.5	5.3 ± 0.5				NS
Placebo	5.3 ± 0.7	5.3 ± 0.6				NS
P_ANOVA	NS	NS
AI
BFTZ	-2.2 ± 14.6	-5.9 ±17.7				NS
Amilorid	0.4 ± 12.5	-1.4 ± 13.4				NS
Placebo	-1.6 ± 14.6	-4.9 ± 18.6				0.034
P_ANOVA	NS	NS

Values are mean ± SD. General linear model (GLM) with repeated measures was performed for comparison within the group and intervention as between subjects factor for brachial systolic (bSBP), brachial diastolic blood pressure (bDBP) and pulse rate. Bonferroni correction was used for multiple comparisons between study-periods vs baseline.

^aP < 0.05;

^bP < 0.001;

^dP < 0.001; Paired t-test was used for comparison between post infusion vs baseline for central systolic (cSBP), central diastolic (cDBP), pulse wave velocity (PWV) and augmentation index (AIx).

Citation: Jensen JM, Mose FH, Kulik AEO, Bech JN, Fenton RA, Pedersen EB. Changes in urinary excretion of water and sodium transporters during amiloride and bendroflumethiazide treatment. World J Nephrol 2015; 4(3): 423-437
URL: https://www.wjgnet.com/2220-6124/full/v4/i3/423.htm
DOI: https://dx.doi.org/10.5527/wjn.v4.i3.423