Hydrochlorothiazide efficacy and polymorphisms in ACE, ADD1 and GNB3 in healthy, male volunteers.
OBJECTIVE
The antihypertensive effect of thiazide diuretics has recently been associated with genetic variation in the angiotensin I-converting enzyme (ACE), alpha-adducin (ADD1) and the G protein subunit beta3 (GNB3). Analysis of short-term diuretic effects may provide insight into the mechanisms behind these findings.


METHODS
A total of 103 male volunteers took 25 and 100 mg hydrochlorothiazide (HCT) after a placebo day, each. We measured volume, sodium, chloride, potassium, calcium excretion, blood pressure and heart rate.


RESULTS
Excretion and cardiovascular parameters were highly constant between the 2 placebo days. The resting heart rate was 2-3 beats/minute (bpm) higher per ACE insertion allele on all 4 study days. The HCT-induced excretion of sodium, chloride and volume was independent of the genotypes. The additional potassium excretion induced by 100 mg HCT was 44+/-21, 33+/-27 and 16+/-26 mmol (mean+/-SD, p<0.001) in ACE II, ID and DD carriers and the same trend was observed after 25 mg HCT. As a second finding, the 100 mg HCT-induced calcium retention was 0.2+/-1.2, 0.7+/-0.8 and 1.7+/-2.1 mmol in ADD1 Gly/Gly, Gly/Trp and Trp/Trp carriers (p=0.002) and the same trend existed after 25 mg HCT.


CONCLUSIONS
The effects of genetic polymorphisms were stronger with the higher diuretic dose. ACE insertion allele carriers appeared to be more prone to hypokalaemia than deletion allele carriers. ADD1 Trp460 carriers may especially benefit from the calcium-sparing effect of thiazides. Both associations should be further studied in long-term treatment with thiazide diuretics.
Vormfelde
Stefan Viktor
SV
Department of Clinical Pharmacology University Medical Center, Georg-August-University, Robert-Koch-Str. 40, 37075 Göttingen, Germany. svormfe@gwdg.de
Sehrt
Daniel
D
Bolte
Daniela
D
Pahl
Susanne
S
Tzvetkov
Mladen
M
Brockmöller
Jürgen
J
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000652:urine; D002118:Calcium / Q000652:urine; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002712:Chlorides / Q000652:urine; D004232:Diuretics / Q000494:pharmacology / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology* / Q000652:urine; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011188:Potassium / Q000652:urine; D016037:Single-Blind Method; D012964:Sodium / Q000652:urine; D000099291:Adducins
D000959:Antihypertensive Agents; D002118:Calcium; D002148:Calmodulin-Binding Proteins; D002712:Chlorides; D004232:Diuretics; D020962:Heterotrimeric GTP-Binding Proteins; D006852:Hydrochlorothiazide; D007703:Peptidyl-Dipeptidase A; D011188:Potassium; D012964:Sodium; D000099291:Adducins; C454420:G-protein beta3 subunit