Genetic contribution to the acute effects of angiotensin II type 1 receptor blockade.
OBJECTIVE
Clinical observations point towards heterogeneity in patients' responses to antihypertensive drugs. As our earlier work showed that angiotensin II (AngII) sensitivity is associated with the A1166C polymorphism of the AngII type 1 receptor (AT1R) gene, we conducted the present study in which the responses to acute AT1R blockade were evaluated.


METHODS
After 7 days of low and high sodium diet, the hormonal as well as systemic and renal hemodynamic responses to acute AT1R blockade with EXP3174 (active metabolite of losartan) were studied in 15 AA and 14 CC essential hypertensive patients. By means of platelet-binding studies the baseline AT1R density (Bmax) and affinity (KD) was tested.


RESULTS
During low and high salt diet, baseline Bmax and KD were comparable between both genotype groups. At baseline, during low salt diet, CC patients had significantly lower glomerular filtration rate and a trend towards lower effective renal plasma flow (ERPF) compared to AA patients. Blood pressure responses to EXP3174 during high salt were significantly blunted in CC patients compared to AA patients (mean arterial pressure: 1.8 versus 7.5%; P < 0.05). During low salt the increase in ERPF (12.9 versus 16.1%; P = 0.08), as well as the decrease in filtration fraction (9.0 versus 14.0%; P = 0.05) and renal vascular resistance (7.5 versus 15.1%; P = 0.06) were blunted in CC patients compared to AA patients. Humoral effects did not differ between the groups.


CONCLUSIONS
This study shows that the systemic and renal hemodynamic responses to acute AT1R blockade are, at least in part, genetically determined.
Spiering
Wilko
W
Department of Internal Medicine, University Hospital Maastricht and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
Kroon
Abraham A
AA
Fuss-Lejeune
Monique Jmj
MJ
de Leeuw
Peter W
PW
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D004039:Diet, Sodium-Restricted; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics*; D007093:Imidazoles / Q000008:administration & dosage*; D019808:Losartan; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013777:Tetrazoles / Q000008:administration & dosage*; D014655:Vascular Resistance / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; C066026:losartan carboxylic acid; D019808:Losartan