Several investigations have shown heterogeneity in the functional responses to angiotensin II (Ang II) in patients with essential hypertension. The present study was initiated to evaluate whether the A(1166)C polymorphism of the Ang II type 1 receptor (AT(1)R) gene contributes to this variability in Ang II responses. After 7 days of a high-sodium diet (220 mmol Na(+) per day), we measured in 42 essential hypertensive patients blood pressure, heart rate, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), active plasma renin concentration, aldosterone, and atrial natriuretic peptide (ANP) before and during Ang II infusion (increasing doses of 0.3, 1.0, and 3.0 ng/kg per minute). Calculated variables were filtration fraction and renal vascular resistance (RVR). Patients in the 3 genotype groups (AA: n=14; AC: n=17; CC: n=11) were matched for gender, age, and body mass index. At baseline, CC patients had decreased GFR (P:=0.06) and aldosterone (P:<0.05) and increased ANP (P:<0.05) compared with AA patients. Moreover, responses of ERPF, GFR, and RVR to the lowest concentration of Ang II (0.3 ng/kg per minute) were more pronounced in CC patients than in AA patients (ERPF/GFR: P:<0.05; RVR: P:=0.07), whereas maximal responses were all comparable between the groups. Heart rate was decreased at all levels of Ang II infusion in CC patients, while it did not change in AA or AC patients. There were no differences in responses of active plasma renin concentration, aldosterone, and ANP to Ang II between the 3 groups. From these data, we conclude that the C allele of the AT(1)R A(1166)C polymorphism is associated with increased sensitivity but not reactivity to Ang II. An augmented response to Ang II may well be responsible for the increased incidence of cardiovascular abnormalities found in patients with 1 or 2 C alleles.