Angiotensin II type 1 receptor gene polymorphism predicts response to losartan and angiotensin II

Background. Most of the known actions of angiotensin II (Ang II) are mediated by the Ang II type 1 receptor (AGT(1)R). A noncoding polymorphism of the AGT(1)R gene has been described in which there is either an adenine (A) or cytosine (C) base at position 1166, The functional significance of this polymorphism is unknown, prompting us to examine the relationship between this polymorphism and the systemic and renal responses to AGT(1)R blockade and subpressor Ang II infusion. Methods. Sixty-six healthy Caucasian men and women, genotyped for the AGT(1)R polymorphism by polymerase chain reaction, were chosen to form two homogeneous groups: AA and AC/CC. Renal hemodynamic function was assessed with inulin and para-aminohippurate clearance before and after AGT(1)R receptor blockade with losartan and Ang II infusion. Results. The mean values at baseline for glomerular filtration rate (GFR), renal plasma flow (ERPF), and renal blood flow (RBF) were significantly lower in the AC/CC group compared with the AA group. Losartan increased the GFR and decreased the mean arterial pressure (MAP) in the AC/CC group, but did not influence these parameters in the AA group. The aldosterone responses to losartan were blunted in the AA subgroup. During Ang TT infusion, AC/CC subjects maintained GFR despite equivalent declines in RBF, suggesting an enhanced efferent arteriolar constrictive response. Conclusions. Taken together, these results suggest that there is a relationship between the AGT(1)R A(1166)-->C polymorphism and the humoral and renal hemodynamic responses to AGT(1)R blockade and to Ang II infusion in the sodium-replete state, and that the C allele is associated with enhanced intrarenal and peripheral Ang II activity. Further studies are required to determine the genetic locus for this effect.