Genetic variants of alpha adducin (ADD1) taken alone or in interaction with those of beta (ADD2) and gamma (ADD3) subunits have been associated with primary hypertension in humans and in Milan hypertensive (MHS) rats. In this study, we report the dissection of the individual contribution of each rat Add gene to blood pressure, by congenic substitution mapping. Congenic strains were developed by introgressing Add1, Add2, and Add3 genes (and chr14, chr4, and chr1 associated segments) of MHS in the Milan normotensive rat (MNS) genetic background (MNS.H-Add1, MNS.H-Add2, and MNS.H-Add3) and vice versa (MHS.N-Add1, MHS.N-Add2, and MHS.N-Add3). Systolic blood pressure (SBP) of MNS.H-Add1 rats was significantly higher (+10mmHg) than that of MNS, whereas SBP of MHS.N-Add1 was significantly lower (-10mmHg) than that of MHS. The differences account for 43% of the blood pressure differences between MHS and MNS. In contrast, SBPs of Add2 and Add3 congenic strains were not different from those of the correspondent recipient parental strain. The fine mapping of chr14 congenic segment supports the identity of blood pressure QTL with Add1 gene. (C) 2004 Elsevier Inc. All rights reserved.