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Renin–angiotensin–aldosterone system blockade is a cornerstone in cardiovascular protection. Angiotensin-converting enzyme (ACE)-DD genotype has been associated with resistance to angiotensin-converting enzyme inhibition (ACEi), but data are conflicting. As sodium intake modifies the effect of ACEi as well as the genotype–phenotype relationship, we hypothesize gene–environment interaction between sodium-status, the response to ACEi, and ACE genotype.Thirty-five male volunteers (26 ± 9 years; II n = 6, ID n = 18, DD n = 11) were studied during placebo and ACEi (double blind, enalapril 20 mg/day) on low [7 days 50 mmol Na+/day (low salt)] and high [7 days 200 mmol Na+/day (high salt)] sodium, with a washout of 6 weeks in-between. After each period mean arterial pressure (MAP) was measured before and during graded infusion of angiotensin II (Ang II).During high salt, ACEi reduced MAP in II and ID, but not in DD [II: 88 (78–94) versus 76 (72–88); ID: 87 (84–91) versus 83 (79–87); both P < 0.05 and DD: 86 (82–96) versus 88 (80–90); ns, P < 0.05 between genotypes]. However, during low salt, ACEi reduced MAP in all genotype groups [II: 83 (78–89) versus 77 (72–83); ID: 88 (84–91) versus 82 (78–86); DD: 84 (80–91) versus 81 (75–85); all P < 0.05]. During high salt + ACEi, the Ang II response was blunted in DD, with an 18% rise in MAP during the highest dose versus 22 and 31% in ID and II (P < 0.05). Low salt annihilated these differences.In healthy participants, the MAP response to ACEi is selectively blunted in DD genotype during high salt, accompanied by blunted sensitivity to Ang II. Low salt corrects both abnormalities. Further analysis of this gene–environment interaction in patients may contribute to strategies for improvement of individual treatment efficacy.