Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEi) is attributed partially to increased nitric oxide bioavailability. It is possible that functional polymorphisms in endothelial nitric oxide synthase (eNOS) and bradykinin receptor B2 (BDKRB2) genes may affect the antihypertensive response to enalapril. We evaluated 106 hypertensive patients treated only with enalapril for 60 days. The difference between the mean arterial pressure (MAP) before and after the antihypertensive treatment was defined as Delta MAP. If Delta MAP were below or above the median value, the patients were classified as poor responders (PR) or good responders (GR), respectively. eNOS genotypes for the T-786C, G894T and 4b/4a polymorphisms were determined and haplotype frequencies were estimated by PHASE and Haplo.stats programs. The C-58T and BE1 +9/-9 polymorphisms of BDKRB2 genes and their haplotypes were determined by DNA sequencing. Robust multifactor dimensionality reduction analysis was used to characterize gene-gene interactions. The TC/CC genotypes and the C allele for the eNOS T-786C polymorphism were more frequent in GR than in PR. Furthermore, the TT genotype for the BDKRB2 C-58T polymorphism was more frequent in PR than GR. No other significant differences in genotypes or haplotypes were found. However, we found significant gene-gene interactions: the CC genotype for the BDKRB2 C-58T polymorphism was associated with response to enalapril depending on eNOS T-786C genotypes. These findings suggest that eNOS T-786C and BDKRB2 C-58T polymorphisms may synergically affect the antihypertensive response to enalapril.692167177Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)