169 ISSN 1462-2416 10.2217/PGS.13.202 © 2014 Future Medicine Ltd Pharmacogenomics (2014) 15(2), 169–178 ReseaRch aRticle Different phenotypes of the NAT2 gene infuences hydralazine antihypertensive response in patients with resistant hypertension Hypertension is the leading attributable cause of death worldwide. It is a signi fcant costly and escalating global healthcare problem affecting approximately 1.2 million people, and is associated with an increased risk of myocardial infarction, stroke, heart failure, kidney disease and death. It is a multifacto- rial disorder infuenced by several genetic and epigenetic factors. Different studies have been performed with candidate genes. In particular, polymorphisms of the angiotensinogen gene (M235T), and insertion/deletion of angioten- sin-1, were associated with essential arterial hypertension in a Slovene population. Addi- tionally, an association between the -262C/T polymorphism in the catalase gene promoter and the C242T polymorphism of the NADPH oxidase P22phox gene and essential arterial hypertension in patients with diabetes mellitus Type 2 has also been reported, indicating the possible implication of the oxidative stress gene NADPH oxidase in the pathogenesis of arterial hypertension in these patients [1,2]. Approxi- mately 5–15% of all patients with high blood pressure (BP) have resistant hypertension (RH) [3–5]. RH is defned as failure to achieve BP targets (i.e., BP <140/90 mmHg in general; and <130/80 mmHg in patients with diabetes mellitus or chronic renal disease) despite the concurrent use of three or more antihyper- tensive drugs of different classes, including a diuretic, at their optimal doses [3,6]. Cases of pseudoresistance, which may result from poor compliance with treatment, inadequate antihy- pertensive medication, incorrect BP measure- ment or the white-coat effect, must be iden- tifed. Exaggerated white-coat effect (called white-coat RH) is present when the patient’s BP is <140/90 mmHg at the doctor’s of fce or hospital and <135/85 mmHg when measured out of of fce, preferentially by ambulatory BP monitoring [3,6]. The objective of treating high BP is the pre- vention of hypertensive end-organ damage and reduction of cardiovascular morbidity and mor - tality. Control of ambulatory BP is the most important factor in improving cardiovascular prognosis in RH [7]. Its pharmacological treat- ment usually consists of the use of at least three antihypertensive drugs including a diuretic. Several drugs are commonly used as frst-line combinations in RH treatment, including diuretics, b-blockers, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonists, and calcium channel blockers. As an add-on fourth antihypertensive drug, spironolactone, an aldosterone antagonist diuretic, is often recommended [8]. Aim: Hydralazine, a vasodilator used in resistant hypertension (RH) treatment is metabolized by an acetylation reaction mediated by N-acetyltransferase 2, the activity of which depends on NAT2 polymorphisms. Our aim was to evaluate whether different acetylation phenotypes influenced the antihypertensive effect of hydralazine in patients with RH. Patients & methods: DNA samples from 169 RH patients using hydralazine were genotyped by sequencing the NAT2 coding region, and acetylation phenotypes were defined. Results: Sixty-five patients (38.5%) were intermediate, 60 (35.5%) slow and 21 (12.4%) fast acetylators. Twenty-three (13.6%) patients were indeterminate. Upon association analysis, only slow acetylators had significant blood pressure reductions after hydralazine use, with mean 24-h systolic and diastolic blood pressure reductions of 9.2 and 5.5 mmHg. Four patients presented hydralazine adverse effects resulting in drug withdrawal, three of them were slow acetylators. Conclusion: The slow acetylation phenotype, determined by polymorphisms within NAT2, influenced both the antihypertensive and adverse effects of hydralazine in RH. Original submitted 31 May 2013; Revision submitted 7 October 2013 KEYWORDS: Brazilian population n hydralazine n NAT2 polymorphism n resistant hypertension n SNP Lizania Borges Spinasse 1 , Adalberto Rezende Santos* 1 , Philip Noel Sufys 1 , Elizabeth Silaid Muxfeldt 2 & Gil Fernando Salles 2 1 Laboratory of Molecular Biology Applied to Mycobacteria – Oswaldo Cruz Insttute – Fiocruz, Av. Brazil 4365, CEP: 21040–360, Manguinhos, Rio de Janeiro, Brazil 2 Department of Internal Medicine, University Hospital Clementno Fraga Filho, School of Medicine, Universidade Federal do Rio de Janeiro, Brazil *Author for correspondence: Tel.: +55 21 2562 1564 Fax: +55 21 2562 1531 adalbertorezende@yahoo.com.br part of For reprint orders, please contact: reprints@futuremedicine.com