Uncontrolled blood pressure represents the main factor in the development of target organ lesions and, consequently, cardiovascular events, which are the leading cause of morbidity and mortality worldwide. In most cases resistant hypertension is preceded by target organ lesions, and is strongly influenced by risk factors or associated diseases. To control this disease requires an adequate and intense therapeutic approach that includes lifestyle changes and the use of several antihypertensive drugs. However, the results are not always satisfactory despite intensive treatment. Of the different pathophysiological mechanisms involved in the pathogenesis of resistant hypertension (RH), two, sympathetic overstimulation and therapies that block the sympathetic system, have been widely studied. But, these approaches are invasive and expensive. Another possible approach is by transcutaneous electrical nerve stimulation (TENS), a non-invasive method that modulates activity by inhibiting primary afferent pathways using low-frequency transcutaneous electrical stimulation. Some studies have shown that TENS reduces blood pressure in patients with hypertension. The current study will evaluate the effect of applying TENS in the cervicothoracic region of subjects with resistant hypertension, seeking to develop a new low cost and readily available therapy to treat this group of hypertensive individuals.

Patients will be divided into two groups: treatment and control (sham group). The sham group will be submitted to the procedure to fit the stimulation equipment. However, these patients will not be submitted to stimulation. Both groups will undergo a physical examination at the start and end of the study period to determine anthropometric variables. The BMI, defined as the weight (kg) divided by the patient's height squared (m2), will be calculated. The height will be determined in centimeters using a measuring tape with the individual barefoot. Individuals with BMI <25 kg/m² will be classified as normal, overweight as a BMI between 25 and 30 kg/m², and obese as a BMI ≥30 kg/m². The waist circumference will be measured using a measuring tape at half the distance between the iliac crest and the lower costal margin. Patients will undergo the following tests before and after the end of the four-week study period: 24-hour ambulatory blood pressure monitoring (ABPM), 24-hour dynamic electrocardiography, continuous measurement of beat-to-beat BP, endothelial function measurement and radial artery applanation tonometry (AT).

Biochemical tests will be performed at two time points, before and after the four-week study period and include blood sugar, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), creatinine, potassium, uric acid, and plasma insulin levels. Blood sugar, TC, HDL-C and TG levels will be determined by colorimetry after fasting for 12 hours using a dimension device with the Dade Behring reagent. Diagnosis of diabetes mellitus (DM) will be established by patient history, the use of hypoglycemic drugs and measurement of the serum glucose. The LDL-C fraction will be calculated using the formula LDL-C = TC - HDL-C - TG / 5 (for TG <400 mg/dL). Additionally, the electrochemiluminescence method will be used to measure plasma insulin (immunoassay for the in vitro quantitative determination of human insulin in serum and plasma using the Elecsys 1010/2010 immunoassay and E170 modular analytics analyzers by Roche). The homeostasis model assessment of insulin resistance (HOMA-IR) index will be applied after obtaining blood sugar and insulin levels in order to determine insulin resistance and the functional capability of the pancreatic beta cells. Insulin resistance will be characterized when this ratio exceeds 2.71. The HOMA-IR index is calculated using the following formula:

HOMA-IR: Fasting insulin (McU/mL) x fasting glucose (mmol/L*) 22.5

In order to convert the glucose concentration to mmol/L it is necessary to multiply the value in mg/dL by 0.0555. Measurement of serum creatinine will be performed by a standardized enzyme-kinetic biochemical test and will be considered high when serum creatinine >1.4 mg/dL. Urinary sodium and potassium levels (mEq/L) will be evaluated by flame photometry. Urinary sodium excretion will be calculated by multiplying the urinary sodium and potassium concentrations in mEq/L by the 24-hour urine volume. The 24-hour urine volume and urinary creatinine concentrations will be assessed to calculate creatinine clearance adjusted for body surface.

Specific biochemical tests will be considered: serum aldosterone (AS), plasma renin activity (PRA), high-sensitivity C-reactive protein (hsCRP), metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2), nitrites and nitrates, interleukin-1, 6, 8, 10 and 18 (IL-1, IL-6, IL-8, IL-10 and IL-18), tumor necrosis factor (TNF-α), thromboxane B2 (TXB2), fibrinogen, intercellular adhesion molecule (ICAM-1), plasminogen activator inhibitor (PAI-1), angiotensin converting enzyme (ACE) and angiotensin II (Ang II).

Inclusion Criteria:

• RH patients taking at least three antihypertensive drugs at full doses, one of which is preferably a thiazide diuretic; Age between 40 and 70 years.

Exclusion Criteria:

• Use of a cardiac pacemaker
• Cardiac electrical conduction abnormalities evidenced by ECG or stress test (ergometry)
• Dermatological abnormalities at the site of the application of TENS
• Uncontrolled diabetes patients using oral hypoglycemic agents or insulin with glycated Hb ≥ 7.5%
• Secondary Hypertension
• Patients who do not adhere to the lifestyle changes recommended by their physician such as low-sodium diet and weight loss
• Moderate to severe cervical-thoracic scoliosis
• Obesity with body mass index (BMI) ≥35 kg/m2