The management of patients with resistant arterial hypertension, who are characterized by a very high cardiovascular risk, remains a major therapeutic issue. The use of endothelin-1 (ET-1) receptor antagonists, in addition to lowering blood pressure, may also improve endothelial function in these patients. The objective of this study is to assess the vascular impact of an ET-1 receptor antagonist on vascular function and systemic and central hemodynamics in patients with resistant arterial hypertension and ensure their good renal tolerance.

Inclusion Criteria:

• age between 30 and 80 years old
• Patients with resistant hypertension defined according to the criteria recognized by the French Society of Hypertension (SFHTA): arterial pressure greater than or equal to 140 and / 90 mm Hg under triple antihypertensive therapy at optimal dose comprising at least one diuretic pendant at less than 4 weeks.
• Patients with resistant hypertension confirmed by self-measurement (≥135 / 85 mmHg on average) or by ambulatory blood pressure measurement (mean of 24h ≥130 / 80 mmHg).
• Hemoglobin level ≥ 12 g / dL
• For women of childbearing potential, reliable methods of contraception (as defined by the WHO-Pearl Index) should be used (hormonal contraception should not be the only contraceptive method used during bosentan treatment).
• For postmenopausal women: confirmatory diagnosis (non-medically induced amenorrhea for at least 12 months and age greater than 45, before the inclusion visit)
• Patient who read and understood the newsletter and signed the consent form
• Patient affiliated to a social security scheme

Exclusion Criteria:

• Patients with hypertension
• Patients with secondary arterial hypertension other than sleep apnea syndrome or chronic renal failure stage 2 or 3.
• Patients with hypertension greater than or equal to 180 and / or 110mmHg
• Chronic renal failure stage 4 and 5 (defined by DFG CKD-EPI <30 ml / min / 1,73m²)
• Renal transplant patient XML File Identifier: CEyMau8sPo+QFyOLD1ZEY3ZGFow= Page 11/22
• Orthostatic hypotension (decreased SBP> 20mmHg and / or DBP> 10mmHg occurring within 3 minutes of standing).
• Contra-indication to NATISPRAY 0.30 mg / dose, oral spray solution (including nitrate hypersensitivity) in accordance with the NATISPRAY

SPC:

• shock, severe hypotension,

• in combination with sildenafil

• obstructive cardiomyopathy,

• inferior court inferior myocardial infarction with right ventricular extension, except in case of evidence of left ventricular failure,

• intracranial hypertension,

  • Contra-indication to BOSENTAN MYLAN 62.5 mg and 125 mg filmcoated tablets:

• Hypersensitivity to the active substance or to any of the excipients listed in the SPC Moderate to severe hepatic insufficiency corresponding to class B or C of the Child-Pugh classification

• Serum levels of liver aminotransferases, ASAT and / or ALAT> 3 times the upper limit of normal at start of treatment (results less than 3 months old).

• Association with ciclosporin A

  • Known allergy to cellulose
  • Patients treated with: tacrolimus or sirolimus, fluconazole or other CYP2C9 or CYP3A4 inhibitors, glibenclamide, rifampicin, antiretroviral drugs including lopinavir + ritonavir, warfarin, simvastatin, ketoconazole, epoprostenol, sildenafil and digoxin
  • Pregnant, breastfeeding woman, or woman of childbearing potential not using reliable methods of contraception (hormonal contraception should not be the only contraceptive method used during bosentan treatment) or no proven reliable effective contraception;
  • Person deprived of liberty by an administrative or judicial decision or person placed under the protection of justice, under tutorship or curatorship
  • Patient participating or having participated in the 4 weeks prior to inclusion in a clinical trial

Modification of the pharmaceutical form, removal from the primary packaging and repackaging-> tablet of Bosentan will be encapsuled. The pharmaceutical form of placebo and bosentant will be identical