This is a research study of a new experimental drug called darusentan. Darusentan is not currently approved by the U.S. Food and Drug Administration (FDA) for use in the United States, which means that a doctor cannot prescribe this drug. The purpose of this study is to determine if darusentan is effective in reducing systolic blood pressure in subjects with resistant systolic hypertension, despite treatment with full doses of three or more antihypertensive drugs, including a diuretic.

Inclusion Criteria:

• Subjects who are competent to provide written consent
• Aged 35 to 80 years
• Subjects with diabetes and/or chronic kidney disease must have a mean systolic blood pressure ≥130 mmHg
• All other subjects must have a mean systolic blood pressure ≥140 mmHg
• Receiving and adhering to full doses of appropriate guideline-recommended antihypertensive drugs from three different classes of antihypertensive agents, including a diuretic
• Female subjects of non-childbearing potential (i.e., post-menopausal for at lest 2 years; surgically sterile)

Exclusion Criteria:

• Average sitting systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg
• Serum ALT or AST >2 x the upper limit of the normal range (ULN)
• Subjects who have experienced myocardial infarction, unstable angina pectoris, or a cerebrovascular accident (CVA) within 6 month; or sick sinus syndrome or second or third degree atrioventricular block, atrial fibrillation or recurrent atrial tachyarrhythmia, recurrent ventricular tachycardia, or symptomatic bradycardia
• Implanted pacemakers or implanted cardioverter defibrillator (ICD)
• Symptomatic congestive heart failure requiring treatment
• Hemodynamically significant valvular heart disease
• Type I diabetes mellitus
• Hemodialysis or peritoneal dialysis; or history of renal transplant
• Diagnosis or recurrence of malignancy within the past 3 years
• Sleep apnea, unless a recent sleep study demonstrates arterial oxygen saturation greater than or equal to 90%
• Subjects who perform alternating shift or night work
• Subjects who have participated in a clinical study involving another investigational drug or device within 4 weeks prior to Screening