The results of our three PATHWAY-2 mechanistic substudies show that the blood pressure response to spironolactone in resistant hypertension is predicted by ARR and by plasma renin alone, that the superior reduction of blood pressure achieved with spironolactone is associated with elimination of thoracic volume excess rather than vasodilatation, and that amiloride is similarly effective as spironolactone in reducing blood pressure in patients with resistant hypertension. This evidence concerns the gene REN and Hypertension resistant to conventional therapy.