Endothelin antagonism in patients with resistant hypertension and hypertension nephropathy

Resistant hypertension is a failure to achieve a blood pressure (BP) goal of < 140/90 mm Hg despite treatment with at least three different antihypertensive medications classes at a maximally tolerated dose and including a diuretic. The most important systems that require alteration include the renin-angiotensin-aldosterone system, sympathetic nervous system, and (more recently) the endothelin (ET) system. To date, several clinical trials have assessed the effects of ET antagonism, both selective and nonselective, on BP control in humans. The nonselective ET antagonist bosentan was evaluated in patients with mild-to-moderate hypertension. Bosentan was able to lower diastolic BP when compared to placebo and, similarly, to enalapril. Similar findings have been published for darusentan, an ET receptor antagonist with higher affinity for the type A receptor. More recent research has focused on the impact of ET in the setting of resistant hypertension. Studies with darusentan as an add-on therapy in patients with resistant hypertension found a significant BP-lowering effect of 17/10 mm Hg compared to placebo. This BP-lowering effect was similar at higher doses. In a similar patient cohort, darusentan also lowered mean 24-hour BP to a greater extent than the central α₂-agonist guanfacine. Another selective ET(A) antagonist, atrasentan, provided other benefits on metabolism in addition to its antihypertensive effect. Atrasentan significantly decreased glucose in diabetes and improved lipid profiles while slowing coronary artery disease progression. Selective ET receptor blockade also has dose-dependent side effects. In a large number of trials, almost one third of the patients suffered excessive fluid retention and edema that was significantly higher than in the placebo groups. One trial, ASCEND, was terminated early due to an increased incidence of fluid retention and increased episodes of heart failure. Thus, this class of agents is effective in resistant hypertension, but lower doses with fewer side effects need to be developed.