Efficacy and safety of darusentan: a novel endothelin receptor antagonist

Ann Pharmacother. 2008 Jul;42(7):1060-9. doi: 10.1345/aph.1L024. Epub 2008 Jun 3.


Objective: To summarize the role of the endothelin system (ETS) in cardiovascular disease (CVD) and evaluate the potential usefulness of darusentan, a selective endothelin type A (ET(A)) receptor antagonist, in the treatment of hypertension and chronic heart failure (CHF).

Data sources: A literature search was conducted in MEDLINE (1966-February 2008), International Pharmaceutical Abstracts (1970-February 2008), and EMBASE (1990-February 2008) using the search terms endothelin, darusentan, LU 135252, hypertension, and heart failure.

Study selection and data extraction: Studies evaluating the role of the ETS in CVD and the pharmacology, pharmacokinetics, safety, and efficacy of darusentan for the treatment of hypertension and CHF were included.

Data synthesis: Darusentan represents a novel treatment strategy for patients with resistant hypertension. Its safety and efficacy have been evaluated in the treatment of hypertension and CHF. Darusentan selectively blocks the ET(A) receptor, promoting vasodilatation and preventing several proliferative and inflammatory processes, while promoting the actions of the ET(B) receptor. Studies in patients with stage 2 or resistant hypertension concluded that darusentan safely and effectively lowers blood pressure. Darusentan's unique mechanism of action, dose-dependent blood pressure-lowering profile, once-daily dosing regimen, and sustained 24-hour blood pressure-lowering effect are valuable features. Darusentan is well tolerated, with only peripheral edema, headache, and nasal symptoms being reported more frequently than with placebo. Endothelin receptor antagonists, including darusentan, have been associated with a decrease in hemoglobin and hematocrit and are teratogens. Darusentan does not appear to cause hepatotoxicity. Additional studies in CHF are warranted to assess the safety and efficacy of darusentan, especially given its association with peripheral edema and decreased red blood cell count.

Conclusions: Given the important role of the ETS in hypertension and available data with darusentan, selective antagonism of the ET(A) receptor represents a promising approach to managing resistant hypertension. Darusentan's role will be more clearly elucidated by ongoing Phase 3 studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use*
  • Endothelin A Receptor Antagonists*
  • Heart Failure / drug therapy*
  • Humans
  • Hypertension / drug therapy*
  • Phenylpropionates / adverse effects
  • Phenylpropionates / pharmacokinetics
  • Phenylpropionates / pharmacology
  • Phenylpropionates / therapeutic use*
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Substrate Specificity


  • Antihypertensive Agents
  • Endothelin A Receptor Antagonists
  • Phenylpropionates
  • Pyrimidines
  • darusentan