In the scheme of things, treatment-resistant hypertension (failure to reach goal SBP with 3 or more drugs) is not as big a problem as untreated or undertreated hypertension. However, this is a therapeutic problem which is not uncommon and causes considerable consternation among both physicians and patients. This report by Weber et al provides some hope that a new vasodilatory selective endothelin type A antagonist (darusentan) may be effective in such patients. They studied 379 patients with treatment resistant-hypertension who continued their baseline therapy and were randomized to darusentan (in 3 different doses) or placebo over a 14 week period. There was a significantly lower systolic blood pressure (9/5 mm Hg) in the darusentan groups (combined) with a sustained 24 hour effect shown by ambulatory monitoring. A dose response effect was not observed in the drug range of 50-300 mg. The notable adverse effect reported was edema/fluid retention (27%) which occurred within the first 6 weeks of therapy and responded to increased intensity of diuretic therapy. In addition, there was a modest increase in serum creatinine accompanied by a small decrease in the GFR compared to placebo. Baseline albuminuria, however, was reduced in darusentan group by 60%. The effects of this investigational drug on renal function need to be more fully studied. With very small numbers, there was a slight trend to excess cardiac events requiring hospital admission (8/247 with darusentan vs 0/132 with placebo). This obviously bears watching. Also the potential tertatogenicity for this class of drugs has been previously been reported. This new class of drug appears to have some potential use in patients with resistant-hypertension but it appears that patients with a history of heart failure or severe LV dysfunction are not appropriate candidates. While we welcome this report, it is fair to say the jury is still out on this new agent. Jerome D. Cohen, M.D.