The proposed research is a multicenter Phase II clinical trial of a new endothelin receptor antagonist (L-753,037), with a large ETz/ETb selectivity ratio). Its antihypertensive efficacy, as well as safety and tolerability, will be explored in Afreican American patients with essential hypertension. This project targets patients of African American background because the prevalence of salt-sensitivity of blood pressure is highest in this racial group (about 75%) and because there is evidence (in experimental animals and humans) that endothellin may be important in the regulation of vasoconstriction and blood pressure in salt-sensitive hypertension. The trial will be double blind, with two comparators, placebo, and the antigypertensive dihydropyridine amlodipine. Patients will be selected according to strict inclusion/exclusion criteria, including a narrow blood pressure window to be determined during an outpatient washout period (discontinuation of previous medications). The actual study will be carried out during an 8-day (9-night) admission to the GCRC. After two days on placebo, to establish a baseline and to exclude those patients that may fall below the blood pressure window as a response to hospitalization, the drugs will be administered as oral solutions for five days. The pharmacist will be the only member of the research team that will not be blind to the medication administered. Blood pressures will be recorded several times per day. Routine laboratory measurements will be carried out to assess safety of the compound. Measurements of vasoactive compounds and hormones will be also carried out, to unravel the mechanisms of blood pressure reduction, if any, by endothelin receptor blockade. Pulmonary function tests and blood gases will be measured because high doses of the compound have been found to have untoward effects on repiratory function of experimental animals. Once the period of administration of the drug is completed, the patients will be observed for an additional day at the GCRC, and later, on a follow-up outpatient visit.
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