Pharmacodynamic activity of intravenous E-3174, an angiotensin II antagonist, in patients with essential hypertension.
Losartan potassium (DuP 753), an orally active angiotensin II receptor antagonist, is metabolized to a more potent active metabolite, E-3174, which contributes to losartan's long duration of action. The acute pharmacodynamic actions of intravenous (i.v.) E-3174 (20 mg infused over 4 h) were compared to placebo (vehicle) in two groups of patients with essential hypertension. Patients with supine diastolic blood pressure (SuDBP) of 100 to 120 mm Hg entered a 2-day inpatient phase and received vehicle on day 1. Patients with SuDBP > or = 95 mm Hg were randomized to double-blind treatment the next day. E-3174 significantly (P < .05) reduced SuDBP compared to placebo, beginning at approximately 100 min after the start of the infusion, with a maximum hypotensive effect at 8 h. Supine systolic blood pressure was also reduced by E-3174. Supine and standing heart rates did not differ between treatments. Mean E-3174 plasma levels were 324.6 ng/mL at 20 min and approximately 1000 ng/mL at the end of the 4-h infusion; during this time there was a modest decrease in blood pressure. Following the infusion, the relationship between plasma E-3174 levels and SuDBP was confounded by much larger decreases in blood pressure, which occurred as plasma drug concentrations declined. Urinary excretions of sodium, potassium, or chloride were not significantly altered by E-3174 nor was the fractional excretion of uric acid significantly different between groups. There were no drug-related or serious adverse experiences and no patient discontinued treatment due to an adverse experience.(ABSTRACT TRUNCATED AT 250 WORDS)
Sweet
C S
CS
Department of Clinical Cardiovascular Research, Merck Research Laboratories, West Point, Pennsylvania 19486.
Bradstreet
D C
DC
Berman
R S
RS
Jallard
N
N
Saenz
A
A
Weidler
D J
DJ
D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007275:Injections, Intravenous; D007677:Kidney Function Tests; D019808:Losartan; D008297:Male; D008875:Middle Aged; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014527:Uric Acid / Q000097:blood
D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D014527:Uric Acid; D012083:Renin; C066026:losartan carboxylic acid; D019808:Losartan