We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.

A series of experiments (Falk, unpublished paper; Falk, in press) has shown that the depletion of extracellular fluid electrolyte by the method of transperitoneal dialysis not only increases water intake, but also produces a large increase in the consumption of hypertonic NaCl solution. The measure of NaCl appetite used was the total amount of solution drunk in a 13-hr, period following a 4-hr, rest period after dialysis. During such a session of voluntary repletion, the animal has a protracted opportunity to sample the test fluids available and to learn, on the basis of postingestional effects, to compensate the induced deficiency by adjusting intake. However, the increased acceptability of a highly hypertonic NaCl solution following dialysis may result from a more immediate adjustive mechanism, e.g., a centrally mediated change in hedonic tone (Young, 1952). In order to test this notion, the animal may be given a series of fluid preference tests of brief over-all duration wherein it ingests minimal amounts of test solution. When testing time is short and intake very small, factors attributable to the actual electrolyte repletion value of the test fluid can be eliminated. Therefore, evidence for increased NaCl acceptance obtained under these conditions would argue that at least some aspect of compensatory intake is based on an immediately altered behavioral response to the test fluids. METHOD SubjectsTwenty-three male albino rats (Charles River Breeding Laboratories) were used. They were 90 to 100 clays old and obtained in three groups as they were needed. The weights of the first and third groups were between 300 and 400 gm., while the weights of the second group lay between 500 and 550 gm. They were caged in a constantly illuminated, temperaturecontrolled room.

This multicenter, dose-ranging study evaluated the antihypertensive effectiveness of once-daily administration of fosinopril sodium in 220 patients with supine diastolic blood pressure of 95-115 mm Hg. After a 4-week placebo period, patients were randomly assigned to double-blind therapy with either placebo or 10, 40, or 80 mg fosinopril once daily for 4 weeks. If treatment goals were not met, chlorthalidone 25 mg/day was added for weeks 5 to 8. Thereafter, patients could enter the long-term, open-label phase and receive 10-80 mg/day fosinopril plus chlorthalidone, if needed. After 4 weeks of monotherapy, the average decreases in supine diastolic blood pressure were 9% (10 mg), 11.5% (40 mg), and 12.5% (80 mg) compared with 6% in the placebo group. After 8 weeks, the average decreases, with or without diuretic therapy, were 12.5-18.2%, compared with 10.8% with placebo. Blood pressure continued to be well controlled, and the patients showed no evidence of tachyphylaxis or tolerance through 12-15 months of treatment Fosinopril was well tolerated. During the short-term phase, no patient withdrew because of adverse events possibly related to fosinopril; during the long-term phase, nine of 148 patients (6.1%) withdrew for that reason. In patients with mild-to-moderate hypertension, once-daily fosinopril (40 and 80 mg) provided significant antihypertensive effects with or without diuretic therapy. The 10 mg dose was effective in some patients and may be considered a starting dose. (Hypertension 1991;17:636-642)

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