HEMODYNAMIC AND NEUROHUMORAL EFFECTS OF THE ANGIOTENSIN-II ANTAGONISTLOSARTAN IN PATIENTS WITH HEART-FAILURE

Background: Losartan is a specific angiotensin II receptor antagonist with no agonist properties. This agent permits evaluation of the respo nse to selective angiotensin II antagonism in patients with congestive heart failure. Objective: A study was designed to assess the acute he modynamic and neurohumoral response to losartan in a controlled, blind ed fashion. Design: Sixty-six patients in New York Heart Association f unctional class II, III or IV with a radionuclide ejection fraction of < 40% were randomly allocated to treatment with placebo and then sequ entially to 5, 10, 25, 75 and 150 mg losartan. Hemodynamic and neurohu moral measurements were obtained at selected times for 24 h following ingestion of a single dose of losartan. Results: Treatment with losart an led to dose-dependent vasodilation. Mean arterial pressure and syst emic vascular resistance decreased progressively up to a dose of 25 mg . The higher doses of 75 and 150 mg did not produce additional vasodil ation. Similarly, the decrease in pulmonary capillary wedge pressure w as not greater with doses exceeding 25 mg. The increase in the cardiac index was modest and similar for all doses. No variation in the heart rate was observed at any dose. The hemodynamic changes were accompani ed by marked neurohumoral changes. Large dose-related increases in pla sma renin activity and angiotensin II levels were observed, especially following the 150-mg dose. Moderate reductions occurred in serum aldo sterone and plasma noradrenaline. The peak effect for these parameters occurred 4-6 h after the dose, with persistent changes still evident 24 h after the dose. Conclusions: These data demonstrate that selectiv e blockade of the angiotensin II receptor with losartan causes a favor able vasodilatory and neurohumoral response in patients with heart fai lure. Further studies are needed to determine the most effective dose in these patients. Nevertheless, losartan should be of substantial cli nical use in the management of this large population.