Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with heart failure.
BACKGROUND
Losartan is a specific angiotensin II receptor antagonist with no agonist properties. This agent permits evaluation of the response to selective angiotensin II antagonism in patients with congestive heart failure.


OBJECTIVE
A study was designed to assess the acute hemodynamic and neurohumoral response to losartan in a controlled, blinded fashion.


METHODS
Sixty-six patients in New York Heart Association functional class II, III or IV with a radionuclide ejection fraction of < 40% were randomly allocated to treatment with placebo and then sequentially to 5, 10, 25, 75 and 150 mg losartan. Hemodynamic and neurohumoral measurements were obtained at selected times for 24 h following ingestion of a single dose of losartan.


RESULTS
Treatment with losartan led to dose-dependent vasodilation. Mean arterial pressure and systemic vascular resistance decreased progressively up to a dose of 25 mg. The higher doses of 75 and 150 mg did not produce additional vasodilation. Similarly, the decrease in pulmonary capillary wedge pressure was 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 accompanied by marked neurohumoral changes. Large dose-related increases in plasma renin activity and angiotensin II levels were observed, especially following the 150-mg dose. Moderate reductions occurred in serum aldosterone 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 selective blockade of the angiotensin II receptor with losartan causes a favorable vasodilatory and neurohumoral response in patients with heart failure. Further studies are needed to determine the most effective dose in these patients. Nevertheless, losartan should be of substantial clinical use in the management of this large population.
Dickstein
K
K
Cardiology Division, Central Hospital in Rogaland, Stavanger, Norway.
Gottlieb
S
S
Fleck
E
E
Kostis
J
J
Levine
B
B
DeKock
M
M
LeJemtel
T
T
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D019808:Losartan; D018377:Neurotransmitter Agents / Q000097:blood*; D013777:Tetrazoles / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D018377:Neurotransmitter Agents; D013777:Tetrazoles; D019808:Losartan