Treatment with darusentan over 21 days improved cGMP generation in patients with chronic heart failure.
In heart failure, the cGMP to natriuretic peptide ratio is decreased and infusion of atrial natriuretic peptide (ANP) induces less cGMP generation. The ratio of the second messenger cGMP to plasma concentrations of ANP or brain natriuretic peptide (BNP) correlates with the effectiveness of natriuretic peptides. It was investigated whether blockade of the ET(A) receptor might improve the cGMP:NP ratio in heart failure. Patients with chronic heart failure (n=142; mean age=57 years) received oral treatment with the ET(A) antagonist darusentan (either 30, 100, 300 mg/day or placebo) on top of standard therapy over a period of 21 days in a randomized, double-blind, placebo-controlled, multicentre study. Plasma concentrations of ANP, BNP and cGMP were determined before randomization and after 21 days of treatment. In parallel with decreased pulmonary and systemic vascular resistance, 3 weeks of oral treatment with the ET(A) receptor antagonist darusentan reduced BNP plasma levels and increased the cGMP:BNP ratio significantly. The improved cGMP:BNP ratio might reflect the ability of chronic ET(A) receptor blockade to facilitate the generation of the second messenger cGMP, which points towards a favourable modulation of the natriuretic peptide effector system, in addition to haemodynamic improvement in heart failure patients.
Philipp
Sebastian
S
Franz-Volhard-Klinik, Charite Campus Berlin-Buch, Helios Klinikum Berlin, Humboldt University, Wiltbergstrasse 50, 13125 Berlin, Germany.
Monti
Jan
J
Pagel
Ines
I
Langenickel
Thomas
T
Notter
Thomas
T
Ruschitzka
Frank
F
Lüscher
Thomas
T
Dietz
Rainer
R
Willenbrock
Roland
R
D009320:Atrial Natriuretic Factor / Q000032:analysis; D002302:Cardiac Output; D006152:Cyclic GMP / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D014665:Vasodilator Agents / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D014665:Vasodilator Agents; D020097:Natriuretic Peptide, Brain; C107831:darusentan; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP