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Treatment with darusentan over 21 days improved cGMP generation in patients with chronic heart failure
Sebastian Philipp1, Jan Monti, Ines Pagel
1Franz-Volhard-Klinik, Charite Campus Berlin-Buch, Helios Klinikum Berlin, Humboldt University, Wiltbergstrasse 50, 13125 Berlin, Germany.
Insights
ET(A) receptor antagonist darusentan improved the cyclic guanosine monophosphate (cGMP) to brain natriuretic peptide (BNP) ratio in heart failure patients. This suggests darusentan favorably modulates the natriuretic peptide system and improves hemodynamics.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Heart failure is associated with a decreased cyclic guanosine monophosphate (cGMP) to natriuretic peptide (NP) ratio.
- Natriuretic peptides (NPs) and their second messenger cGMP play crucial roles in cardiovascular homeostasis.
- The cGMP:NP ratio is a biomarker for natriuretic peptide system effectiveness.
Purpose of the Study:
- To investigate the effect of ET(A) receptor blockade on the cGMP:NP ratio in patients with chronic heart failure.
- To assess whether the ET(A) antagonist darusentan can improve the natriuretic peptide effector system.
Main Methods:
- A randomized, double-blind, placebo-controlled, multicentre study involving 142 heart failure patients.
- Patients received oral darusentan (30, 100, or 300 mg/day) or placebo for 21 days, alongside standard therapy.
- Plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and cGMP were measured before and after treatment.
Main Results:
- Darusentan treatment significantly reduced plasma BNP levels.
- A significant increase in the cGMP:BNP ratio was observed following 3 weeks of darusentan administration.
- These changes occurred in parallel with reductions in pulmonary and systemic vascular resistance.
Conclusions:
- Chronic ET(A) receptor blockade with darusentan improves the cGMP:BNP ratio in heart failure patients.
- This improvement suggests a favorable modulation of the natriuretic peptide effector system.
- Darusentan offers potential benefits beyond hemodynamic improvement in heart failure management.
Abstract:
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.