Short‐ and long‐term administration of the non‐steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome‐related cardio‐renal dysfunction

• Published in: Diabetes, obesity & metabolism Vol. 20; no. 10; pp. 2399 - 2407
• Main Authors: Lachaux, Marianne, Barrera‐Chimal, Jonatan, Nicol, Lionel, Rémy‐Jouet, Isabelle, Renet, Sylvanie, Dumesnil, Anais, Wecker, Didier, Richard, Vincent, Kolkhof, Peter, Jaisser, Frederic, Ouvrard‐Pascaud, Antoine, Mulder, Paul
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2018; Wiley Subscription Services, Inc; Wiley
• Subjects: Acute effects; animal pharmacology; Animals; Bioavailability; Biotechnology; Blood pressure; Cardiology and cardiovascular system; cardiovascular disease; Cardiovascular Diseases - complications; Cardiovascular Diseases - prevention & control; Collagen; Diabetes; diabetes complications; Drug Administration Schedule; drug development; Echocardiography; experimental pharmacology; Heart rate; Heart Rate - drug effects; Hemodynamics; Hemodynamics - drug effects; Human health and pathology; Immunology; Kidney Diseases - complications; Kidney Diseases - prevention & control; Life Sciences; Long-term effects; Magnetic resonance imaging; Male; Metabolic syndrome; Metabolic Syndrome - complications; Metabolic Syndrome - drug therapy; Metabolic Syndrome - pathology; Metabolic Syndrome - physiopathology; Mineralocorticoid Receptor Antagonists - administration & dosage; Mineralocorticoid Receptor Antagonists - adverse effects; Naphthyridines - administration & dosage; Naphthyridines - adverse effects; Nephropathy; Nitric oxide; Nitric Oxide - metabolism; Oxidative stress; Oxidative Stress - drug effects; Perfusion; Pharmaceutical sciences; Proteinuria; Rats; Rats, Zucker; Reactive oxygen species; Renal function; Time Factors; Tissues and Organs; type 2 diabetes; Ventricle; Ventricular Function, Left - drug effects; drug development; cardiovascular disease; type 2 diabetes; diabetes complications; experimental pharmacology; animal pharmacology
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.13393

Aim
To determine whether non‐steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome‐related end‐organ, i.e. cardiac, damage.
Materials and methods
In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non‐steroidal MR antagonist finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods).
Results
Long‐term (90 days) finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end‐diastolic pressure and LV end‐diastolic pressure‐volume relationship, without modifying LV end‐systolic pressure and LV end‐systolic pressure‐volume relationship. Simultaneously, long‐term finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short‐term (7 days) finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short‐term finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio‐availability, were increased.
Conclusions
In rats with metabolic syndrome, the non‐steroidal MR antagonist finerenone opposed metabolic syndrome‐related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/increased NO bioavailability, as well as long‐term effects, such as modifications in the myocardial structure.