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

Diabetes Obes Metab. 2018 Oct;20(10):2399-2407. doi: 10.1111/dom.13393. Epub 2018 Jun 27.

Abstract

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.

Keywords: animal pharmacology; cardiovascular disease; diabetes complications; drug development; experimental pharmacology; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiovascular Diseases / complications
  • Cardiovascular Diseases / prevention & control*
  • Drug Administration Schedule
  • Heart Rate / drug effects
  • Hemodynamics / drug effects
  • Kidney Diseases / complications
  • Kidney Diseases / prevention & control*
  • Male
  • 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
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Zucker
  • Time Factors
  • Ventricular Function, Left / drug effects

Substances

  • BAY 94-8862
  • Mineralocorticoid Receptor Antagonists
  • Naphthyridines
  • Nitric Oxide