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Nitric oxide-sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction.
- Source :
-
JCI insight [JCI Insight] 2018 Feb 22; Vol. 3 (4). Date of Electronic Publication: 2018 Feb 22 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.
- Subjects :
- Administration, Oral
Angiotensinogen genetics
Animals
Arrhythmias, Cardiac etiology
Blood Pressure drug effects
Chronic Disease drug therapy
Disease Models, Animal
Drug Evaluation, Preclinical
Echocardiography
Heart Failure complications
Heart Failure genetics
Heart Failure mortality
Heart Ventricles diagnostic imaging
Heart Ventricles drug effects
Heart Ventricles physiopathology
Humans
Isolated Heart Preparation
Male
Morpholines pharmacology
Pyrimidines pharmacology
Rats
Rats, Transgenic
Renin genetics
Stroke Volume physiology
Survival Rate
Treatment Outcome
Arrhythmias, Cardiac prevention & control
Heart Failure drug therapy
Morpholines therapeutic use
Pyrimidines therapeutic use
Soluble Guanylyl Cyclase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 3
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 29467337
- Full Text :
- https://doi.org/10.1172/jci.insight.96006