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PDE5 inhibition improves cardiac morphology and function in SHR by reducing NHE1 activity: Repurposing Sildenafil for the treatment of hypertensive cardiac hypertrophy
- Source :
- European journal of pharmacology. 891
- Publication Year :
- 2020
-
Abstract
- Previously, we have shown that an increased cGMP-activated protein Kinase (PKG) activity after phosphodiesterase 5 (PDE5) inhibition by Sildenafil (SIL), leads to myocardial Na+/H+ exchanger (NHE1) inhibition preserving its basal homeostatic function. Since NHE1 is hyperactive in the hypertrophied myocardium of spontaneous hypertensive rats (SHR), while its inhibition was shown to prevent and revert this pathology, the current study was aimed to evaluate the potential antihypertrophic effect of SIL on adult SHR myocardium. We initially tested the inhibitory capability of SIL on NHE1 in isolated cardiomyocytes of SHR by comparing H+ efflux during the recovery from an acid load. After confirmed that effect, eight-month-old SHR were chronically treated for one month with SIL through drinking water. Compared to their littermate controls, SIL-treated rats presented a decreased NHE1 activity, which correlated with a reduction in its phosphorylation level assigned to activation of a PKG-p38 MAP kinase-PP2A signaling pathway. Moreover, treated animals showed a decreased oxidative stress that appears to be a consequence of a decreased mitochondrial NHE1 phosphorylation. Treated SHR showed a significant reduction in the pro-hypertrophic phosphatase calcineurin, despite slight tendency to decrease hypertrophy was detected. When SIL treatment was prolonged to three months, a significant decrease in myocardial hypertrophy and interstitial fibrosis that correlated with a lower myocardial stiffness was observed. In conclusion, the current study provides evidence concerning the ability of SIL to revert established cardiac hypertrophy in SHR, a clinically relevant animal model that resembles human essential hypertension.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Sildenafil
Phosphatase
Down-Regulation
Cardiomegaly
Essential hypertension
medicine.disease_cause
p38 Mitogen-Activated Protein Kinases
Sildenafil Citrate
Muscle hypertrophy
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
Rats, Inbred SHR
medicine
Cyclic GMP-Dependent Protein Kinases
Animals
Myocytes, Cardiac
Protein Phosphatase 2
Phosphorylation
Pharmacology
Sodium-Hydrogen Exchanger 1
business.industry
Papillary Muscles
Phosphodiesterase 5 Inhibitors
medicine.disease
Fibrosis
Calcineurin
Disease Models, Animal
030104 developmental biology
Endocrinology
chemistry
cGMP-specific phosphodiesterase type 5
Hypertension
cardiovascular system
business
030217 neurology & neurosurgery
Homeostasis
Oxidative stress
Signal Transduction
Subjects
Details
- ISSN :
- 18790712
- Volume :
- 891
- Database :
- OpenAIRE
- Journal :
- European journal of pharmacology
- Accession number :
- edsair.doi.dedup.....5ce3bb79be43bc63f0bac5490038fdc8