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Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling.
Cardiovasc Res. 2009 Apr 01; 82(1):30-9.CR

Abstract

AIMS

Inhibition of phosphodiesterase 5 (PDE5) decreases pulmonary pressure and improves symptoms in patients with pulmonary arterial hypertension. It is unclear however, whether inhibition of PDE5 can prevent myocardial remodelling during right-ventricular pressure overload.

METHODS AND RESULTS

Right-ventricular pressure overload was produced in male rats in a pulmonary hypertension model (monocrotaline 60 mg/kg s.c.) or by surgical pulmonary artery banding. PDE5 inhibition using oral sildenafil (50 mg/kg/day in drinking water) or placebo was initiated 14 days after monocrotaline treatment and continued for 14 days until final examination. In the pulmonary artery banding groups, rats were treated with sildenafil (50 mg/kg/day) or placebo for 21 days following surgical pulmonary artery banding. At the final experiments, right-ventricular haemodynamics were measured and remodelling was analysed using histological, biochemical, and gene expression markers. Both monocrotaline and pulmonary artery banding increased right-ventricular systolic pressure to approximately 80 mmHg. In parallel, both interventions induced markers of hypertrophy (upregulation of natriuretic peptides, increase in myocyte diameter) and fibrosis (upregulation of collagen types 1A2 and 3A1) as well as mRNA expression of the tissue inhibitor of matrix metalloproteases 1 and osteopontin in the right ventricle. In monocrotaline model, sildenafil decreased pulmonary pressure, reduced right-ventricular hypertrophy, and prevented fibrosis marker gene upregulation. After pulmonary artery banding, in contrast, sildenafil increased markers of myocardial remodelling and right-ventricular myocyte diameter.

CONCLUSION

Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right-ventricular unloading.

Authors+Show Affiliations

Cardiology Research, Bayer Schering Pharma, Aprather Weg 18, 42096 Wuppertal, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19131365

Citation

Schäfer, Stefan, et al. "Chronic Inhibition of Phosphodiesterase 5 Does Not Prevent Pressure-overload-induced Right-ventricular Remodelling." Cardiovascular Research, vol. 82, no. 1, 2009, pp. 30-9.
Schäfer S, Ellinghaus P, Janssen W, et al. Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling. Cardiovasc Res. 2009;82(1):30-9.
Schäfer, S., Ellinghaus, P., Janssen, W., Kramer, F., Lustig, K., Milting, H., Kast, R., & Klein, M. (2009). Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling. Cardiovascular Research, 82(1), 30-9. https://doi.org/10.1093/cvr/cvp002
Schäfer S, et al. Chronic Inhibition of Phosphodiesterase 5 Does Not Prevent Pressure-overload-induced Right-ventricular Remodelling. Cardiovasc Res. 2009 Apr 1;82(1):30-9. PubMed PMID: 19131365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling. AU - Schäfer,Stefan, AU - Ellinghaus,Peter, AU - Janssen,Wiebke, AU - Kramer,Frank, AU - Lustig,Klemens, AU - Milting,Hendrik, AU - Kast,Raimund, AU - Klein,Martina, Y1 - 2009/01/08/ PY - 2009/1/10/entrez PY - 2009/1/10/pubmed PY - 2009/5/15/medline SP - 30 EP - 9 JF - Cardiovascular research JO - Cardiovasc Res VL - 82 IS - 1 N2 - AIMS: Inhibition of phosphodiesterase 5 (PDE5) decreases pulmonary pressure and improves symptoms in patients with pulmonary arterial hypertension. It is unclear however, whether inhibition of PDE5 can prevent myocardial remodelling during right-ventricular pressure overload. METHODS AND RESULTS: Right-ventricular pressure overload was produced in male rats in a pulmonary hypertension model (monocrotaline 60 mg/kg s.c.) or by surgical pulmonary artery banding. PDE5 inhibition using oral sildenafil (50 mg/kg/day in drinking water) or placebo was initiated 14 days after monocrotaline treatment and continued for 14 days until final examination. In the pulmonary artery banding groups, rats were treated with sildenafil (50 mg/kg/day) or placebo for 21 days following surgical pulmonary artery banding. At the final experiments, right-ventricular haemodynamics were measured and remodelling was analysed using histological, biochemical, and gene expression markers. Both monocrotaline and pulmonary artery banding increased right-ventricular systolic pressure to approximately 80 mmHg. In parallel, both interventions induced markers of hypertrophy (upregulation of natriuretic peptides, increase in myocyte diameter) and fibrosis (upregulation of collagen types 1A2 and 3A1) as well as mRNA expression of the tissue inhibitor of matrix metalloproteases 1 and osteopontin in the right ventricle. In monocrotaline model, sildenafil decreased pulmonary pressure, reduced right-ventricular hypertrophy, and prevented fibrosis marker gene upregulation. After pulmonary artery banding, in contrast, sildenafil increased markers of myocardial remodelling and right-ventricular myocyte diameter. CONCLUSION: Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right-ventricular unloading. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/19131365/Chronic_inhibition_of_phosphodiesterase_5_does_not_prevent_pressure_overload_induced_right_ventricular_remodelling_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvp002 DB - PRIME DP - Unbound Medicine ER -