Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 8, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp002
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Chronic inhibition of phosphodiesterase 5 does not prevent pressure overload induced right ventricular remodelling
1 Cardiology Research, Wuppertal, Germany
2 Target Discovery, Wuppertal, Germany
3 Pharmacokinetics, Bayer Schering Pharma, Wuppertal, Germany
4 Heart and Diabetes Center NRW, Bad Oeynhausen, Germany
Address for correspondence: Stefan Schäfer, MD, FESC, Head, Cardiology Research, Bayer Schering Pharma, Aprather Weg 18, 42096 Wuppertal, Germany, Telephone: +49 (0)202 36 8733, Facsimile: +49 (0)202 36 5637, Email: Stefan.schaefer{at}bayerhealthcare.com
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: 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/d 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/d) or placebo for 21 days following surgical pulmonary artery banding. At the final experiments, right ventricular haemodynamics were measured and remodelling was analyzed using histological, biochemical and gene expression markers.
Results: 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 remodeling and right ventricular myocyte diameter.
Conclusions: Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right ventricular unloading.
Time for primary review: 26 Days
W.J.s current address is Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
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