Cardiovascular Research Advance Access first published online on January 8, 2009
This version [Corrected Proof] published online on February 2, 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, Bayer Schering Pharma, Aprather Weg 18, 42096 Wuppertal, Germany
2 Target Discovery, Bayer Schering Pharma, Wuppertal, Germany
3 Pharmacokinetics, Bayer Schering Pharma, Wuppertal, Germany
4 Heart and Diabetes Center NRW, Bad Oeynhausen, Germany
* Corresponding author. Tel: +49 202 36 5488; fax: +49 202 36 5637. E-mail address: Martina.Klein1{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 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 
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.
KEYWORDS Pulmonary hypertension; Remodelling; Sildenafil
Time for primary review: 26 days
Present address. Chief Medical Officer, Synthon B.V., Nijmegen, Netherlands.
Present address. Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
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Cardiovasc Res 2009 82: 4-6.
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  M. Kuhn Cardiac anti-remodelling effects of phosphodiesterase type 5 inhibitors: afterload-(in)dependent? Cardiovasc Res, April 1, 2009; 82(1): 4 - 6. [Full Text] [PDF]
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