Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling.
OBJECTIVE
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.


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.


CONCLUSIONS
Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right-ventricular unloading.
Schäfer
Stefan
S
Cardiology Research, Bayer Schering Pharma, Aprather Weg 18, 42096 Wuppertal, Germany.
Ellinghaus
Peter
P
Janssen
Wiebke
W
Kramer
Frank
F
Lustig
Klemens
K
Milting
Hendrik
H
Kast
Raimund
R
Klein
Martina
M
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D024022:Fibrillar Collagens / Q000378:metabolism; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D016686:Monocrotaline; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D045265:Natriuretic Peptides / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000601:surgery; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013318:Stroke Volume / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
D024022:Fibrillar Collagens; D045265:Natriuretic Peptides; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; C506897:Spp1 protein, rat; D013450:Sulfones; D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin; D016686:Monocrotaline; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP