Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart.
BACKGROUND
Sustained pressure overload of the right ventricle (RV) causes RV hypertrophy and failure. Cyclic-GMP has previously been shown to modulate left ventricular hypertrophy.


OBJECTIVE
To evaluate the effects of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor elevating c-GMP, on myocardial hypertrophy and function in rats with RV hypertrophy.


METHODS
Rats were pulmonary trunk banded (PTB) and randomized to receive sildenafil (SIL) or vehicle (VEC) for three (n=14) and nine weeks (n=18). In addition, rats with established RV hypertrophy were randomized to SIL or VEC (n=17) three weeks after PTB. Right ventricular function was evaluated by echocardiography and RV hypertrophy by histology and RV weight.


RESULTS
Sildenafil failed to inhibit the development of RV hypertrophy when given for both 3 and 9 weeks. On the contrary, sildenafil increased RV hypertrophy after 3 weeks (RV/bodyweight: SIL 0.099+/-0.016 vs. VEC 0.081+/-0.011; p<0.05) and total heart weight after 9 weeks (SIL 1.05+/-0.10 vs. VEC 0.93+/-0.08 g; p<0.05). Sildenafil also failed to reverse established RV hypertrophy, but significantly improved RV myocardial function as measured by Tricuspid Annular Plane Systolic Excursion (TAPSE: SIL 1.85+/-0.027 vs. VEC 1.39+/-0.037 mm; p<0.05).


CONCLUSIONS
PDE5 inhibition by sildenafil failed to prevent or reverse RV hypertrophy in rats operated by pulmonary trunk banding. It actually increased RV hypertrophy and improved RV contractile function when given to rats with established RV hypertrophy.
Andersen
Asger
A
Department of Cardiology, Aarhus University Hospital, Skejby, Denmark. asgerandersen@gmail.com
Nielsen
Jan Møller
JM
Peters
Christian Daugaard
CD
Schou
Uffe Kjaer
UK
Sloth
Erik
E
Nielsen-Kudsk
Jens Erik
JE
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000187:drug effects; D004452:Echocardiography; D006976:Hypertension, Pulmonary / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D016278:Ventricular Function, Right / Q000187:drug effects*
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP