Effects of sildenafil on the gastrocnemius and cardiac muscles of rats in a model of prolonged moderate exercise training.
Moderate exercise training improves energetic metabolism, tissue perfusion and induces cardiac and skeletal muscle remodeling. Sildenafil, a potent phosphodiesterase-5 inhibitor used to treat erectile dysfunction, reduces infarct size and increases tissue oxygenation in experimental models of cardiovascular disease. We have evaluated the effects of prolonged moderate exercise training and a repeat administration of sildenafil on the rat gastrocnemius and cardiac muscles. Animals were divided into two groups: sedentary and trained. Each group was subdivided into animals treated with vehicle or with two doses of sildenafil (10 or 15 mg/kg/day) during the last week of training. Physical exercise did not induce cardiac hypertrophy, whereas it increased mRNA levels of the PGC-1α, HIF-1α and VEGF genes, which are involved in mitochondrial biogenesis and angiogenesis, and reduced mRNA levels of FoxO3a, MuRF-1 and Atrogin-1. Sildenafil dose-dependently promoted both angiogenesis, as shown by increased capillary density, and muscle atrophy, as shown by muscle fibre size. These effects were more pronounced in trained animals. Our data confirm the beneficial effects of a moderate and prolonged training on cardiovascular and skeletal systems and document the positive and negative effects of sildenafil on these tissues at doses higher than those used in clinical practice. This report may impact on the use of sildenafil as a substance able to influence sports performance.
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Centre of Excellence for Cardiovascular Diseases, Second University of Naples, Naples, Italy. barbara.rinaldi@unina2.it
Barbara
B
Rinaldi
Maria
M
Donniacuo
Loredana
L
Sodano
Giulia
G
Gritti
Simona
S
Signoriello
Elisabetta
E
Parretta
Liberato
L
Berrino
Konrad
K
Urbanek
Annalisa
A
Capuano
Francesco
F
Rossi
D000818:Animals; D015153:Blotting, Western; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010879:Piperazines; C501429:Ppargc1a protein, rat; D011687:Purines; D013450:Sulfones; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D042461:Vascular Endothelial Growth Factor A; D000068677:Sildenafil Citrate; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases