Molecular mechanisms of cardiostimulatory effects of sildenafil.
To better understand the molecular mechanisms of the previously described cardiostimulatory action of the phosphodiesterase type-5 (PDE5) inhibitor sildenafil, we first evaluated its effects on cyclic AMP level in the canine ventricular membrane preparation. Sildenafil (10 micromol/L) significantly increased the net cyclic AMP production rate, the potency of which was similar to that of 3-isobutyl-1-methylxanthine (IBMX). Next, we assessed the inhibitory effect of sildenafil on PDE of bovine heart. Sildenafil (> or = 1 micromol/L) as well as IBMX significantly decreased the cyclic AMP hydrolyzing speed of PDE. These results suggest that a supra-therapeutic concentration of sildenafil may directly inhibit cyclic AMP hydrolyzing PDEs in the heart, although indirect inhibition of PDE3 via the "cross-talk" pathway cannot be totally excluded.
Sugiyama
Atsushi
A
Department of Pharmacology, Yamanashi Medical University, Nakakoma-gun, Japan. atsushis@res.yamanashi-med.ac.jp
Takeuchi
Nobuyasu
N
Saegusa
Yoshiki
Y
Sugita
Masao
M
Hashimoto
Keitaro
K
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D000242:Cyclic AMP / Q000096:biosynthesis; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D000068677:Sildenafil Citrate; D013268:Stimulation, Chemical; D013450:Sulfones; D014665:Vasodilator Agents / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine