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.