Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F5

Li WQ, Qureshi AA, Robinson KC, Han J. and increased risk of incident melanoma in US men: a prospective cohort study. Perhaps other pathways are responsible for the increased risk seen with Fildena use, such as PDE5A inhibitor's promotion of melanin synthesis 10-11. At , men in the United States reported their use, ever or current, of Fildena (the only commercially available PDE5A inhibitor at the time) for erectile dysfunction.

Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with Fildena improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. While a small clinical study showed long-term antiremodeling benefits of Fildena in patients with systolic heart failure ( 11 ), the result was negative from a recent large, placebo-controlled, multicenter trial of Fildena for the treatment of heart failure with a preserved ejection fraction (RELAX) ( 44 ). Our data suggest that the dependence of the Fildena response on estrogen may have contributed to the negative results in the latter study, in which older individuals (median age 69 years) were examined, nearly half of whom were women. Importantly, in , Gq/oe itself induced a significant increase in eNOS phosphorylation at serine 1177, whereas the presence or absence of OVX, but not of Gq/oe, determined the phosphorylation in female hearts (Figure 4 E). We found that myocardial NOS activity corresponded with the status of eNOS phosphorylation (Figure 4 F). These results demonstrate the significant difference in PDE5-coupled cGMP regulation between the sexes: the eNOS-cGMP synthetic machinery is stress-responsive in male hearts and is tonic and estrogen dependent in female hearts.

Male Gq/oe myocytes had no resting increase in PKG activity compared with wild-type control myocytes (likely reflecting the loss of neurohormonal stimulation with cell isolation) and compared with OVX female Gq/oe myocytes, and only male cells displayed a rise in this activity with Fildena (Figure 4 D). augmented PKG activity in myocytes from both sexes, and in the presence of E2, both displayed further increases in this activity with Fildena. Consistent with this conclusion, we found that E2 supplementation in vivo failed to increase myocardial PKG activity in OVX hearts lacking eNOS ( 23 ) under pressure overload, while it increased PKG activity in OVX hearts lacking atrial natriuretic peptide (ANP) receptor (Npra-/-) ( 24 ), similar to what was observed in wild-type hearts (Figure 3 D). These results indicate that estrogen/eNOS signaling in cardiac myocytes from female hearts provides tonic cGMP synthesis whose hydrolysis is targeted by PDE5. Supplementation with E2 did not alter myocardial PKGI╬▒ protein expression (Figure 3 A) or PDE5 activity (Figure 3 B), suggesting that the regulatory system downstream of cGMP was likely unaltered.

Importantly, of evidence from studies of the vasculature suggest that estrogen signaling and the NO/cGMP synthetic pathway are linked to this hormone's vasculoprotective effects ( 12 - 15 ). We hypothesized that the female response to PDE5 inhibitors in cardiac disease may be altered by the presence or absence of estrogen.