| Title | cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium. | | Author(s) | Vandeput F, Krall J, Ockaili R, Salloum FN, Florio V, Corbin JD, Francis SH, Kukreja RC, Movsesian MA | | Institution | University of Utah. | | Source | J Pharmacol Exp Ther 2009 Jun 22. | | Abstract | In mouse models of cardiac disease, the PDE5-selective phosphodiesterase inhibitor sildenafil has anti-hypertrophic and cardioprotective effects attributable to the inhibition of cGMP hydrolysis. To investigate the relevance of these findings to humans, we quantified cGMP-hydrolytic activity and its inhibition by sildenafil in cytosolic and microsomal preparations from the left ventricular myocardium of normal and failing human hearts. The vast majority of cGMP-hydrolytic activity was attributable to PDE1 and PDE3. Sildenafil had no measurable effect on cGMP hydrolysis at 10 nM, at which it is selective for PDE5, but had a marked effect on cGMP and cAMP hydrolysis at 1 microM, at which it inhibits PDE1. In contrast, in preparations from the left ventricles of normal mice and mice with heart failure resulting from coronary artery ligation, sildenafil's effects on cGMP hydrolysis were attributable to inhibition of both PDE5 and PDE1; PDE5 comprised ~22 and ~43% of the cytosolic cGMP-hydrolytic activity in preparations from normal and failing mouse hearts, respectively. These differences in PDE5 activities in human and mouse hearts call into question the extent to which the effects of sildenafil in mouse models are likely to be applicable in humans, and raise the possibility of PDE1 as an alternative therapeutic target. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19546307 |
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