Phosphodiesterases (PDEs) play a key role in the control of cardiac contraction. PDE
inhibitors are associated with cardiotoxicity, and increased knowledge of
cardiomyocyte PDEs is required for improved pharmaceutical development. PDE
activity and function were compared in animal and human cardiomyocytes in order to
determine a suitable model for the human response, and to generate new insights into
the role of cardiomyocyte PDEs. Ventricular myocytes were isolated from rat, guinea
pig and diseased human heart. PDE gene expression was measured using RTPCR;
PDE activity was measured using a scintillation proximity assay and isoform-specific
PDE inhibitors. Effects of PDE inhibition on cardiomyocyte contractility were
measured using electrically paced isolated cells. The human cardiomyocyte PDE
expression and activity profile was closer to the guinea pig than the rat. High levels of
PDE1 activity against cAMP and lower levels of possible PDE5 activity were found
in guinea pig and human cardiomyocytes, but not rat. Non-specific PDE inhibition
increased basal cardiomyocyte percentage shortening in cells from all three species;
PDE3 inhibition only increased percentage shortening in guinea pig and human
cardiomyocytes; PDE4 inhibition did not affect basal percentage shortening in
cardiomyocytes from any of the three species. Further studies using rat
cardiomyocytes found that PDE3 and PDE4 inhibition both significantly increased
percentage shortening when cAMP levels were raised; rat β1- and β2- adrenergic
receptors were also differentially regulated by PDE3 and PDE4. The functional
effects of PDE1 inhibition were investigated in guinea pig cardiomyocytes but no
significant effects were measured. Dual PDE1/PDE5 inhibition was shown to have a
small negative effect on isoprenaline-stimulated contractility in rat, guinea pig and
human cardiomyocytes. This study has revealed new insights into cardiomyocyte
PDEs and demonstrated that the guinea pig may be a more suitable model for diseased
human cardiomyocytes than the rat.