| First Author | Isidori AM | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 106 |
| Issue | 3 | Pages | 408-20 |
| PubMed ID | 25852085 | Mgi Jnum | J:250640 |
| Mgi Id | MGI:6106221 | Doi | 10.1093/cvr/cvv123 |
| Citation | Isidori AM, et al. (2015) Inhibition of type 5 phosphodiesterase counteracts beta2-adrenergic signalling in beating cardiomyocytes. Cardiovasc Res 106(3):408-20 |
| abstractText | AIMS: Compartmentalization of cAMP and PKA activity in cardiac muscle cells plays a key role in maintaining basal and enhanced contractility stimulated by sympathetic nerve activity. In cardiomyocytes, activation of adrenergic receptor increases cAMP production, which is countered by the hydrolytic activity of selective phosphodiesterases (PDEs). The intracellular regional dynamics of cAMP production and hydrolysis modulate downstream signals resulting in different biological responses. The interplay between beta receptors (betaARs) signalling and phosphodiesterase 5 (PDE5) activity remains to be addressed. METHODS AND RESULTS: Using combined strategies with pharmacological inhibitors and genetic deletion of PDEs and betaAR isoforms, we revealed a specific pool of cAMP that is under dual regulation by PDE2 and, indirectly, PDE5 activity. Inhibition of PDE5 with sildenafil produces a cGMP-dependent activation of PDE2 that attenuates cAMP generation induced by betaAR agonists, with concomitant modulation of stimulated contraction rate and calcium transients. PDE2 haploinsufficiency abolished the effects of sildenafil. The negative chronotropic effect of PDE5 inhibition through PDE2 activation was also observed in sinoatrial node tissue from adult mice. PDE5 inhibition selectively lowered contraction rate stimulated by beta2AR, but not beta1AR activation, supporting a compartmentalization of the cGMP-modulated pool of cAMP. CONCLUSION: These data identify a new effect of PDE5 inhibitors on the modulation of cardiomyocyte response to adrenergic stimulation via PDE5-PDE2-mediated cross-talk. |
