cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases.

Abstract

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular wall remodeling and severe loss of cross−sectional area of the precapillary pulmonary vessels. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether a combined phosphodiesterase (PDE) 3 and 4 inhibitor ameliorates endothelial function by regulating the ADMA−DDAH axis. We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on ADMA−induced apoptosis and DDAH expression in endothelial cells and in vivo on monocrotaline (MCT)−induced pulmonary hypertension in rats. Real−time PCR analysis, immunocytochemistry and PDE activity assays suggested high expression of isoforms PDE3 and 4 in endothelial cells. Further, treatment of endothelial cells with the PDE3/4 inhibitor tolafentrine significantly decreased ADMA−induced apoptosis, concomitantly with upregulation of DDAH2. Chronic nebulization of the PDE3/4 inhibitor significantly attenuated all MCT−induced hemodynamic abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA levels, elevated nitric oxide/cGMP levels, and augmented DDAH2 expression and activity. In addition, the PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung. Combined inhibition of PDE3 and 4 prevents the development of PAH and promotes endothelial regeneration by modulating DDAH2 expression and ADMA levels.This abstract is funded by: SFB 547 and Else−Kröner−Fresenius Foundation.