Partial reversal of experimental pulmonary hypertension by phosphodiesterase 3/4 inhibition

¹ University of Giessen Lung Centre (UGLC), 35392 Giessen, Germany
² Altana Pharma, Konstanz, Germany

^* To whom correspondence should be addressed. E-mail: ralph.schermuly{at}uglc.de.

	Abstract

Phosphodiesterase (PDE) inhibitors are currently under investigation for the therapy of pulmonary hypertension.

The present study was designed to investigate chronic effects of oral pumafentrine, a mixed-selective PDE3/4 inhibitor, in monocrotaline-induced pulmonary hypertension in rats.

When chronically administered from weeks 4 to 6 after a single injection of monocrotaline (60mg·kg^-1), pumafentrine (10 mg·kg^-1 daily) partially reversed pulmonary hypertension and right heart hypertrophy in rats. In addition, small pulmonary arterial muscularization, media hypertrophy and decrease in lumen area were largely reversed. Inhibition of smooth muscle proliferation under pumafentrine was demonstrated in vivo as well as a pro-apoptotic effect of pumafentrine on vascular cells. Moreover, pumafentrine dose-dependently increased cAMP-levels and inhibited proliferation of cultured pulmonary arterial smooth muscle cells.

We conclude that oral pumafentrine partially reverses monocrotaline-induced pulmonary hypertension, lung vascular remodeling and right heart hypertrophy in rats.