Prostanoids and phosphodiesterase inhibitors in experimental pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis, characterized by intimal lesions, medial hypertrophy, and adventitial thickening of precapillary pulmonary arteries. Several approved therapies are currently available for the treatment of PAH, of which intravenous epoprostenol is the best explored over the past decade. Newly available oral endothelin receptor antagonists, although clinically efficacious, bear the risk of liver toxicity in a significant portion of patients. Substances that stimulate the formation of the second messengers cyclic adenosine monophosphate (cAMP) or guanosine monophosphate (cGMP) have proved useful in the treatment of various forms of pre-capillary pulmonary hypertension. These second messengers of the endogenous vasodilator mediators that include prostacyclin and nitric oxide (NO) are hydrolyzed by cyclic nucleotide phosphodiesterases (PDEs), a class of enzymes from which 11 isoforms have been characterized. This chapter highlights developments in the treatment of experimental pulmonary hypertension with special attention to prostanoids and PDE inhibitors. We summarize findings for the acute vasodilatory as well as chronic effects of prostanoids, PDE inhibitors, or combinations of both, in animal models of pulmonary hypertension.

Subthreshold doses of nebulized prostacyclin and rolipram synergistaically protect against lung ischemia-reperfusion.

BACKGROUND: Pulmonary edema caused by increased microvascular permeability is an important feature of lung ischemia-reperfusion (I/R) injury. METHODS: We investigated the impact of co-aerosolized prostaglandin (PG)I(2) and the 3',5-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor rolipram on microvascular leakage following I/R injury. Buffer-perfused rabbit lungs were exposed to 270 minutes of warm ischemia while anoxic ventilation and a positive intravascular pressure were maintained. RESULTS: On reperfusion, a massive increase of the capillary filtration coefficient and severe edema formation were noted, whereas microvascular pressures displayed only minor changes. Short-time aerosolization of subthreshold doses of either rolipram (33 microg) or PGI(2) (2.6 microg) at the beginning of ischemia did not attenuate the leakage response, whereas the co-aerosolization of both agents largely blocked any permeability increase and edema formation, independent of hemodynamic effects. The same was true when the co-aerosolization was undertaken before onset of ischemia. Similarly, the intravascular administration of rolipram and PGI(2) showed a synergistic reduction of I/R-induced vascular leak but demanded 10-fold higher doses. Intravascular release of cAMP was markedly enhanced on combined PGI(2)-rolipram administration but depended on the mode of delivery of these agents. CONCLUSIONS: Low doses of aerosolized prostacyclin and rolipram synergistically protect against severe lung I/R injury and can be used independently of lung perfusion. This strategy may be suitable for an improvement of organ preservation in lung transplantation including early management of non-heart-beating donors.