Bronchodilation induced by PGE₂ is impaired in Group III pulmonary hypertension

In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), decreased pulmonary vascular tone and tissue hypoxia is therapeutically beneficial. PGE₂ and PGI₂ induce potent relaxation of human bronchi from non-PH (control) patients via EP₄ and IP receptors, respectively. However, the effects of PGE₂ /PGI₂ and their mimetics on human bronchi from PH patients are unknown. Here, we have compared relaxant effects of several PGI₂ -mimetics approved for treating PH Group I with several PGE₂ -mimetics, in bronchial preparations derived from PH Group III and control patients.

Relaxation of bronchial muscle was assessed in samples isolated from control and PH Group III patients. Expression of prostanoid receptors was analysed by western blot and real-time PCR, and endogenous PGE₂ , PGI₂ , and cAMP levels were determined by ELISA.

Maximal relaxations induced by different EP₄ receptor agonists (PGE₂ , L-902688, and ONO-AE1-329) were decreased in human bronchi from PH patients, compared with controls. However, maximal relaxations produced by PGI₂ -mimetics (iloprost, treprostinil, and beraprost) were similar for both groups of patients. Both EP₄ and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH patients. cAMP levels significantly correlated with PGI₂ but not with PGE₂ levels.

The PGI₂ -mimetics retained maximal bronchodilation in PH Group III patients, whereas bronchodilation induced by EP₄ receptor agonists was decreased. Restoration of EP₄ receptor expression in airways of PH Group III patients with respiratory diseases could bring additional therapeutic benefit.