Adenovirus-mediated atrial natriuretic protein expression in the lung protects rats from hypoxia-induced pulmonary hypertension

Endogenous as well as exogenous atrial natriuretic peptide (ANP) attenuates the development of chronic hypoxic pulmonary hypertension (CHPH) in rats. We built a recombinant adenovirus type 5 containing ANP cDNA under the cont rol of the Rous sarcoma virus long terminal repeat (Ad.ANP), The efficiency of this vector in delivering the ANP gene was first examined in rat primar y cultures of pulmonary vessel smooth muscle cells (SMCs) in comparison wit h Ad.beta GAL, Conditioned medium collected from Ad.ANP-infected cells (100 0 TCID50/cell) contained 5 x 10(9) M immunoreactive ANP and elicited relaxa tion of isolated rat pulmonary arteries preconstricted with phenylepinephri ne. To examine the effects of adenovirus-mediated ANP expression in the CHP H rat lung, Ad.ANP or Ad.beta GAL was administered via the tracheal route. Immunoreactive ANP was detected in bronchoalveolar fluid as early as 4 days and until 10-17 days after Ad.ANP administration (5 x 10(8) TCID50), Lung ANP immunostaining was mainly localized in bronchial and alveolar epithelia l cells. As compared with Ad.beta GAL-treated controls, rats given Ad.ANP ( 5 x 10(8) TCID50) on the day before a 2-week exposure to hypoxia (10% O-2) had lower values for pulmonary artery pressure (32.1 +/- 1.93 vs. 35.5 +/- 2 mmHg, p < 0.01) and Fulton's index (0.52 +/- 0.089 vs. 0.67 +/- 0.12, p < 0.001) and less severe right ventricular hypertrophy and distal vessel mus cularization. These results suggest that induction of ANP expression ill th e lung may hold promise in the treatment of pulmonary hypertension.