CYCLIC-GMP-BINDING, CYCLIC-GMP-SPECIFIC PHOSPHODIESTERASE (PDE5) GENE-EXPRESSION IS REGULATED DURING RAT PULMONARY DEVELOPMENT

Increased nitric oxide (NO) production plays a critical role in the ma mmalian pulmonary vascular adaptation to extrauterine life. NO activat es soluble guanylate cyclase, increasing intracellular cGMP concentrat ions, thereby inducing relaxation of vascular smooth muscle. cGMP is i nactivated by cyclic nucleotide phosphodiesterases (PDEs). One PDE iso zyme, PDES, specifically hydrolyzes cGMP, is abundant in lung tissues, and modifies the pulmonary vasodilatory response to exogenous NO. To investigate the regulation of PDES gene expression during pulmonary de velopment, PDES mRNA levels, as well as cGMP-metabolizing PDE enzyme a ctivity, were measured in the lungs of perinatal and adult rats. RNA b lot hybridization revealed that PDE5 mRNA was detectable in fetal lung tissue as early as 18.5 d of the 22-d term gestation and reached maxi mal levels in neonatal lungs. mRNA levels in adult rat lungs were 3-4- fold less than the levels measured in lungs of 1- and 8-d-old rats. Pu lmonary cGMP hydrolytic activity in 1-d-old animals was 30-fold greate r than the cGMP hydrolytic activity of adult rat lungs. Zaprinast, a s pecific PDES antagonist, inhibited 52 and 56% of cGMP hydrolytic activ ity in lungs of 1- and 8-d-old rats, respectively, but only 18% of the activity in adult lungs. In situ hybridization revealed that PDE5 mRN A transcripts were present in the vascular smooth muscle cells of neon atal and adult lungs. PDE5 mRNA was also detected in the alveolar wall s of neonatal rat lungs. These results demonstrate that the gene encod ing PDES is abundantly expressed in the lungs of perinatal rats, and i s available to participate in the mammalian pulmonary vascular transit ion to extrauterine life. Extravascular PDE5 gene expression in neonat al lungs suggests a potentially important nonvascular role for this en zyme during pulmonary development.