Adenovirus-Mediated iNOS Gene Transfection Attenuates U-46619 Induced Pulmonary Arterial Constriction in Isolated Rat Lungs

Abstract 1751 Poster Session I, Saturday, 5/1 (poster 96)

Nitric oxide (NO) is an important modulator of the pulmonary vascular response to vasoconstrictors. To examine the role of gene therapy in enhancing pulmonary NO production we hypothesized that adenovirus-mediated inducible nitric oxide synthase (iNOS) gene transfection into the rat pulmonary vasculature would attenuate the constrictor responses to the thromboxane mimetic U-46619 and hypoxia. Following cannulation of the left pulmonary artery, 3 × 10⁹ plaque forming units of a recombinant adenovirus containing a CMV promoter regulated iNOS gene (AdCMViNOS) or an adenoviral construct with the β-galactosidase gene (AdCMVβ-gal) were instilled into the left pulmonary vasculature. Sham operated animals were similarly prepared except virus-free normal saline was administered. Two weeks following transfection we examined segmental vasoconstrictor responses to U-46619 and hypoxia in isolated, saline-perfused left lungs from each group using double occlusion techniques. Resistances were calculated from pressure data obtained under constant flow conditions. Pulmonary arterial constrictor responses to U-46619 were significantly (p < 0.05) decreased in the AdCMViNOS transfected group compared to the AdCMVβ-gal or sham treated animals. Vasoconstrictor responses to hypoxia were similarly decreased in the AdCMViNOS treated group, but did not reach statistical significance (p = 0.053) probably due to the small sample size in this ongoing study. These findings demonstrate that AdCMViNOS transfection with subsequent NO production attenuates pulmonary arterial vasoconstriction induced by U-46619. We conclude that adenovirus-mediated iNOS gene transfection might be a useful tool in the future study and management of conditions presenting with pulmonary hypertension. (Figure)

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