PO2 MODULATION OF NO AND ET1 IN PULMONARY HYPERTENSION

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Pulmonary hypertension (PHT), both primary and secondary, leads to significant morbidity and mortality with few acceptable therapeutic options. While there are well known associated disease states with primary PHT (collagen vascular diseases, anorexigen exposure, idiopathic) and secondary PHT (COPD, congenital heart disease) the initial injury leading to vasoconstriction, vascular remodeling, and increased pulmonary vascular resistance is unknown. Derangements in endogenous vasodilators and vasoconstrictors (NO and ET-1 respectively) have been implicated in the hypertensive pulmonary circulation in experimental models of PHT as well as in the human disease. Our laboratory is interested in the role of endogenously derived nitric oxide (NO) from eNOS (endothelial derived nitric oxide synthase), endothelin-1 (ET-1), and the effect of hypoxia on the development of PHT. Specifically, using mice congenitally deficient in eNOS, alterations in activity of ET-1 and the effect of physiologic levels of hypoxia on the development of PHT are actively being studied. We hypothesize that eNOS deficiency imparts an increased sensitivity to hypoxia leading to the development of PHT under mild, physiologic hypoxia as seen in Denver, CO and in many disease states associates with PHT. Further, we hypothesize that there is significant interactions, or cross-talk, between NO and ET-1 in vivo such that NO acts, in part, to downregulate the expression and activity of ET-1. We will present preliminary data using isolated perfused mouse lung preparations demonstrating increased pulmonary vasoreactivity to hypoxia in eNOS deficient mice. We will also report the development of PHT in eNOS knock-out mice at mild hypoxia (Denver's altitude) compared to controls, which is attenuated by conditions equivalent to sea level. Preliminary data suggesting an increase in expression of ET-1 in eNOS deficient vs. control mice will also be presented. Specifically, we will address the questions: 1) does NO modulate pulmonary vascular tone in a PO2- dependent manner and 2) does NO act, in part, to oppose the expression and activity of ET-1. We will utilize ex vivo and in vivo measurements of pulmonary vasoreactivity and PHT under normoxic (sea level), mild, physiologic hypoxic (as seen in Denver, CO), and severe hypoxic conditions to determine the consequences of eNOS deficiency. By using transgenic mice, we will avoid the problems inherent using pharmacologic antagonists of NOS isoforms. Additionally, we will use well established techniques in our laboratory to study the interaction of NO and the expression and activity of ET-1 in vivo. Improved understanding of these endogenous vasoregulatory substances, their interactions with one another, and the effect of modest hypoxia in vivo are the major goals of this proposal and may lead to new therapeutic options.