IN VIVO ARGININE METABOLISM IN IDIOPATHIC AND SECONDARY PULMONARY HYPERTENSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Pulmonary arterial hypertension (PAH) is a disease of unknown etiology that is characterized by increased pulmonary artery pressure and vascular resistance. It can be idiopathic or secondary to other disease conditions, such as sickle cell disease. Decreased production of the vasodilatory molecule nitric oxide (NO) is believed to play an important role in the pathogenesis of PAH, but further in vivo studies of NO metabolism in patients with PAH are needed. We propose that there is a shortage of NO in PAH resulting from the combined effects of decreased availability of the NO precursor arginine and impaired activity of nitric oxide synthase, the enzyme that synthesizes NO. Specifically, we hypothesize that compared to healthy controls, patients with PAH will have less arginine available for NO synthesis secondary to increased activity of arginase, the enzyme that breaks down arginine to urea and ornithine, and decreased de novo arginine synthesis. In addition, they will have increased concentrations of asymmetric dimethylarginine, leading to inhibition of NO synthase activity. To test these hypotheses, stable isotope tracer techniques will be used to measure arginine and nitric oxide metabolism in healthy controls, patients with idiopathic PAH, and patients with PAH secondary to sickle cell disease. These measurements will be correlated with hemodynamic and clinical parameters. This project will increase our knowledge about the role of the arginine-NO pathway in the pathogenesis of PAH. In addition, it may identify future targets for therapeutic trials. I. HYPOTHESIS In this project, we propose to test the general hypothesis that decreased availability of the vasodilatory molecule nitric oxide (NO) underlies the pathogenesis of pulmonary arterial hypertension (PAH). This shortage of NO is a result of decreased synthesis due to the combined effects of the decreased availability of the NO precursor arginine and impaired nitric oxide synthase activity. Specific hypotheses to be tested are as follows: 1. Compared to healthy controls, patients with PAH have less arginine available for NO synthesis secondary to a) increased arginase activity leading to increased conversion of arginine to urea and ornithine and 2) decreased de novo arginine synthesis. 2. Compared to healthy controls, patients with PAH will have slower NO synthesis because of inhibition of nitric oxide synthase activity by asymmetric dimethylarginine (ADMA). As a consequence, pulmonary artery pressures and disease severity will be negatively correlated with the rate of NO synthesis and positively correlated with plasma ADMA concentration. II.SPECIFIC AIMS To test the above hypotheses, stable isotope tracer techniques and biochemical methods will be used to make the following measurements in vivo in 3 groups of subjects: patients with idiopathic pulmonary hypertension, patients with sickle cell disease and pulmonary hypertension, and controls. 1. Arginine flux (rate of production or rate of appearance), its plasma concentration, and the rate of de novo arginine synthesis from its precursor, citrulline. 2. Urea flux and ornithine flux (indices of arginase activity), plasma ornithine concentration, and the ratio of plasma concentration of arginine to ornithine 3. Citrulline flux, its plasma concentration, and the rate of conversion of arginine to citrulline (an index of NO synthesis) 4. Plasma concentration of asymmetric dimethylarginine. These measurements will be correlated with hemodynamic and clinical parameters, including: pulmonary artery pressures, right atrial pressure, and cardiac index by echocardiogram or right heart catheterization, and six minute walk distance.