INTRAMURAL RESEARCH PROJECT Z01 CL-00190-02 CCMD
October 1, 1998 to September 30, 1999
Title of Project: Physiologic Effects of Inhaled Nitric Oxide, Nitroglycerin, and Placebo in Study Subjects with Sickle Cell Anemia
Principal Investigator: M. Gladwin, M.D. (Senior Staff Fellow) CCMD, CC, NIH Bethesda, MD 20892
Other Personnel: F.P. Ognibene, M.D. (Medical Advisory Investigator), CCMD J.H. Shelhamer, M.D., CCMD A.F. Suffredini, M.D., CCMD R.L. Danner, M.D., CCMD
Collaborating Units: NIDDK (A.N. Schechter, M.D.; G.P. Rodgers, M.D.; C.T. Noguchi, Ph.D.) LCE, NHLBI (A.H. Aletras, Ph.D.; R.S. Balaban, Ph.D.; A.E. Arai, M.D.; C.A. Combs, Ph.D.; B. Hrinczenko, M.D.) Statistics Collaborative (M. Foulks, Ph.D.)
Staff-Years: 0.5
Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither (a1) Minors (a2) Interviews
Summary of Work: Sickle cell anemia is an autosomal recessive disorder and the most common genetic disease affecting African Americans. Approximately 0.15 percent of African Americans are homozygous for sickle cell disease, and 8 percent have sickle cell trait. Acute pain crisis and acute chest syndrome (ACS) are common complications of sickle cell anemia. Inhaled nitric oxide (NO) has been proposed as a possible therapy for the ACS. Anecdotally, NO has been described to rapidly improve the hypoxemia and the clinical course of the ACS. Furthermore, a number of recent studies have suggested that NO may have a favorable impact on sickle hemoglobin at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia.
This clinical trial is designed to evaluate the physiologic and molecular effects of inhaled NO and a currently available, safe, Food and Drug Administration-approved medication, nitroglycerin, that is a nitric oxide donor (i.e., a source of NO after metabolism in the body) in study subjects with and without sickle cell anemia. Whole blood will be analyzed to characterize the metabolism of NO and NO donors, the molecular interactions between hemoglobin and NO, the duration of effect of these therapies on hemoglobin oxygen affinity, and other properties of the erythrocyte and intracellular hemoglobin (including the solubility of deoxy sickle hemoglobin).
We also plan to characterize the effect of NO delivery on microvascular perfusion in study subjects with and without sickle cell anemia. Measurements in study subjects will be made before and while receiving either NO, nitroglycerin, or placebo. These perfusion measurements will occur at rest and during concentric dorsiflexion exercise. Magnetic resonance imaging of lower extremity skeletal muscle enhancement during first passage of intravenously injected gadolinium contrast will be used to evaluate regional skeletal muscle perfusion. Perfusion measurements will be paired with a 31-phosphorus magnetic resonance spectroscopy study of the concentration of muscle high-energy phosphate compounds. Changes in their levels reflect the energy state of muscle and are dependent on the adequacy of blood flow.
This study will allow three major assessments: first, the characterization of the microvascular perfusion at rest and during exercise in study subjects with sickle cell anemia; second, the effects of NO on red cell and hemoglobin function and skeletal muscle perfusion in normal study subjects (without sickle cell anemia); and finally, the effects of NO on red cell and hemoglobin function and skeletal muscle perfusion in study subjects with sickle cell anemia. Our hypothesis is that one or more of these effects could be of potential therapeutic benefit to sickle cell anemia patients.