Sickle cell anemia is the most common genetic disease affecting African-Americans. About 1
in every 1000 African-Americans has the disease and 1 in every 12 carry the genes that could
be passed on to their children. People with sickle cell anemia have abnormal hemoglobin,
the molecules responsible for carrying oxygen in the blood. The abnormal hemoglobin can
cause damage to the red blood cells. The damaged red blood cell may then stick in the
blood vessels and cause pain and injury to organs. Some of the complications caused by the
sticking of blood cells are called acute pain crisis and acute chest syndrome (ACS).
Nitric oxide (NO) is a gas that has been proposed as a possible therapy for the ACS
complication of sickle cell anemia. Studies have shown that NO may favorably affect sickle
cell hemoglobin molecules, thereby improving blood flow through small vessels.
This study is designed to evaluate the effects of NO, when taken in combination with a drug
called nitroglycerin on patients with sickle cell anemia and normal volunteers. The effects
of these two drugs only last while the patient is receiving them. Researchers hope the
information learned from this study will help to develop new therapies for sickle cell
Sickle cell anemia is an autosomal recessive disorder and the most common genetic disease
affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for
sickle cell disease, and 8% 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, FDA-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
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
prior to and while receiving either NO, nitroglycerin, or placebo. These perfusion
measurements will occur at rest and during concentric dorsiflexion exercise. Magnetic
resonance imaging (MRI) 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 Phosphorus Magnetic
Resonance Spectroscopy (P-MRS) 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: firstly, the characterization of the
microvascular perfusion at rest and during exercise in study subjects with sickle cell
anemia. Secondly, 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.
Males or females 18 to 65 years of age.
Diagnosis of sickle cell disease (electrophoretic documentation of SS homozygosity is
required) or identification as a normal volunteer.
Hematocrit greater than 18% (with an absolute reticulocyte count greater than 100,000/ml).
Hematocrit 18-21% (with an absolute reticulocyte count greater than 100,000/ml): Only 100
ml of blood may be drawn. The study subject may be re-entered in the study after four
weeks (with repeat full screening labs).
Clinically unstable sickle cell anemia defined by the following:
Having greater than two acute pain crises in the last two months; on hydroxyurea or
butyrate therapy any time in the last 12 months; or blood transfusion within last three
months, or % hemoglobin A greater than 20%.
Age less than 18 years or greater than 65 years.
Current pregnancy or lactation.
Inability to exercise the anterior tibialis muscle.
Active cigarette smoker-defined as the inhalation of smoke from any tobacco product in the
last one month.
Medical conditions: diabetes mellitus; coronary artery disease; peripheral vascular
disease; migraine headaches in the last 12 months; history of previous CVA or stroke; or
creatinine greater than 1.0 mg/dL.
MRI Exclusions: cardiac pacemaker or implantable defibrillator; aneurysm clip; neural
stimulator (e.g. TENS-Unit); any type of ear implant; or metal in the eye (e.g. from
machining); any implanted device (e.g. insulin pump, drug infusion device); or any
metallic foreign body, shrapnel, or bullet.
Hematocrit less than or equal to 18 percent: will not be eligible for the study; may
return for evaluation at a later date.
No aspirin or non-steroidal anti-inflammatory drugs (no NSAIDS and caffeine the day of the
study.) Patients on opiates and acetaminophen will not be excluded.
Patients taking Viagra will be excluded from the study.