Nitric oxide is important in regulating blood vessel dilation, and consequently, blood flow.
This gas is continuously produced by cells that line the blood vessels. It is also
transported from the lungs by hemoglobin in red blood cells. This study will examine how
this gas regulates blood vessels and blood flow in people with sickle cell anemia. It will
also look at a possible benefit of using certain genetic information to compare the white
blood cells of people with sickle cell anemia to those without the disease.
Patients with sickle cell anemia and healthy normal volunteers 18 to 65 years of age may be
eligible for this study. Candidates will be screened with a medical history, cardiovascular
physical examination, electrocardiogram and routine blood tests. Participation of
volunteers without sickle cell anemia will be limited to a single blood draw for genetic
study. Sickle cell disease patients will undergo the following procedures:
Patients will lie in a reclining chair during the study. After administration of a local
anesthetic, small tubes will be inserted through a needle into the artery and vein of the
patient's forearm. These are used to measure blood pressure and draw blood samples during
the study. Forearm blood flow will be measured using pressure cuffs placed on the wrist and
upper arm, and a strain gauge (a rubber band device) placed around the forearm. When the
cuffs are inflated, blood flows into the arm, stretching the strain gauge, and the flow
measurement is recorded. A small lamp will be positioned over the hand. Light reflected
back from the hand provides information about nitric oxide and hemoglobin in the blood of
the skin. A squeezing device called a dynamometer will be used to measure handgrip
Baseline blood flow, nitric oxide, hemoglobin, and handgrip will be measured after an
infusion of glucose (sugar) and water. These measurements will be repeated at various times
before, during and after administration of small doses of the following drugs:
- Sodium nitroprusside - causes blood vessels to dilate and increases blood flow to the
- Acetylcholine - causes blood vessels to dilate and slows heart rate
- LNMMA - decreases blood flow by blocking the production of nitric oxide
There will be a 20- to 30-minute rest period between injections of the different drugs.
When the above tests are completed, the patient will breathe a mixture of room air and
nitric oxide for 1 hour through a facemask placed over the face, after which forearm blood
flow and light reflected from the hand will be measured. Then the patient will do the
handgrip exercise for 5 minutes, after which blood flow and hand lamp measurements will be
taken. After a 20-minute rest period (with continued breathing of room air/nitric oxide),
L-NMMA will be infused again. The handgrip exercise, blood flow and hand lamp measurements
will be repeated. The face mask will then be removed, and the tubes will be removed 20
Blood samples will be collected at various times during the 5- to 6-hour study through the
tubes in the arm. Some of the blood will be used to look at genes that make proteins
involved in cell-to-cell communication, inflammation, and in making red and white blood
cells stick to the lining of blood vessels.
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 are common complications of sickle cell anemia. Inhaled nitric oxide (NO) has been
proposed as a possible therapy for the acute chest syndrome. Anecdotally, NO has been
described to rapidly improve the hypoxemia and the clinical course of the acute chest
syndrome. Furthermore, a number of recent studies have suggested that NO may have a
favorable impact on sickle red cells at the molecular level and could improve the abnormal
microvascular perfusion that is characteristic of sickle cell anemia. This clinical trial
is designed to test the hypotheses that 1) individuals with sickle cell anemia have
endothelial dysfunction with reduced local synthesis and release of NO, that may reduce
regional perfusion at rest and impair the vasodilator response to stress, and 2) during NO
inhalation, delivery of NO bound to hemoglobin will be enhanced and will improve these
abnormalities in regional vascular perfusion. Studies will be performed on untreated sickle
cell anemia patients and on patients managed with chronic hydroxyurea therapy.
Demonstration of improved regional perfusion with NO therapy could have significant
implications for patient management during acute pain crisis and the acute chest syndrome.
Males or females 18 to 65 years of age are eligible.
Diagnosis of sickle cell disease (electrophoretic documentation of SS, SC, or S beta(0)
thallassemia genotype is required).
Hematocrit greater than 18 percent (with an absolute reticulocyte count greater than
Volunteer subjects taking hydroxyurea must have been on therapy with the drug for at least
four months. Volunteer subjects not taking hydroxyurea must have been off of therapy with
the drug for at least 4 months.
Clinically unstable sickle cell anemia defined as having an acute pain crisis within the
Age less than 18 years or greater than 65 years.
Current pregnancy or lactation.
Conditions that may independently affect endothelial function:
1. Diabetes mellitus or Fasting blood sugar greater than 120 mg/dL
2. Cigarette smoking within two years
3. Hypertension (diastolic blood pressure greater than 90 mmHg)
4. Lipid abnormalities (LDL cholesterol greater than 160 mg/dL, HDL cholesterol less
than 30 mg/dL, triglycerides greater than 500 mg/dL)
5. Creatinine greater than 1.0 mg/dL
Hematocrit less than or equal to 18 percent: however, patients may return for evaluation
at a later date.
No aspirin or non-steroidal antiinflammatory drugs (NSAIDs for one week and caffeine the
day of the study). Patients on opiates and acetaminophen will not be excluded.
Patients taking sildenafil (Viagra) will be excluded from the study.
Recent transfusion (last 4 weeks) or hemoglobin A greater than 5 percent.