Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 65

directly with FeO 2 . Thus, native RBCs respond to changes in oxygen tension (pO 2 )
with graded vasodilator and vasoconstrictor activity, which emulates the human
physiological response subserving O 2 uptake and delivery. The ability to monitor
and manipulate blood levels of NO, in conjunction with O 2 and carbon dioxide, may
therefore prove useful in the diagnosis and treatment of many human conditions and
in the development of new therapies. These results also help elucidate the link
between RBC dyscrasias and cardiovascular morbidity.
Hb needs its natural partner in the blood, NO, to do its job of delivering oxygen
to tissues, but current treatments deliver Hb without NO. Hb by itself actually
reduces oxygenation to tissue because it constricts blood vessels, reducing blood
flow. Thus, when delivered alone, hemoglobin may cause potentially fatal side
effects and limit the effectiveness of radiation and chemotherapy. Some studies have
shown that S-nitrosohemoglobin (SNO-Hb) behaves as a NO donor at low oxygen
tensions. This property, in combination with oxygen transport capacity, suggests that
SNO-Hb may have unique potential to reoxygenate hypoxic tissues. Simply addi-
tion of NO to the Hb can make it deliver more oxygen to tissues without boosting
heart rate or constricting blood vessels (Sonveaux et al. 2005 ). These findings open
up the possibility of using S-nitrosohemoglobin (SNO), combination of NO and Hb,
therapeutically in patients where there is inadequate oxygen perfusion to tissue.
Nitrite anions comprise the largest vascular storage pool of NO, provided that
physiological mechanisms exist to reduce nitrite to NO. In an experimental study,
nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated
Hb and, to a lesser extent, S-nitroso-Hb (Cosby et al. 2003 ). NO-modified Hb for-
mation was inversely proportional to oxyHB saturation. Vasodilation and formation
of both NO gas and NO-modified Hb resulted from the nitrite reductase activity of
deoxyHb and deoxygenated erythrocytes. This finding links tissue hypoxia, Hb,
and nitrite bioactivation suggesting that nitrite represents a major bioavailable pool
of NO. Thus, a new physiological function for Hb is that of a nitrite reductase,
which potentially contributes to hypoxic vasodilation. These findings indicate that
therapeutic application of nitrite should result in selective vasodilation of hypox-
emic tissue and could be used to treat disease associated with ischemic tissue,
neonatal pulmonary hypertension and hemolytic conditions such as sickle cell ane-
mia where Hb released during hemolysis scavenges and disrupts NO-dependent
vascular function. Nitrite would not only inhibit the ability of free Hb to scavenge
NO by oxidizing it to methemoglobin but would also generate NO in tissue beds
with low oxygen tension.
Myoglobin and NO
Myoglobin (Mb) is a molecular relative of Hb and together these hemoproteins play
vital roles in one of the most important aspects of animal metabolism: the acquisi-
tion and utilization of O 2 . Mb not only is a key element determining the magnitude
of the NO response in muscle but also plays an important role in overall NO inac-
tivation in vivo. Experiments in myo(−/−) mice have shown that beyond its func-
tion in O 2 supply Mb substantially contributes to NO homeostasis in the heart