Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 66

(Flögel et al. 2010 ). They found that decrease in tissue O 2 tension drives the conversion
of Mb from being a NO scavenger under normoxia to a NO producer during
hypoxia, and mitochondrial respiration is reversibly adapted to the intracellular O 2
tension. Therefore, Mb may act as an important O 2 sensor through which NO can
regulate muscle energetics and function. It was concluded that Mb's multifunc-
tional properties may create an environment characterized by a tightly adapted
aerobic mitochondrial respiration and low levels of free radicals, and thus serve an
essential and beneficial role within the myocardium.
NO and Pulmonary Circulation
In contrast to systemic vascular smooth muscle, pulmonary vascular smooth muscle
constricts in response to local hypoxia. This is because of the basic differences
between the two circulatory systems. The goal of systemic circulation is to deliver
oxygen to those tissues most in need, whereas pulmonary circulation aims to match
ventilation and perfusion for optimal alveolar gas exchange. Thus local hypoxia
anywhere in the systemic circulation results in vasodilation and increased blood
flow to the hypoxic regions. On the other hand, hypoxic pulmonary vasoconstric-
tion acts to divert blood away from hypoxic lung regions. This minimizes the effect
of lung pathology on the arterial PO 2 by reducing blood flow to the poorly venti-
lated, hypoxic alveoli. The pulmonary vasculature responds predominantly to
alveolar rather than circulatory hypoxia and the response is rapid with rise of pul-
monary artery pressure. There are several proposed mechanisms for the initiation
of hypoxic pulmonary vasoconstriction. According to one of these hypotheses,
hypoxia increases free radical production and activates K channels in systemic
arteries, but it decreases free radical production and inhibits K channels in the pul-
monary circulation. Various oxygen sensor mechanisms to explain this difference
are not satisfactory. This has focused attention on the role of NO and hemoglobin
on hypoxic pulmonary vasoconstriction.
Role of NO in the Regulation of Hypoxic Pulmonary Vasoconstriction
Basal release of NO from pulmonary vascular endothelium and airway epithelium
acts to moderate hypoxic pulmonary vasoconstriction through activation of guany-
late cyclase and production of cGMP. Hypoxic pulmonary vasoconstriction is
markedly enhanced by NOS and is inhibited by inhalation of NO. NOS enzyme
activity is dependent on oxygen concentration. Therefore, a fall in NO production
during hypoxia due to reduced NOS activity may enhance pulmonary vasoconstric-
tion. Another explanation for the pulmonary vasoconstriction despite continuous
NO production lies within the vascular lumen in the form of red blood cells (RBCs)
because hemoglobin contained in these cells inactivates NO. This interaction
between RBCs, NO, and the pulmonary circulation is critical in understanding the
effects of anemia and polycythemia on pulmonary blood flow distribution, gas
exchange, and global oxygen delivery and in understanding the development of
hemoglobin-based oxygen carriers. Pharmacologic (cross-linking) modification of