4.11.4 Non-Neurologic Roles of NONitric oxide has many roles as a messenger outside of the nervous system. In organ
systems, ranging from the brain to the gut, NO exhibits significant vascular effects
by influencing vascular smooth muscle tone and blood pressure. A reduction in NO
synthesis (achieved using NOS inhibitors) increases vascular tone and elevates the
mean arterial blood pressure. Conversely, an enhancement of NO-mediated effects
tends to decrease vascular tone, causing dilation of blood vessels and reduction of blood
pressure. These vascular effects of NO are diffusely distributed throughout the body.
Not surprisingly, NO is involved in diseases in which altered vascular tone and blood
pressure are important mechanistic participants. For instance, NO may play a major
role in arterial hypertension associated with pregnancy. Pre-eclampsiaandeclampsia,
medical conditions for which no explanation currently exists, are major causes of
maternal and perinatal morbidity throughout the world. Clinically, these conditions are
characterized by increased blood pressure, edema (swelling of the extremities), and
proteinuria (protein in the urine, arising from kidney injury) in the mother and by
intrauterine growth retardation in the fetus. As the condition progresses, the mother
experiences severe elevation in blood pressure, resulting in organ damage and failure
(e.g., liver and kidney dysfunction, seizures). Some workers speculate that NO may
play a central role in pre-eclampsia. One hypothesized mechanism invokes reduced
production of NO that is associated with enhanced formation of thromboxanes and
free radicals. Indeed, the use of L-arginine as a nutritional supplement to augment NO
levels has been proposed as a therapeutic approach to pre-eclampsia.
NO also seems to play a role in the hypotension of septic shock. Septic shock is a
life-threatening clinical condition occurring as a complication of bacterial infections
and characterized by hypotension, shock, organ failure, and death. In severe Gram-
negative bacterial infections, increased urinary excretion of nitrates, an oxidative
byproduct of NO, has been described; bacterial wall lipopolysaccharides activate the
NOS enzyme.
NO exerts other effects on blood vessels. For example, atherosclerotic plaques aris-
ing from hypercholesterolemia produce narrowed blood vessels and reduced formation
of NO. In animal models, the thickening of blood vessel walls after surgical procedures
such as angioplasty can be blocked using NO donors, NO inhalation, or NOS gene
transfer. One instance in which NO participation in atherosclerosis is particularly evi-
dent concerns organ transplantation. Accelerated atherosclerosis in the blood vessels
within the transplanted organ is a common chronic condition that may lead to transplant
failure and death. By reducing free radical toxicity, NO may act as a cytoprotective agent
under such transplantation conditions; in fact, careful (and not excessive) L-arginine sup-
plementation has been demonstrated to reduce transplant organ atherosclerosis.
Of equal significance is the role played by NO on platelet function. Platelets are
small bodies (2–4 μm in diameter) found in the circulating blood at a concentration of
300,000 per μL of blood; when a blood vessel is transected or injured, platelets clump
together, stopping the leakage of blood. However, excessive platelet “stickiness” can
lead to unwanted blood vessel blockage, enhancing the likelihood of occluded blood
vessels in the heart (precipitating a heart attack) or brain (leading to a stroke). Nitric
oxide is a potent inhibitor of platelet adhesion and aggregation.
294 MEDICINAL CHEMISTRY