In the lungs, NO affects not only blood vessels but also the bronchi and bronchioles
as well. In newborns with defective gas exchange, NO inhalation decreases pulmonary
arterial blood pressure, enabling more blood to be oxygenated. In adults with obstruc-
tive lung diseases, NO inhalation seems to relax airway smooth muscle, thus acting as
a bronchodilator.
Finally, NO has significant involvement in both acute and chronic inflammation. In
acute inflammation, NO promotes swelling and increased vascular permeability. In
animal models of acute inflammation, NOS inhibitors have a dose-dependent protective
effect. In models of chronic inflammation (arthritis), NO is detrimental and L-arginine
supplementation causes inflammatory exacerbation. At a molecular level, NO stimu-
lates inflammation by activating the cyclooxygenase enzyme. Further supportive data
are provided by the observation that fluid drained from the swollen joints of people with
arthritis contains peroxynitrate and other oxidation products of NO.
4.11.5 Drug Design Exploitation of NOAlthough the discovery of NO as a neurotransmitter is relatively recent, the use of NO-
related drugs has a much longer history. Patients have been “popping nitros” for years to
alleviate the chest pain associated with angina. Organic nitrates, nitrites, nitroso com-
pounds, and various other nitrogen-containing therapeutics, including sodium nitroprus-
side, exert their pharmacological effect (i.e., vasodilation) through the release and/or
generation of NO. NO achieves vasodilation by activating guanylate cyclase, which in
turn activates cGMP-dependent protein kinases which then phosphorylate the myosin
light chain kinase enzyme, causing its inactivation, which leads to an associated muscle
relaxation in the wall of the artery. As this muscle relaxes, the vessel dilates, heralding
improved blood flow and a reduction in blood pressure. Contraction of smooth muscle
in arterial walls is regulated by reversible phosphorylation of myosin. Smooth muscle
myosin consists of two heavy chain proteins (MW=200,000) associated with two pairs
of light chains; when combined with actin, they participate in a protein kinase-dependent
biochemical cascade that ultimately culminates in either muscle contraction or relaxation.
Since these nitrate-based compounds cause blood vessels to dilate, they are called
nitrovasodilators. Nitrovasodilators have clinical utility in the treatment of angina and
in the treatment of malignant hypertension (high blood pressure that is severely out
of control). Some of the available nitrovasodilator products include amyl nitrite (4.228),
nitroglycerin (4.229), isosorbide dinitrate (4.230), erythrityl tetranitrate (4.231), pentaery-
thritol tetranitrate (4.232) and sodium nitroprusside (4.233).
The recent expanded appreciation of NO’s ubiquitous presence as a messenger sub-
stance in a multitude of organ systems (especially the brain) has motivated the search for
additional NO-related therapeutic molecules. As discussed above, NO is a simple two-
atom molecule not amenable to “analoging.” Rather, the drug designer must either upreg-
ulate or downregulate the enzyme (NOS) central to the biosynthesis of NO. Traditionally,
arginine analogs have represented the largest class of compounds to be exploited as NOS
inhibitors. N-methyl-L-arginine (4.234) is one of the most exhaustively studied arginine
analogs. Owing to the importance of NO, ongoing research continues to design NOS
inhibitors, with an emphasis on compounds that are not arginine analogs.
NEUROTRANSMITTERS AND THEIR RECEPTORS 295