Page 358 - Basic _ Clinical Pharmacology ( PDFDrive )

344 SECTION IV Drugs with Important Actions on Smooth Muscle

the NOS inhibitors used in these trials to differentiate between postsynaptically may function as a retrograde messenger and
NOS isoforms, or may reflect concurrent inhibition of beneficial diffuse to the presynaptic terminal to enhance the efficiency of
aspects of iNOS signaling. neurotransmitter release, thereby regulating synaptic plasticity,
the process of synapse strengthening that underlies learning
and memory. Because aberrant NMDA receptor activation and
INFECTION & INFLAMMATION excessive NO synthesis is linked to excitotoxic neuronal death in
several neurologic diseases, including stroke, amyotrophic lateral
The generation of NO has both beneficial and detrimental sclerosis, and Parkinson’s disease, therapy with NOS inhibitors
roles in the host immune response and in inflammation. The may reduce neuronal damage in these conditions. However,
host response to infection or injury involves the recruitment clinical trials have not clearly supported any benefit of NOS
of leukocytes and the release of inflammatory mediators, such inhibition, which may reflect nonselectivity of the inhibitors,
as tumor necrosis factor and interleukin-1. This leads to a resulting in inhibition of the beneficial effects of eNOS.
marked increase in iNOS levels and activity in leukocytes,
fibroblasts, and other cell types. The NO that is produced,
along with peroxynitrite that forms from its interaction with THE PERIPHERAL NERVOUS SYSTEM
superoxide, is an important microbicide. NO also appears to
play an important protective role in the body via immune cell Nonadrenergic, noncholinergic (NANC) neurons are widely
function. When challenged with foreign antigens, Th1 cells distributed in peripheral tissues, especially the gastrointestinal
(see Chapter 55) respond by synthesizing NO, which has roles and reproductive tracts (see Chapter 6). Considerable evidence
in Th1 cells. The importance of NO in Th1 cell function is implicates NO as a mediator of certain NANC actions, and
demonstrated by the impaired protective response to injected some NANC neurons appear to release NO. Penile erection
parasites in animal models after inhibition of iNOS. NO also is thought to be caused by the release of NO from NANC
stimulates the synthesis of inflammatory prostaglandins by neurons; NO promotes relaxation of the smooth muscle in the
activating cyclooxygenase isoenzyme 2 (COX-2). Through its corpora cavernosa—the initiating factor in penile erection—and
effects on COX-2, its direct vasodilatory effects, and other inhibitors of NOS have been shown to prevent erection caused
mechanisms, NO generated during inflammation contributes by pelvic nerve stimulation in the rat. An established approach
to the erythema, vascular permeability, and subsequent edema in treating erectile dysfunction is to enhance the effect of NO
associated with acute inflammation. signaling by inhibiting the breakdown of cGMP by the phos-
However, in both acute and chronic inflammatory conditions, phodiesterase (PDE isoform 5) present in the smooth muscle of
prolonged or excessive NO production may exacerbate tissue the corpora cavernosa with drugs such as sildenafil, tadalafil, and
injury. Indeed, psoriasis lesions, airway epithelium in asthma, and vardenafil (see Chapter 12).
inflammatory bowel lesions in humans all demonstrate elevated
levels of NO and iNOS, suggesting that persistent iNOS induc-
tion may contribute to disease pathogenesis. Moreover, these RESPIRATORY DISORDERS
tissues also exhibit increased levels of nitrotyrosine, indicating
excessive formation of peroxynitrite. In several animal models of NO is administered by inhalation to newborns with hypoxic
arthritis, increasing NO production by dietary l-arginine supple- respiratory failure associated with pulmonary hypertension. The
mentation exacerbates arthritis, whereas protection is seen with current treatment for severely defective gas exchange in the new-
iNOS inhibitors. Thus, inhibition of the NO pathway may have born is with extracorporeal membrane oxygenation (ECMO),
a beneficial effect on a variety of acute and chronic inflammatory which does not directly affect pulmonary vascular pressures.
diseases. NO inhalation dilates pulmonary vessels, resulting in decreased
pulmonary vascular resistance and reduced pulmonary artery
pressure. Inhaled NO also improves oxygenation by reducing
THE CENTRAL NERVOUS SYSTEM mismatch of ventilation and perfusion in the lung. Inhalation of
NO results in dilation of pulmonary vessels in areas of the lung
NO has an important role in the central nervous system as a with better ventilation, thereby redistributing pulmonary blood
neurotransmitter (see Chapter 21). Unlike classic transmitters flow away from poorly ventilated areas. NO inhalation does not
such as glutamate or dopamine, which are stored in synaptic ves- typically exert pronounced effects on the systemic circulation.
icles and released in the synaptic cleft upon vesicle fusion, NO Inhaled NO has also been shown to improve cardiopulmonary
is not stored, but rather is synthesized on demand and immedi- function in adult patients with pulmonary artery hypertension.
ately diffuses to neighboring cells. NO synthesis is induced at An additional approach for treating pulmonary hypertension
postsynaptic sites in neurons, most commonly upon activation is to potentiate the actions of NO in pulmonary vascular beds.
of the NMDA subtype of glutamate receptor, which results in Due to the enrichment of PDE-5 in pulmonary vascular beds,
calcium influx and activation of nNOS. In several neuronal PDE-5 inhibitors such as sildenafil and tadalafil induce vasodila-
subtypes, eNOS is also present and activated by neurotrans- tion and marked reductions in pulmonary hypertension (see also
mitter pathways that lead to calcium influx. NO synthesized Chapters 12 and 17).