Page 356 - Basic _ Clinical Pharmacology ( PDFDrive )

342 SECTION IV Drugs with Important Actions on Smooth Muscle

arginine-binding site. Since each of the NOS isoforms has high 4. NO Gas Inhalation—NO itself can be used therapeutically.
structural similarity, most of these inhibitors do not exhibit selectivity Inhalation of NO results in reduced pulmonary artery pressure
for individual NOS isoforms. In inflammatory disorders and sepsis and improved perfusion of ventilated areas of the lung. Inhaled
(see below), inhibition of the iNOS isoform is potentially beneficial, NO is used for pulmonary hypertension, acute hypoxemia, and
whereas in neurodegenerative conditions, nNOS-specific inhibi- cardiopulmonary resuscitation, and there is evidence of short-term
tors may be useful. However, administration of nonselective NOS improvements in pulmonary function. NO for inhalation is stored
inhibitors leads to concurrent inhibition of eNOS, which impairs as a compressed gas mixture with nitrogen, which does not readily
its homeostatic signaling and also results in vasoconstriction and react with NO, and further diluted to the desired concentration
potential ischemic damage. Thus, NOS isoform-selective inhibitors upon administration. NO can react with O to form nitrogen
2
are being designed that exploit subtle differences in substrate binding dioxide, a pulmonary irritant that can cause deterioration of lung
sites between the isoforms, as well as newer isoform-selective inhibi- function (see Chapter 56). Additionally, NO can induce the for-
3+
tors that prevent NOS dimerization, the conformation required for mation of methemoglobin, a form of hemoglobin containing Fe
2+
enzymatic activity. The efficacy of NOS isoform-selective inhibitors rather than Fe , which does not bind O (see also Chapter 12).
2
in medical conditions is under investigation. Therefore, nitrogen dioxide and methemoglobin levels are moni-
tored during inhaled NO treatment.
Nitric Oxide Donors
5. Alternate Strategies—Another mechanism to potentiate the
NO donors, which release NO or related NO species, are used actions of NO is to inhibit the phosphodiesterase enzymes that
clinically to elicit smooth muscle relaxation. Different classes degrade cGMP. Inhibitors of type 5 phosphodiesterase such as
of NO donors have differing biologic properties, depending on sildenafil allow NO-induced cGMP elevations to achieve higher
the nature of the NO species released and the mechanism that is cytosolic levels and result in prolongation of the duration of the
responsible for its release. cGMP elevations in a variety of tissues (see Chapter 12). This
can allow otherwise insufficient NO production to have more
1. Organic Nitrates—Nitroglycerin, which dilates veins and pronounced physiologic effects.
coronary arteries, is metabolized to NO by mitochondrial alde-
hyde reductase, an enzyme enriched in venous smooth muscle,
accounting for the potent venodilating activity of this molecule.
Venous dilation decreases cardiac preload, which along with ■ NITRIC OXIDE IN DISEASE
coronary artery dilation accounts for the antianginal effects of
nitroglycerin. Other organic nitrates, such as isosorbide dinitrate, VASCULAR EFFECTS
are metabolized to an NO-releasing species through a poorly
understood enzymatic pathway. Unlike NO, organic nitrates have NO has a significant effect on vascular smooth muscle tone and
less significant effects on aggregation of platelets, which appear blood pressure. Numerous endothelium-dependent vasodilators,
to lack the enzymatic pathways necessary for rapid metabolic such as acetylcholine and bradykinin, act by increasing intracel-
activation. Patients taking organic nitrates exhibit rapid tolerance lular calcium levels in endothelial cells, leading to the synthesis
during continuous administration. This nitrate tolerance may of NO. NO diffuses to vascular smooth muscle, leading to vaso-
derive from the generation of reactive oxygen species that inhibit relaxation (Figure 19–2). Mice with a knockout mutation in the
mitochondrial aldehyde reductase, endogenous NO synthesis, and eNOS gene display increased vascular tone and elevated mean
other pathways (see Chapter 12). arterial pressure, indicating that eNOS is a fundamental regulator
of blood pressure.
2. Organic Nitrites—Organic nitrites, such as the antianginal Apart from being a vasodilator and regulating blood pressure,
inhalant amyl nitrite, also require metabolic activation to elicit NO also has antithrombotic effects. Both endothelial cells and
vasorelaxation, although the responsible enzyme has not been platelets contain eNOS, which acts via an NO-cGMP pathway to
identified. Nitrites are arterial vasodilators and do not exhibit inhibit platelet activation, an initiator of thrombus formation. In
the rapid tolerance seen with nitrates. Amyl nitrite is abused for diseases such as diabetes, endothelial cells are dysfunctional and
euphoric effects, and combining it with phosphodiesterase inhibi- produce reduced levels of NO, resulting in an increased propen-
tors, such as sildenafil, can cause lethal hypotension. In clinical sity for abnormal platelet function and thrombosis. NO may have
medicine, amyl nitrite has been largely replaced by nitrates, such an additional inhibitory effect on blood coagulation by enhancing
as nitroglycerin, which are more easily administered. fibrinolysis via an effect on plasminogen.
NO also protects against atherogenesis. A major antiathero-
3. Sodium Nitroprusside—Sodium nitroprusside, which genic mechanism of NO involves the inhibition of proliferation
dilates arterioles and venules, is used for rapid pressure reduction and migration of vascular smooth muscle cells. In animal models,
in arterial hypertension. In response to light as well as chemical or myointimal proliferation following angioplasty can be blocked
enzymatic mechanisms in cell membranes, sodium nitroprusside by NO donors, by NOS gene transfer, and by NO inhalation.
breaks down to generate five cyanide molecules and a single NO. NO reduces the ability of monocytes and leukocytes to adhere
See Chapter 11 for additional details. to endothelial cells, which is an early step in the development of