PHARMACOLOGIC MANIPULATION OF NITRIC OXIDE
The primary strategy to reduce NO generation in cells is to use NOS inhibitors. The majority of these inhibitors are arginine analogs that bind to the NOS arginine-binding site. Since each of the NOS isoforms has high structural similarity, most of these inhibitors do not exhibit selectivity for individual NOS isoforms. In inflammatory disorders and sepsis , inhibition of the iNOS isoform is potentially beneficial, whereas nNOS-specific inhibitors may be useful for the treatment of neurodegenerative conditions. However, administration of nonselective NOS inhibi-tors leads to concurrent inhibition of eNOS, which impairs its homeostatic signaling and also results in vasoconstriction and potential ischemic damage. Thus, NOS isoform-selective inhibi-tors are being designed that exploit subtle differences in substrate binding sites between the isoforms, as well as newer iso-form-selective inhibitors that prevent NOS dimerization, the conformation required for enzymatic activity. The efficacy of NOS isoform-selective inhibitors in medical conditions is under investigation.
NO donors, which release NO or related NO species, are used to elicit smooth muscle relaxation. Different classes of NO donors have differing biologic properties, depending on the nature of the NO species released and the mechanism that is responsible for its release.
1. Organic nitrates—Nitroglycerin, which dilates veins andcoronary 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 coronary artery dilation accounts for the antianginal effects of nitroglycerin. Other organic nitrates, such as isosorbide dini-trate, are metabolized to an NO-releasing species through a poorly understood enzymatic pathway. Unlike NO, organic nitrates have less significant effects on aggregation of platelets, which appear to lack the enzymatic pathways necessary for rapid metabolic activation. Organic nitrates exhibit rapid tolerance during continuous administration. This nitrate tolerance may derive from the generation of reactive oxygen species that inhibit mitochondrial aldehyde reductase, endogenous NO synthesis, and other pathways .
2. Organic nitrites—Organic nitrites, such as the antianginalinhalant amyl nitrite, also require metabolic activation to elicit vasorelaxation, although the responsible enzyme has not been identified. Nitrites are arterial vasodilators and do not exhibit the rapid tolerance seen with nitrates. Amyl nitrite is abused for euphoric effects and combining it with phosphodiesterase inhibi-tors, such as sildenafil, can cause lethal hypotension. Amyl nitrite has been largely replaced by nitrates, such as nitroglycerin, which are more easily administered.
3. Sodium nitroprusside—Sodium nitroprusside, whichdilates arterioles and venules, is used for rapid pressure reduction in arterial hypertension. In response to light as well as chemical or enzymatic mechanisms in cell membranes, sodium nitroprusside breaks down to generate five cyanide molecules and a single NO..
4. NO gas inhalation—NO itself can be used therapeutically.Inhalation of NO results in reduced pulmonary artery pressure and improved perfusion of ventilated areas of the lung. Inhaled NO is used for pulmonary hypertension, acute hypoxemia, and cardiopulmonary resuscitation, and there is evidence of short-term improvements in pulmonary function. Inhaled NO is stored as a compressed gas mixture with nitrogen, which does not readily react with NO, and further diluted to the desired concentration upon administration. NO can react with O2 to form nitrogen dioxide, a pulmonary irritant that can cause deterioration of lung function . Additionally, NO can induce the for-mation of methemoglobin, a form of hemoglobin containing Fe3+ rather than Fe2+, which does not bind O2. Therefore, nitrogen dioxide and methemoglobin levels are moni-tored during inhaled NO treatment.
5. Alternate strategies—Another mechanism to potentiatethe actions of NO is to inhibit the phosphodiesterase enzymes that degrade cGMP. Inhibitors of type 5 phosphodiesterase such as sildenafil result in prolongation of the duration of NO-induced cGMP elevations in a variety of tissues .