**7.5 NO donor drugs**

66 Liver Transplantation – Basic Issues

concentrations. The measurement of iNO and NO2 concentrations can be undertaken using chemiluminescence or electrochemical devices. There are some drawbacks of chemiluminescence devices such as cost, the need for a relatively high sample volume, noise and maintenance difficulties (Mupanemunda & Edwards, 1995). However, an electrochemical analyzer is relatively insensitive, and these measurements may be affected by pressure, humidity, temperature and the presence of other gases in the environment (Macrae et al., 2004). The delivery system should display the pressure of iNO in the cylinder and should have a backup power supply to avoid sudden discontinuation of iNO. Inhaled NO is usually supplied in nitrogen at various concentrations. The gas mixture concentration should be sampled downstream of the input port just proximal to the patient manifold. iNO also can be administered via nasal cannula, oxygen mask and oxygen hood (Ambalavanan, St John, Carlo, Bulger, & Philips, 2002). Finally, the exhausted gas should be scavenged by passing it through carbon and filters, soda lime or activated charcoal (Ambalavanan, El-

In the presence of high concentrations of O2, NO oxidizes to nitrogen dioxide (NO2). NO2 reacts with the alveolar lining fluid to form nitric acid. NO dissolves in the alveolar lining

Squadrito, 1995). Nitration of tyrosine residues of proteins is used as a marker of oxidative stress (Ischiropoulos, 1998). The rate at which NO is oxidized to NO2 depends on the square of NO concentration and fractional concentration of oxygen to which it is exposed. The Occupational and Health Administration recommend 5 ppm/8 hr/24 hour interval as the upper safe limit of human exposure (Fullerton & McIntyre, 1996). In order to protect against NO2 toxicity, iNO should be given with the least possible O2 concentration. Inhaled NO and NO2 concentrations should be monitored, exhaled gases should be scavenged and a soda

The simple molecule nitrite had been thought to be just an index of NO production for decades (Köken & Inal, 1999). Recently, a number of evidence suggests that nitrite is a promediator of NO homeostasis. Administration of nitrite at near physiological concentrations (<5 μg) leads to vasodilatation in animals and human studies (Fullerton & McIntyre, 1996). Gladwin *et al* observed that nitrite was metabolized across the peripheral circulation. In addition, nitrite caused an increase in peripheral forearm blood flow when 80 ppm iNO was administered (Shiva & Gladwin, 2009). Under distinct conditions such as hypoxia and acidosis, nitrite can be reduced to NO by a number of deoxyhemeproteins (hemoglobin, myoglobin, neuroglobin and cytoglobin), enzymes (cytochrome P450 and xanthine oxidoreductase), and components of the mitochondrial electron transport chain (Zaky et al., 2009). Since nitrite can be converted back to NO during hypoxia nitrite therefore is expected to be utilized during ischemia reperfusion injury. Furthermore, nitrite shows more potential benefits than NO in terms of safety and ease of administration. In other words, nitrite concentrations administered need only a small dose in order to increase plasma and tissue nitrite level several-fold. Routes of administration are oral, intravenous injection or infusion, intraperitoneal, nebulizer or topical (Duranski et al., 2005). Nitrite has now been

lime canister should be placed in the inspiratory limb of the breathing circuit.

then decomposes into a hydroxyl anion (Pryor &

Ferzli, Roane, Johnson, & Carlo, 2009).

fluid reacts with O2- yielding OONO,-

**7.4 Nitrite** 

**7.3 Potential toxicities during inhalation** 

Since nitric oxide is not considered to be an ideal gas for the treatment of ischemia reperfusion injury, NO donor drugs are now being explored as an alternative to the parent compound. Novel drugs have been developed and used for the delivery of NO in order to compensate for the very short half-life of NO in vivo. However, there are only two types of NO donor drugs that are currently used clinically: organic nitrates and sodium nitroprusside. Organic nitrates are the most commonly used NO donor drugs treatment for coronary artery disease and congestive heart failure because the drugs produce clear clinical responses through their vasodilatory effects. Preparations of drugs include: slow release oral forms, ointments, transdermal patches, nebulizers and traditional intravenous forms. The main limitation of organic nitrates is the induction of drug tolerance with prolonged continuous use. NO release from nitroglycerin is likely via the enzyme mitochondrial aldehyde dehydrogenase (Yang, Chen, Kong, Xu, & Lou, 2007). On the other hand, the mechanism of NO release from sodium nitroprusside is more complex as demonstrated by


Table 2. Nitric oxide donors

Yang et al in a murine model of hepatic IRI. Sodium nitroprusside is thought to downregulate the mRNA expression of several enzymes related to hepatic injury (Katsumi et al., 2008). Lastly, enhanced eNOS activation affords hepatoprotection during IRI and serves as yet another potential treatment option. Interestingly, liver preservation solutions supplemented with the agents trimetazidine (TMZ), 5-amino-4-imidazole carboxamide riboside (AICAR) or activated protein C (APC) have demonstrated allograft protection during conditions of cold ischemia (Katsumi, Nishikawa, Yasui, Yamashita, & Hashida, 2009). Below, we summarize other novel NO donor drugs in Table 2.
