Nitric oxide donor molecules

Apart from being a vasodilator, nitric oxide is also a potent inhibitor of neutrophil adhesion to the vascular endothelium. This is due to the inhibitory effect of nitric oxide on the expression of adhesion molecules on the endothelial surface. The role of nitric oxide in protecting the endothelium has been demonstrated by studies that showed that treatment with nitric oxide donors protects against ischemia- and reperfusion-mediated endothelial dysfunction. 

When the effect of nitric oxide donors on cGMP-accumulation is studied, one must take into account the rate of NO-release from the donor compound The diffusion rate of NO is quite high, because of the small size and hpophihcity of this molecule (45), Sodium nitroprusside (SNP) is often used an NO-donor. This compound is inexpensive, which is an important asset. However, the byproduct after NO-release, [Fe(CN)5], is not devoid of pharmacological activity (46) In addition, SNP is light sensitive, although in most cases this property should not rule out use of this compound. In 10-min incubations with brain slices, SNP and the NO-donors S-nitroso-acetyl-penicillamine and streptozotocin were equally effective in raising cGMP levels (unpublished). 

Nitric oxide (NO) is an intercellular signaling molecule that can inhibit neuronal energy production (Brorson et al., 1999 Malefic et al., 2004). It has been found that NO donors cause large increases in extracellular adenosine in cultures of forebrain neurons (Rosenberg et al., 2000). These were shown to be caused by NO release, and the accumulation of adenosine was not blocked by probenecid (ENT blocker) or GMP (a blocker of AMP hydrolysis), suggesting that adenosine was likely of intracellular origin. Indeed, it was found that NO donors caused a decrease in intracellular ATP and the inhibition of adenosine kinase activity, possibly due to the rise in adenosine. 

These compounds contain the fragment R as an alkyl or aryl moiety. In other words, they result from the esterification of an alcohol or a phenol with nitrous acid, nitric acid, phosphoric acid, sulfuric acid, or sulfamic acid, respectively. Many of the esters to be examined in this chapter must be activated prior to eliciting their effects, e.g., the organic nitrites and nitrates, which act as donors of nitric oxide or an analogous molecule, and phosphates, which are activated by hydrolysis or even by phosphorylation (antiviral agents). Sulfates are very seldom active or used as prodrugs, but they have significance as metabolites and as industrial xenobiotics. 

Fig. 4. The enviromnent of the di heme in various states of the P. pantotrophus cytochrome cdi. (a) The oxidized enz3rme. (b) The reduced enzyme, (c) The reduced enzyme to which nitrite has been added, (d) The reduced enzyme that has converted bound nitrite to nitric oxide. T3rr25 provides an axial oxygen ligand to the di heme iron in the oxidized enz3rme (a). This T3rr25 is displaced in the reduced enzyme (b) but can be seen returning to the di heme in the structures with nitrite (c) or nitric oxide (d) bound. His 345 and His 388 are proposed proton donors to the substrate. In (b) the di heme iron is five-coordinate. The water molecule (Wat) that is seen above the heme ring is not coordinated to the iron. Dashed lines represent potential hydrogen bonds. (Drawn from PDB entries 1 qks, 1 aof, 1 aom and 1 aoq.)...

Treatment of the complex with donor molecules such as pyri-dines, phosphines, bipyridyl (2,2 -bipyridine), etc., results in the cleavage of the dimer and formation of diamagnetic five- and six-coordinate adducts.4 Nitric oxide reacts with the complex forming the unstable green mononitrosyl [Co(NO)S4C4(CN)4]-which has one unpaired electron.3 Treatment with Na2S2C2-(CN)2 results in the formation of [CoS6C6(CN6)]3 which can be isolated as the tetraphenylphosphonium salt.14... 

The copper-protein type nitrite reductases have been purified from several denitrifying bacteria. They have 2 1 copper atoms in the molecule one copper per subunit (30 10 kDa). The enzymes catalyze the reduction of nitrite to nitric oxide, but the physiological electron donors for the enzymes have not been clarified, though they are said to be cytochrome c in some cases and a copper-protein in some cases (see Otsuka and Yamanaka, 1988). 

Mooradian, D. L., Hutsell, T. C., and Keefer, L. K. (1995). Nitric oxide (NO) donor molecules Effect of NO release rate on vascular smooth muscle cell proliferation in vitro. J. Cardiovasc. Pharmacol. 25, 674-678. 

In contrast, drugs that release endogenous nitric oxide and donors of the molecule were in use long before nitric oxide was discovered and continue to be very important in clinical medicine. The cardiovascular applications of nitroprusside (Chapter 11) and the nitrates and nitrites (Chapter 12) have been discussed. The treatments of preeclampsia and of pulmonary hypertension and acute respiratory distress syndrome are currently under clinical investigation. Early results from the pulmonary disease studies appear promising, and one preparation of nitric oxide gas (INOmax) has been approved for use in neonates with hypoxic respiratory failure. 

In search for marker molecules specifically expressed in nitric oxide (1 mM nitroprusside or 0.1-2 mM S-nitroso-N-acetyl-penicillamine as "NO donors) treated islet cells to recognise early events in islet destruction, Fehsel etal. (1997) immuno-cytochemically established the presence of neo-C-reactive protein in rat islet cells as early as 2 h after treatment. 

The compound Tr-CsHsNiNO is regarded as formed by a three-electron donation from the nitric oxide ligand. Most NO complexes are best considered as being formed by an initial one-electron transfer to the metal prior to donation from the nitrosonium ion (NO ). The nitric oxide ligand, a so-called odd molecule, is then effectively a three-electron donor. Such a bonding mode is supported by considerable infrared, ESR, and other structural data. It should be noted, however, that recent interpretation of ESR data in terms of MOT indicates that the nitric oxide ligand also can be described by the formal structures NO- and NO , in some complexes. 

The reaction between iron pentacarbonyl and nitric oxide involves the replacement of three carbonyl groups by two nitric oxide molecules. Electronically, this is the equivalent, as nitric oxide is a three-electron donor ligand, whereas carbon monoxide is a two-electron donor. 

---