NNOS inhibitor

In total, antagonizing direct upstream control over the nNOS isoform can be achieved in part by application of internal and external Ca2+ channel blockers, Ca2+ buffering agents, hyperpolarizing agents or selective nNOS inhibitors such as 6 or 7-nitroindazole, l-(2-trifluoromethylphenyl) imidazole or 6-phenyl-2-aminopyridines [131-133],... 

While all of these events are interconnected, the two most critical are neuronal rapid influx of Ca2+ and activation of nNOS, both which trigger all downstream events. Therefore, directly blocking the toxic effects of glutamate /NO, can be achieved through many means, including selective nNOS inhibitors, Ca2+ channel blockers [NMDA, Kainate/AMPA] [ryanodine-sensitive, IP3], calmodulin antagonists, Ca2+... 

The influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone has been studied in the perfused juxtamedullary nephron preparation [126]. Superfusion with a specific nNOS inhibitor decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume dehvery by papillectomy. When volume delivery to the macula densa segment was increased, afferent arteriolar vasoconstrictor responses to the nNOS inhibitor were enhanced, but this effect was again completely prevented after papillectomy. In contrast, the arteriolar diameter responses to a nonselective NOS inhibitor were only attenuated by papillectomy. Specific nNOS inhibition enhanced the efferent arteriolar vasoconstrictor response to ANG II but did not alter the afferent arteriolar vasoconstrictor responsiveness to ANG II. In contrast, non specific NOS inhibition enhanced both afferent and efferent arteriolar vasoconstrictor responses to ANG It. This study demonstrates that the modulating influence of nNOS on afferent arteriolar tone of juxtamedullary nephrons is dependent on distal tubular fluid flow and that nNOS exerts a differential modulatory action on... 

Phenyl-2-aminopyridines have been explored as potential nNOS inhibitors (52). These compounds have some selectivity for nNOS over eNOS. They point out that the nNOS active site appears to be less sterically hindered than the eNOS active site. When the side-chain in the compound below is quinoline, the ICgo values (joM) for NOS inhibition are 0.21 nNOS and 0.83 eNOS for the PhCOCHa side-chain, the values are 0.14 nNOS and 0.89 eNOS for the PhCHaCO side-chain the values are 0.14 nNOS and 0.69 eNOS for the PhCH2CH2 side-chain the values are 0.26 nNOS and 0.45 eNOS, demonstrating almost complete loss of isoform selectivity. For the iBu side-chain the values are 0.35 nNOS and 0.37 eNOS, demonstrating no isoform selectivity. For the... 

The influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone has been studied in the perfused juxtamedullary nephron preparation [241]. Superfusion with a specific nNOS inhibitor decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume delivery by papillectomy. When volume delivery to the macula densa segment was increased, afferent arteriolar vasoconstrictor responses to the nNOS inhibitor were enhanced. 

Indiscriminate inhibition of all NOS isoforms is achieved by imidazole, N-methyl-L-arginine, L-nitro-arginine methyl ester, or by certain small proteins like PIN. Isoform-specific inhibition has only been achieved for iNOS, with inhibitors like aminoguani-dine, aminoethyl-isothiourea, L-N-6-lysine or 1400W. In particular, the search for an effective and selective nNOS inhibitor has remained fruitless. 

The O2 dependence of NO production in the brain has been investigated under acute hyperbaric conditions in rats with specific nNOS inhibitors and other... 

Similar to nNOS, Ca2+-activated calmodulin is important for the regulation of eNOS activity. However, several other proteins interact with eNOS and regulate its activity. Heat shock protein 90 (hsp90) is found associated with eNOS and probably acts as an allosteric modulator that activates the enzyme. Caveolin-1 binds eNOS and directs it to caveolae. Caveolin-1 is viewed as an inhibitor of eNOS activity, which is being replaced by CaM upon activation of endothelial cells [2]. 

However, more recently, a functionally selective inhibitor of nNOS has been described — 7-nitroindazole (7-NI). It is puzzling that in vitro this compound has no selectivity for nNOS over eNOS but after systemic administration, fails to change blood pressure yet alters neuronal responses that are thought to result from production of NO. A suggested resolution of this action is that 7-NI is metabolised in the periphery but not the CNS, so that once it has crossed the blood-brain barrier, it can only act on nNOS. 

D-GIucal (l,5-anhydro-2-deoxy-D-ara/nno-hex-l-enitol) has been shown to be a competitive inhibitor of a-D-mannosidase,70 but it has less than one-tenth of the inhibitory power of D-mannono-1,5-lactone. D-Glucal is less specific than D-mannono-1,5-lactone, because it also inhibits a- and /3-D-glucosidases.71... 

---