This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, L-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.

/pdf/nitric-oxide-synthases-structure-function-and-inhibition-1t31plqilr.pdf

Nitric oxide synthases: structure, function and inhibition

http://neponosimosti.com/wp-content/uploads/2010/10/histamine-intol-rev-2007.pdf

Histamine and histamine intolerance

Selective pharmacological inhibition of distinct nitric oxide synthase isoforms

Phytogenic agents have traditionally been used by herbalists and indigenous healers for the prevention and treatment of peptic ulcer. This article reviews the anti-acid/anti-peptic, gastro-protective and/or anti-ulcer properties of the most commonly employed herbal medicines and their identified active constituents. Botanical compounds with anti-ulcer activity include flavonoids (i.e. quercetin, naringin, silymarin, anthocyanosides, sophoradin derivatives) saponins (i.e. from Panax japonicus and Kochia scoparia), tannins (i.e. from Linderae umbellatae), gums and mucilages (i.e. gum guar and myrrh). Among herbal drugs, liquorice, aloe gel and capsicum (chilli) have been used extensively and their clinical efficacy documented. Also, ethnomedical systems employ several plant extracts for the treatment of peptic ulcer. Despite progress in conventional chemistry and pharmacology in producing effective drugs, the plant kingdom might provide a useful source of new anti-ulcer compounds for development as pharmaceutical entities or, alternatively, as simple dietary adjuncts to existing therapies.

The plant kingdom as a source of anti‐ulcer remedies

γ-Aminobutyrate (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two types of GAD appear to have significant physiological roles. GABA functions appear to be triggered by binding of GABA to its ionotropic receptors, GABAAand GABAC, which are ligand-gated chloride channels, and its metabotropic receptor, GABAB. The physiological, pharmacological, and molecular characteristics of GABAA receptors are well documented, and diversity in the pharmacologic properties of the receptor subtypes is important clinically. In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain.

GABA and GABA receptors in the central nervous system and other organs.

A sensitive and specific method for the determination of histomine in human whole blood and plasma.

Distribution and properties of human intestinal diamine oxidase and its relevance for the histamine catabolism

A standard procedure for the determination of the diamine oxidase (DAO) activity is described as a modification of the method ofOkuyama andKobyashi [2]. The principle of this method is the assay of14C-Δ1-pyrroline and its polymers formed by the oxydative deamination of14C-putrescine in the presence of DAO. This assay was shown to possess a high sensitivity and precision. Now its accuracy could be enhanced by the comparison with the NADH test for DAO activity. This kind of a reference method made the direct correlation between cpm/min and deamination rates possible. Thus International Units (mU/sample) could be introduced into the isotope assay: In our test system 1 mU corresponded to 215 cpm/min, this value depending on the specific radioactivity of the substrate solution.

Comparison of the 14-C-putrescine assay with the NADH test for the determination of diamine oxidase: description of a standard procedure with a high precision and an improved accuracy.

https://www.gastrojournal.org/article/0016-5085(81)90069-X/pdf

Intestinal diamine oxidase and histamine release in rabbit mesenteric ischemia.

Histamine is not uniformly distributed in the human and animal organisms, but occurs in high concentrations in the gastric mucosa. The enzymes responsible for its metabolism--histidine decarboxylase, histamine N-methyltransferase and diamine oxidase--seem to be less predominantly localized in the stomach. Considerable effort was necessary to detect and measure histamine formation in the gastric mucosa. This was a controversial subject that only was solved recently. Histamine inactivation by histamine methyltransferase occurs in man in the fundic gastric mucosa that has reasonable enzymic activity. However, liver, spleen and intestine show much higher activities indicating less specificity of histamine catabolism in the gastric mucosa. Finally, diamine oxidase activity was once thought to be absent in the corpus mucosa, but more recently, moderate activities of this enzyme were found in several species, including man. Thus, histamine metabolism in the gastric mucosa is by no means unique in mammalian tissues, but the presence of these enzymes may be regarded as an indicator of its physiological function. To some extent enzymic activities involved in histamine formation and inactivation are regulated in the process of acid secretion. Histidine decarboxylase and histamine N-methyltransferase activities are enhanced by gastrin, but are not influenced by vagal stimulation. Hitherto, only histamine methylation was found to be diminished in duodenal ulcer disease. Vagotomy and histamine H2-receptor antagonists modulate histamine catabolism by histamine methyltransferase. The implication of these findings for treatment of duodenal ulcer are discussed.

/pdf/metabolism-and-function-of-gastric-histamine-in-health-and-4g0qr5hfj7.pdf

J. Kusche

Papers

A sensitive and specific method for the determination of histomine in human whole blood and plasma.

Distribution and properties of human intestinal diamine oxidase and its relevance for the histamine catabolism

Comparison of the 14-C-putrescine assay with the NADH test for the determination of diamine oxidase: description of a standard procedure with a high precision and an improved accuracy.

Intestinal diamine oxidase and histamine release in rabbit mesenteric ischemia.

Metabolism and function of gastric histamine in health and disease.