A QSAR and molecular modeling study on a series of 3, 4-dihydro-1-isoquinolinamines and thienopyridines acting as nitric oxide synthase inhibitors.

A quantitative structure-activity relationship (QSAR) and molecular modeling study were performed on a series of 3,4-dihyro-1-isoquinolinamines and thienopyridines reported by Beaton et al. [Beaton et al. (2001) Bioorg Med Chem Lett 11, 1023-1026, 1027-1030] as potent, highly selective inhibitors of two isoforms of nitric oxide synthase (NOS) — neuronal NOS (nNOS) and endothelial NOS (eNOS), in order to find the physicochemical properties that governed their activity and the mode of interaction with the receptors, so that still more potent compounds in the series could be suggested. A multiple regression analysis revealed that nNOS and eNOS inhibition potency of these compounds could be controlled by their hydrophobic property and molar refractivity, respectively. Thus, nNOS and eNOS inhibition was indicated to involve the hydrophobic interaction and steric effects, respectively, suggesting some structural differences of the two isoforms of NOS. Based on the correlations obtained, some new, more potent compounds belonging to the series were predicted. These compounds were then docked into the receptors to see their interactions and find out the docking scores. The docked structures of two representative compounds, whose interaction energies with nNOS and eNOS, respectively were found to be the lowest, were given as an example to exhibit the possible orientation of the compounds to interact with the receptors.

Involvement of nitric oxide pathways in neurogenic pulmonary edema induced by vagotomy

OBJECTIVE: The objective of this study was to evaluate the involvement of peripheral nitric oxide (NO) in vagotomy-induced pulmonary edema by verifying whether the nitric oxide synthases (NOS), constitutive (cNOS) and inducible (iNOS), participate in this mechanism. INTRODUCTION: It has been proposed that vagotomy induces neurogenic pulmonary edema or intensifies the edema of other etiologies. METHODS: Control and vagotomized rats were pretreated with 0.3 mg/kg, 3.0 mg/kg or 39.0 mg/kg of L-NAME, or with 5.0 mg/kg, 10.0 mg/kg or 20.0 mg/kg of aminoguanidine. All animals were observed for 120 minutes. After the animals' death, the trachea was catheterized in order to observe tracheal fluid and to classify the severity of pulmonary edema. The lungs were removed and weighed to evaluate pulmonary weight gain and edema index. RESULTS: Vagotomy promoted pulmonary edema as edema was significantly higher than in the control. This effect was modified by treatment with L-NAME. The highest dose, 39.0 mg/kg, reduced the edema and prolonged the survival of the animals, while at the lowest dose, 0.3 mg/kg, the edema and reduced survival rates were maintained. Aminoguanidine, regardless of the dose inhibited the development of the edema. Its effect was similar to that observed when the highest dose of L-NAME was administered. It may be that the non-selective blockade of cNOS by the highest dose of L-NAME also inhibited the iNOS pathway. CONCLUSION: Our data suggest that iNOS could be directly involved in pulmonary edema induced by vagotomy and cNOS appears to participate as a protector mechanism.

Efeito do óxido nítrico no transporte mucociliar / Effects of nitric oxide in mucociliary transport

As vias aéreas, constituídas por epitélio ciliado e secretor de muco, promovem ao trato respiratório mecanismo de defesa que livra esta superfície das partículas inaladas durante a respiração. É de fundamental importância o entendimento da fisiologia e dos mecanismos envolvidos com a atividade mucociliar. A literatura sugere que o NO, em especial o produzido pela expressão da iNOS, mantém a função mucociliar e a defesa imune da cavidade nasal. Objetivo: Avaliar o envolvimento do NO e das vias enzimáticas da produção do NO no transporte mucociliar, utilizando inibidores da NO sintase constitutiva e indutiva, L-NAME e aminoguanidina, respectivamente. Materiais e métodos: Preparações de palatos de rã foram imersos em soluções de ringer (controle), L-NAME ou aminoguanidina. Os palatos foram imersos nestas soluções por quatro períodos de 15 minutos. Medidas da velocidade do transporte mucociliar foram feitas antes e após cada exposição. Resultos: Palatos controles mantiveram estável a velocidade do transporte. O L-NAME aumentou, enquanto a aminoguanidina reduziu a velocidade de transporte do muco. Conclusão: O bloqueio inespecífico da cNOS com L-NAME e bloqueio relativamente específico da iNOS com aminoguanidina permitiu propor que dependendo da via o NO pode aumentar ou diminuir o transporte mucociliar em palatos de rã.

The airways are made up of ciliated epithelium which secretes mucous, protecting the respiratory tract from particles inhaled during breathing. Its is paramount to understand the physiology and the mechanisms involved in mucociliary activity. Literature suggests that Nitric oxide (NO), especially the one produced by iNOS expression, maintains the mucociliary function and the immune defense of the nasal cavity. AIM: to assess NO participation and the enzymatic pathways in the production of NO and mucociliary transport, using constructive and inductive NO synthetase inhibitors, L-NAME and aminoguanidine, respectively. Materials and methods: frog palates were prepared and immerse in ringer (control), L-NAME or aminoguanidine solutions. The palates were immerse in these solutions for four periods of 15 minutes. Mucociliary transport measures were carried out before and after each exposure. Results: control palates maintained stable their transportation speed. L-NAME increased, while aminoguanidine reduced mucous transportation velocity. Conclusion: unspecific cNOS block with L-NAME and relatively specific iNOS block with aminoguanidine results leads us to propose that depending on the pathway, the NO can increase or reduce mucociliary transport in frog palates.

Nitric oxide synthase activity and endogenous inhibitors in rats recovered from allergic encephalomyelitis

We have previously reported that in comparison with normal rats, the presence of experimental allergic encephalomyelitis (EAE) leads to decreased endogenous inhibitory activity (EIA) of Ca2+-dependent nitric oxide synthase (NOS) in both brain and serum, and increased expression of protein 3-nitrotyrosine (NT) in brain. In this work we show that animals recovered from the clinical signs of EAE are not different from controls in terms of either brain NOS activity, EIA of NOS, or NT expression. These results suggest that parallel to the reversal of the disease symptoms, a normalization of the production of nitric oxide and related species occurs.