Disease relevance of NNOS

• Our previous studies have demonstrated that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity in vivo and that this inhibition is associated with rebound pulmonary hypertension upon acute withdrawal of inhaled NO [1].
• BACKGROUND: The effect of nitric oxide synthase inhibitor on acute lung injury remains controversial [2].
• Effect of chronic hypoxemia on the regulation of nitric-oxide synthase in the fetal sheep brain [3].
• Controversy exists over the status of placental NOS in preeclampsia, although an abnormality of umbilical NOS activity is likely [4].
• Nitric oxide synthase inhibition restores hypoxic pulmonary vasoconstriction in sepsis [5].

High impact information on NNOS

• At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS) [6].
• Inhibition of nNOS or guanylyl cyclase activity prevents both the potentiation of glutamate release and formation of the olfactory memory [7].
• The effects of nNOS inhibition can be reversed by infusion of NO into the olfactory bulb [7].
• Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors [8].
• Lipocortin 1 mediates the inhibition by dexamethasone of the induction by endotoxin of nitric oxide synthase in the rat [9].

Chemical compound and disease context of NNOS

• Nitric oxide synthase inhibition versus norepinephrine for the treatment of hyperdynamic sepsis in sheep [10].
• OBJECTIVE: To investigate whether exogenous L-arginine, the substrate for nitric oxide synthase, modulates systemic hemodynamics in sepsis [11].
• These data suggest that superoxide and peroxynitrite participate in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy [12].
• Immunohistochemical studies showed that ischemia resulted in a significant loss of calbindin-28kd, choline acetyltransferase, parvalbumin, glutamate acid decarboxylase, neuronal nitric oxide synthase and neuropeptide Y immunopositive neurons, compared with sham controls [13].
• Hypothermia (n=7) significantly reduced the loss of calbindin-28 kd and neuronal nitric oxide synthase, but not glutamic acid decarboxylase-immunopositive neurons [14].

Biological context of NNOS

• We conclude that all three isoforms of NOS are constitutively expressed within the fetal brainstem, and the expression of all three forms is reduced with advancing gestation [15].
• We speculate that the reduced expression of NOS in this brain region plays a role in the increased fetal baroreflex activity in late gestation [15].
• Endothelial (e) nitric oxide synthase (NOS) activity modulates pulmonary vascular tone in the normal fetus and decreases pulmonary vascular resistance (PVR) at birth [16].
• Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae [17].
• The effects of cell growth induced by serum stimulation were also evaluated, and NOS enzymatic activity was threefold greater in quiescent, serum-deprived cells compared with that in serum-stimulated cells [18].

Anatomical context of NNOS

• Effects of pulsatile shear stress on nitric oxide production and endothelial cell nitric oxide synthase expression by ovine fetoplacental artery endothelial cells [19].
• Cell growth modulates nitric oxide synthase expression in fetal pulmonary artery endothelial cells [18].
• RESULTS: Basal eNOS and nNOS mRNA was greatest (P <.02) in reproductive artery endothelium and VSM, respectively [20].
• Finally, the uterus has NOS activity, which decreases at the end of gestation, and exogenous NO relaxes the myometrium, but whether endogenous NO contributes to uterine quiescence during pregnancy has yet to be confirmed [4].
• Nitric oxide synthase isoform expression in the developing lung epithelium [21].

Associations of NNOS with chemical compounds

• Treatment with the nitric oxide synthase inhibitor nitro-L-arginine (L-NA) reversed the E2-induced fall in PVR (0.15+/-0.05 versus 0.51+/-0.15 mm Hg/mL/min; before versus after L-NA, p<0.05) [22].
• Nitric oxide (NO), produced by endothelial (e) nitric oxide synthase (NOS), is a critical mediator of vascular function and growth in the developing lung [18].
• To determine if there is a reciprocal effect of NO on PAEC growth, studies of NOS inhibition or the provision of exogenous NO from spermine NONOate were performed [18].
• Estrogen selectively up-regulates eNOS and nNOS in reproductive arteries by transcriptional mechanisms [20].
• Paracrine role of soluble guanylate cyclase and type III nitric oxide synthase in ovine fetal pulmonary circulation: a double labeling immunohistochemical study [23].

Regulatory relationships of NNOS

• Many studies of rodent peripheral blood mononuclear cells (PBMCs) exposed to endotoxin demonstrate increased cationic amino acid transporter function (particularly through the y+ transporter) to supply arginine substrate to upregulated nitric oxide synthase [24].

Other interactions of NNOS

• Neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) mRNA was measured using real-time PCR methodology specific for ovine NOS isoforms [15].
• In addition, changes in mRNA expression for VEGF, Flt and KDR were positively correlated with changes in ANGPT2, Tie-2, and NOS3, indicating a functional relationship [25].
• Cell death is independent of cytotoxic response and does not involve the tumor necrosis factor alpha/NF-kappaB/nitric oxide synthase/cyclooxygenase pathway [26].
• The cARC contained neurons that were immunoreactive for tyrosine hydroxylase, dynorphin, estrogen receptor alpha, cocaine- and amphetamine-regulated transcript peptide (CART), and nitric oxide synthase (NOS) [27].

Analytical, diagnostic and therapeutic context of NNOS

• After at least 14 days, animals were killed, and lungs were harvested for histology, immunostaining, Western blot analysis for eNOS protein content, and biochemical assays of NOS activity [28].
• We conclude that, despite the absence of pulmonary blood flow and marked lung hypoplasia, eNOS content and NOS activity were not reduced after LPA ligation in the late fetal lung [28].
• Thus, we investigated the vasoconstrictive effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in sheep, in which a reversible sympathetic block was established by thoracic epidural anesthesia [29].
• MATERIALS AND METHODS: Longitudinal and transverse sections of the external urethral sphincter from 10 female and 10 male lambs were studied using reduced nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry and nNOS immunocytochemistry [30].
• OBJECTIVE: To determine whether methylene blue (MB), an inhibitor of soluble guanylate cyclase and nitric oxide synthase, alters lung hemodynamics and fluid filtration after endotoxin in sheep [31].

References