NO System (no + system)

Distribution by Scientific Domains

Selected Abstracts

CPU-86017 improves the compromised blood,brain barrier permeability mediated by impaired endothelial no system and oxidative stress caused by L -thyroxine

Rong-Hui Du
Abstract Impaired endothelial cell (EC) function leads to alterations in the permeability of the blood,brain barrier (BBB). There are two aspects of the transport through the BBB: from the blood to the brain (influx) and from the brain to the blood (efflux). An impaired EC model induced by L -thyroxine that compromises the influx and efflux properties of the BBB was used to assess responses to the intervention of CPU-86017 (an antioxidant and calcium channel blocker) and propranolol. CPU-86017 (t1/2=1.5 h) was also used as a target drug, leaving no traces in the brain and blood 24 h after administration. The permeability of the BBB was evaluated by using CPU-86017 after iv and icv injection and concentrations in the blood and brain being measured by high-performance liquid chromatography. The bidirectional permeability of CPU-86017 was impaired and associated with a reduced NO bioavailability assessed functionally by the vasoactivity in the model. Partial relief of NO bioavailability and oxidative stress induced by propranolol was consistent with a recovery of BBB efflux alone. Complete recovery in the efflux and influx of the BBB by CPU-86017 was a result of the complete restoration of NO bioavailability and reduction in oxidative stress. Normal BBB influx is dependent on an intact endothelial NO system, and efflux could be restored easily by partial improvement of NO bioavailability. CPU-86017 is thus more effective than propranolol in protecting the endothelium from damage produced by L -thyroxine through oxidative stress. Drug Dev. Res. 64:145,156, 2005. 2005 Wiley-Liss, Inc. [source]

Detrimental role of endogenous nitric oxide in host defence against Sporothrix schenckii

IMMUNOLOGY, Issue 4 2008
Karla Simone S. Fernandes
Summary We earlier demonstrated that nitric oxide (NO) is a fungicidal molecule against Sporothrix schenckii in vitro. In the present study we used mice deficient in inducible nitric oxide synthase (iNOS,/,) and C57BL/6 wild-type (WT) mice treated with N,-nitro-arginine (Nitro-Arg-treated mice), an NOS inhibitor, both defective in the production of reactive nitrogen intermediates, to investigate the role of endogenous NO during systemic sporotrichosis. When inoculated with yeast cells of S. schenckii, WT mice presented T-cell suppression and high tissue fungal dissemination, succumbing to infection. Furthermore, susceptibility of mice seems to be related to apoptosis and high interleukin-10 and tumour necrosis factor-, production by spleen cells. In addition, fungicidal activity and NO production by interferon-, (IFN-,) and lipopolysaccharide-activated macrophages from WT mice were abolished after fungal infection. Strikingly, iNOS,/, and Nitro-Arg-treated mice presented fungal resistance, controlling fungal load in tissues and restoring T-cell activity, as well as producing high amounts of IFN-, Interestingly, macrophages from these groups of mice presented fungicidal activity after in vitro stimulation with higher doses of IFN-,. Herein, these results suggest that although NO was an essential mediator to the in vitro killing of S. schenckii by macrophages, the activation of NO system in vivo contributes to the immunosuppression and cytokine balance during early phases of infection with S. schenckii. [source]

The neuronal apoptotic death in global cerebral ischemia in gerbil: Important role for sodium channel modulator,

Manoja Kumar Brahma
Abstract Global ischemia was induced in gerbil by bilateral occlusion of the common carotid arteries for 5 min. Sodium ionophore monensin or sodium channel blocker tetrodotoxin (TTX) was administered at doses of 10 ,g/kg, i.p., 30 min before ischemia induction; the dose was repeated after 22 hr. Subsequently, brain infarct occurred, determined at 24 hr after occlusion. Large, well-demarcated infarcts were observed in both hemispheres, an important observation because it critically influences the interpretation of the data. Because nitric oxide (NO) production is thought to be related to ischemic neuronal damage, we examined increases in Ca2+ influx, which lead to the activation of nitric oxide synthase (NOS). Then we evaluated the contributions of neuronal NOS, endothelial NOS, and inducible NOS to NO production in brain cryosections. The cytosolic release of apoptogenic molecules like cytochrome c and p53 were confirmed after 24 hr of reflow. TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) labeling detected the apoptotic cells, which were confirmed in neuron-rich cell populations. After 24 hr, all the ischemic changes were amplified by monensin and significantly attenuated by TTX treatment. Additionally, the nesting behavior and histological outcomes were examined after 7 day of reflow. The neuronal damage in the hippocampal area and significant decrease in nesting scores were observed with monensin treatment and reduced by TTX pretreatment after day 7 of reflow. To our knowledge, this report is the first to highlight the involvement of the voltage-sensitive Na+ channel in possibly regulating in part NO system and apoptosis in a cytochrome c,dependent manner in global ischemia in the gerbil, and thus warrants further investigation. 2008 Wiley-Liss, Inc. [source]

Nitric Oxide Synthesis Inhibition Attenuates Conditioned Reinstatement of Ethanol-Seeking, but Not the Primary Reinforcing Effects of Ethanol

ALCOHOLISM, Issue 8 2004
Xiu Liu
Background: Nitric oxide (NO) signaling has been implicated in regulating aspects of the reinforcing and addictive actions of cocaine. These experiments were designed to examine whether NO-dependent neurotransmission also participates in mediating the addictive actions of another drug of abuse, ethanol, with emphasis on both the primary reinforcing effects of ethanol and the incentive motivational effects of ethanol-related contextual stimuli. Methods: Male Wistar rats were operantly trained to orally self-administer 10% (w/v) ethanol in daily 30-min sessions and to associate distinct discriminative stimuli with the availability of ethanol (S+) versus nonreward (S,). Rats were treated with the NO synthase inhibitor NG -nitro-l-arginine methyl ester (l-NAME; 0, 10, or 40 mg/kg intraperitoneally) 30 min before self-administration tests that were conducted after establishment of stable levels of daily ethanol intake and conditioned reinstatement tests that were performed after extinction of ethanol-maintained operant responding. Results: l-NAME did not alter the primary reinforcing effects of ethanol in self-administration tests. In contrast, l-NAME dose-dependently attenuated the recovery of extinguished responding induced by the ethanol S+ in the absence of ethanol availability during reinstatement tests. Conclusions: These results suggest that the NO system does not play a role in behavior reinforced directly by ethanol. However, the results implicate NO-dependent neurotransmission in alcohol-seeking responses elicited by drug-related contextual stimuli. [source]

Effects of intraperitoneally injected lithium, imipramine and diazepam on nitrate levels in rat amygdala

Abstract, Nitric oxide (NO) has been studied in relation to the etiologies of various neurologic and psychiatric diseases. However, little is known about whether clinically available psychotropic drugs affect the NO system in the brain. Using an in vivo brain microdialysis method, the effects of intraperitoneally administered lithium, imipramine and diazepam on levels of , a marker of in vivo NO production, were investigated in the rat amygdala. Lithium significantly reduced, while imipramine raised, levels as compared with controls. These observations suggest that lithium and imipramine induce opposite effects on NO-related systems in the brain. [source]

Downregulation of oxytocin and natriuretic peptides in diabetes: possible implications in cardiomyopathy

Jolanta Gutkowska
Regular physical activity is beneficial in preventing the risk of cardiovascular complications of diabetes. Recent studies showed a cardioprotective role of oxytocin (OT) to induce natriuretic peptides (NPs) and nitric oxide (NO) release. It is not known if the diabetic state is associated with a reduced OT,NPs,NO system and if exercise training improves this system. To address this, we investigated the effects of treadmill running using the db/db mouse model of type 2 diabetes. Eight-week-old db/db mice were subjected to running 5 days per week for a period of 8 weeks. The lean db/+ littermates were used as controls. Sedentary db/db mice were obese and hyperglycaemic, and exercise training was not effective in reducing body weight and the hyperglycaemic state. Compared to control mice, db/db mice had lower heart weight and heart-to-body weight ratios. In these mice, this was associated with augmented cardiac apoptosis, cardiomyocyte enlargement and collagen deposits. In addition, db/db mice displayed significant downregulation in gene expression of OT (76%), OT receptors (65%), atrial NP (ANP; 43%), brain NP (BNP; 87%) and endothelial nitric oxide synthase (eNOS) (54%) in the heart (P < 0.05). Exercise training had no effect on expression of these genes which were stimulated in control mice. In response to exercise training, the significant increment of anti-apoptotic Bcl-2 gene expression was observed only in control mice (P < 0.05). In conclusion, downregulation of the OT,NPs,NO system occurs in the heart of the young db/db mouse. Exercise training was not effective in reversing the defect, suggesting impairment of this cardiac protective system in diabetes. [source]

Differential action of bradykinin on intrarenal regional perfusion in the rat: waning effect in the cortex and major impact in the medulla

ena B
The renal kallikrein,kinin system is involved in the control of the intrarenal circulation and arterial pressure but bradykinin (Bk) effects on perfusion of individual kidney zones have not been examined in detail. Effects of Bk infused into renal artery, renal cortex or medulla on perfusion of whole kidney (RBF, renal artery probe) and of the cortex, outer- and inner medulla (CBF, OMBF, IMBF: laser-Doppler fluxes), were examined in anaesthetized rats. Renal artery infusion of Bk, 0.3,0.6 mg kg,1 h,1, induced no sustained increase in RBF or CBF. OMBF and IMBF increased initially 6 or 16%, respectively; only the IMBF increase (+10%) was sustained. Pre-treatment with l -NAME, 2.4 mg kg,1i.v., prevented the sustained but not initial transient elevation of medullary perfusion. Intracortical Bk infusion, 0.75,1.5 mg kg,1 h,1, did not alter RBF or CBF but caused a sustained 33% increase in IMBF. Intramedullary Bk, 0.3 mg kg,1 h,1, did not alter RBF or CBF but caused sustained increases in OMBF (+10%) and IMBF (+23%). These responses were not altered by pre-treatment with 1-aminobenzotriazole, 10 mg kg,1i.v., a cytochrome P-450 (CYP450) inhibitor, but were prevented or significantly attenuated by l -NAME or intramedullary clotrimazole, 3.9 mg kg,1 h,1, an inhibitor of CYP450 epoxygenase and of calcium-dependent K+ channels (KCa). Thus, cortical vasodilatation induced by Bk is only transient so that the agent is unlikely to control perfusion of the cortex. Bk selectively increases perfusion of the medulla, especially of its inner layer, via activation of the NO system and of KCa channels. [source]

Role of NO in retinal vascular disease

Purpose Nitric oxide (NO) is a key regulator of vascular tone in all vascular beds including the eye. Hence, inhibition of NO synthase with L-arginine analogues leads to a reduction of blood flow to all ocular tissues. This enables the investigation of the role of NO in the physiology of blood flow regulation, but also abnormalities of the vascular L-arginine/NO system in ocular vascular disease. Methods A variety of studies investigating the role of NO in healthy humans but also in patients with vascular disease is summarized. Results Inhibition of NO synthase reduces retinal, choroidal and optic nerve head blood. A variety of studies also indicate that NO plays a role in the ocular vasodilator effects of numerous agonists including acetylcholine, bradykinin, carbon dioxide, histamine and insulin. In addition, NO appears to modulate the autoregulatory behavior of ocular vascular beds and is involved in retinal neurovascular coupling. In several ocular diseases such as diabetic retinopathy or open angle glaucoma abnormalities in the NO system can be observed. Conclusion NO is a major regulator of ocular blood flow in humans. The existence of different NO synthase isoforms makes it, however, difficult to therapeutically intervent via the L-arginine/NO pathway. Further studies are required to characterize the role of the NO synthase isoforms in the control of ocular blood flow in more detail and to allow for therapeutic interventions in ischemic ocular eye disease via this attractive pathway. [source]

Interventions via the NO system and tachyphylaxia


Critical role of Nitric Oxide on Nicotine-Induced Hyperactivation of Dopaminergic Nigrostriatal System: Electrophysiological and Neurochemical evidence in Rats

Vincenzo Di Matteo
Nicotine, the main psychoactive ingredient in tobacco, stimulates dopamine (DA) function, increasing DA neuronal activity and DA release. DA is involved in both motor control and in the rewarding and reinforcing effects of nicotine; however, the complete understanding of its molecular mechanisms is yet to be attained. Substantial evidence indicates that the reinforcing properties of drugs of abuse, including nicotine, can be affected by the nitric oxide (NO) system, which may act by modulating central dopaminergic function. In this study, using single cell recordings in vivo coupled with microiontophoresis and microdialysis in freely moving animals, the role of NO signaling on the hyperactivation elicited by nicotine of the nigrostriatal system was investigated in rats. Nicotine induced a dose-dependent increase of the firing activity of the substantia nigra pars compacta (SNc) DA neurons and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the striatum. Pharmacological manipulation of the NO system did not produce any change under basal condition in terms of neuronal discharge and DA release. In contrast, pretreatments with two NO synthase (NOS) inhibitors, N-,-nitro- l -arginine methyl ester (l -NAME) and 7-nitroindazole (7-NI) were both capable of blocking the nicotine-induced increase of SNc DA neuron activity and DA striatal levels. The effects of nicotine in l -NAME and 7-NI-pretreated rats were partially restored when rats were pretreated with the NO donor molsidomine. These results further support the evidence of an important role played by NO on modulation of dopaminergic function and drug addiction, thus revealing new pharmacological possibilities in the treatment of nicotine dependence and other DA dysfunctions. [source]