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Norman E Cameron - One of the best experts on this subject based on the ideXlab platform.

  • effects of poly adp ribose polymerase inhibition on dysfunction of non adrenergic non cholinergic neurotransmission in gastric fundus in diabetic rats
    Nitric Oxide, 2006
    Co-Authors: Michael T Gibson, Mary A Cotter, Norman E Cameron
    Abstract:

    Abstract Diabetes mellitus compromises nitric oxide (NO)-mediated endothelium-dependent relaxation of blood vessels, which has been linked to the excessive generation of reactive oxygen species. There are also deleterious effect on Nitrergic innervation, contributing to autonomic neuropathy symptoms such as impotence and gastroporesis. Poly(ADP-ribose) polymerase (PARP) is a nuclear protein stimulated by DNA damage, caused, for example, by oxidative stress. Activation has been linked to impaired endothelial nitric oxide synthase (eNOS)-mediated vasodilation in experimental diabetes. There is no information on the potential role of PARP in Nitrergic Nerve dysfunction, therefore, the aim was to examine the effects of PARP inhibition, using 3-aminobenzamide (3-AB) on neurally mediated gastric fundus relaxation in streptozotocin-induced diabetic rats. Eight weeks of diabetes caused a 42.5% deficit in maximum relaxation of in vitro gastric fundus strips to electrical stimulation of the non-adrenergic non-cholinergic innervation. This was largely prevented or corrected (4 weeks of treatment following 4 weeks of untreated diabetes) by 3-AB. Diabetes also markedly attenuated the maintenance of relaxation responses to prolonged stimulation, and this was partially corrected by 3-AB treatment. Experiments in the presence of the NOS inhibitor, NG-nitro- l -arginine, and/or blockade of the co-transmitter, vasoactive intestinal polypeptide, by α-chymotrypsin, showed that the beneficial effects of 3-AB were primarily due to improved Nitrergic neurotransmission. Thus, PARP plays an important role in defective Nitrergic neurotransmission in experimental diabetes, which may have therapeutic implications for treatment of aspects of diabetic autonomic neuropathy.

  • the calpain inhibitor a 705253 corrects penile Nitrergic Nerve dysfunction in diabetic mice
    European Journal of Pharmacology, 2006
    Co-Authors: Matthew R Nangle, Mary A Cotter, Norman E Cameron
    Abstract:

    Calpains, a superfamily of Ca(2+)-activated proteases, are associated with an array of physiological and pathological events, including susceptibility to diabetes. Recently, increased calpain activity has been linked to reduced endothelium-derived nitric oxide-mediated vasodilatation in diabetes. However, a similar mechanism for neuronal-derived nitric oxide has not been examined. Thus, the aim was to investigate effects of the calpain inhibitor A-705253, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethyl-aminomethylphenyl)ethen-1-yl]benzamide, on Nitrergic neurovascular function in diabetic mice. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention A-705253 treatment (30 mg/kg/day) was given for 2 weeks following 4 weeks of untreated diabetes. After 6 weeks of diabetes, corpus cavernosa were isolated in organ baths for measurement of agonist- and electrical stimulation-evoked smooth muscle tensions. Adrenergic Nerve- and phenylephrine-mediated contractions were not altered by diabetes or calpain inhibition. In contrast, maximum Nitrergic Nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 29% reduced by diabetes (P<0.001). This neurological deficit was 66% corrected by A-705253 treatment (P<0.05). Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 39% by diabetes (P<0.01). Similarly, maximum endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside, was blunted approximately 23% by diabetes (P<0.001). A-705253 treatment partially improved endothelium-dependent relaxation to acetylcholine but had no effect on the deficit in response to nitroprusside. The data suggest that calpain contributes to the aetiology of diabetic Nitrergic autonomic neuropathy and endothelial dysfunction, which may provide a novel therapeutic target for neurovascular complications.

  • Correction of Nitrergic neurovascular dysfunction in diabetic mouse corpus cavernosum by p38 mitogen-activated protein kinase inhibition
    International Journal of Impotence Research, 2006
    Co-Authors: Matthew R Nangle, Mary A Cotter, Norman E Cameron
    Abstract:

    Increased p38 mitogen-activated protein kinase (MAPK) in response to stress stimuli, including hyperglycemia, contributes to diabetic somatic neuropathy. However, effects on autonomic Nerve and vascular function have not been determined. The aim of this study was to investigate the effects of the p38 MAPK inhibitor, LY2161793, on penile neurovascular function in streptozotocin-induced diabetic mice. Diabetes duration was 6 weeks and intervention LY2161793 treatment was given for the final 2 weeks. In vitro measurements on phenylephrine-precontracted corpus cavernosum revealed a 32% reduction in maximum Nitrergic Nerve-mediated relaxation with diabetes that was 74% corrected by LY2161793 treatment. Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was 42% attenuated by diabetes and 88% restored by LY2161793. Moreover, treatment partially corrected a diabetic deficit in endothelium-independent relaxation to a nitric oxide donor. Thus, p38 MAPK inhibition corrects nitric oxide-dependent indices of diabetic erectile autonomic neuropathy and vasculopathy, a therapeutic approach potentially worthy of consideration for clinical trials.

  • effects of rosuvastatin on nitric oxide dependent function in aorta and corpus cavernosum of diabetic mice relationship to cholesterol biosynthesis pathway inhibition and lipid lowering
    Diabetes, 2003
    Co-Authors: Matthew R Nangle, M A Cotter, Norman E Cameron
    Abstract:

    Elevated plasma lipids contribute to neurovascular dysfunction in diabetes. Statins have lipid-lowering properties and can modulate endothelial nitric oxide (NO) bioavailability. The aim was to assess the impact of these factors on autonomic Nitrergic Nerve and endothelial function. Thus, the effects of diabetes and treatment with the HMG-CoA reductase inhibitor rosuvastatin (RSV) were examined on corpus cavernosum and aorta from streptozotocin-induced diabetic mice in a 4-week prevention study and a 2-week intervention study, following 4 weeks of untreated diabetes. Cotreatment with mevalonate was used to assess the dependence of RSV's effects on HMG-CoA reductase blockade. Diabetes caused a 25% reduction in NO-mediated endothelium-dependent relaxation to acetylcholine for aorta and cavernosum. Relaxations of cavernosum were in the nondiabetic range following prevention or reversal treatment. The aortic deficit was completely prevented and 60% reversed by RSV. Maximum NO-dependent nonadrenergic, noncholinergic Nerve-mediated relaxations of cavernosum were reduced 25-33% by diabetes. RSV treatment prevented 75% and reversed 71% of this diabetic deficit. Cotreatment with mevalonate inhibited the beneficial actions of RSV on aorta and cavernosum. Total plasma cholesterol was unaltered by diabetes or treatment. Thus, RSV corrected defective NO-mediated Nerve and vascular function in diabetic mice independent of cholesterol lowering but via effects dependent on cholesterol biosynthesis pathway inhibition.

  • effects of diabetes and evening primrose oil treatment on responses of aorta corpus cavernosum and mesenteric vasculature in rats
    Life Sciences, 2002
    Co-Authors: Alison M Jack, Mary A Cotter, Alan Keegan, Norman E Cameron
    Abstract:

    Abstract Diabetes causes endothelial dysfunction, with deleterious effects on nitric oxide (NO) mediated vasodilatation. However, in many vessels other local vasodilators such as endothelium-derived hyperpolarizing factor (EDHF), prostacyclin, epoxides or endocannabinoids are also important. Several of these factors may be derived from ω-6 essential fatty acids via arachidonate metabolism. Diabetes inhibits this pathway, a defect that may be bypassed by diets enriched with ω-6 γ-linolenic acid-containing oils such as evening primrose oil (EPO). The aim was to examine the effects of preventive EPO treatment on endothelium-dependent and neurally mediated vasorelaxation. Diabetes was induced by streptozotocin in rats; duration was 8 weeks. Vascular responses were examined in vitro on thoracic aorta, corpus cavernosum and perfused mesenteric bed preparations. Diabetes caused 25% and 35% deficits, respectively, in aorta and corpus cavernosum NO-mediated endothelium-dependent relaxation to acetylcholine that were largely unaffected by EPO treatment. Moreover, a 44% reduction in maximum corpus cavernosum vasorelaxation to Nitrergic Nerve stimulation was not prevented by EPO. However, for the mesenteric vascular bed, a 29% diminution of responses to acetylcholine, mediated by both NO and EDHF, was 84% attenuated by EPO treatment. When the EDHF component was isolated during NO synthase inhibition, a 76% diabetic deficit was noted. This was completely prevented by EPO treatment, which also caused supernormal EDHF responses in nondiabetic rats. EPO treatment prevented the development of deficits in endothelium-dependent relaxation in diabetic rats. Effects were particularly marked on the resistance vessel EDHF system, which may have potential therapeutic relevance for diabetic microvascular complications.

Trinity J Bivalacqua - One of the best experts on this subject based on the ideXlab platform.

  • increased level of tumor necrosis factor alpha tnf α leads to downregulation of Nitrergic neurons following bilateral cavernous Nerve injury and modulates penile smooth tone
    The Journal of Sexual Medicine, 2021
    Co-Authors: Hotaka Matsui, Emmanuel Weyne, Johanna L Hannan, Fabio Castiglione, Nikolai A Sopko, Jeffrey D Campbell, Xiaopu Liu, Allison Reinhardt, Maarten Albersen, Trinity J Bivalacqua
    Abstract:

    ABSTRACT Background Erectile dysfunction (ED) after injury to peripheral cavernous Nerve (CN) is partly a result of inflammation in pelvic ganglia, suggesting that ED may be prevented by inhibiting neuroinflammation. Aim The aim of this study is to examine temporal changes of TNF-α, after bilateral CN injury (BCNI), to evaluate effect of exogenous TNF-α on neurite outgrowth from major pelvic ganglion (MPG), and to investigate effect of TNF-α signal inhibition to evaluate effects of TNF-α on penile tone with TNF-α receptor knockout mice (TNFRKO). Methods Seventy Sprague-Dawley rats were randomized to undergo BCNI or sham surgery. Sham rats’ MPGs were harvested after 48 hours, whereas BCNI groups’ MPGs were at 6, 12, 24, 48 hours, 7, or 14 days after surgery. qPCR was used to evaluate gene expression of markers for neuroinflammation in MPGs. Western blot was performed to evaluate TNF-α protein amount in MPGs. MPGs were harvested from healthy rats and cultured in Matrigel with TNF-α. Neurite outgrowth from MPGs was measured after 3 days, and TH and nNOS immunofluorescence was assessed. Wild type (WT) and TNFRKO mice were used to examine effect of TNF-α inhibition on smooth muscle function after BCNI. MPGs were harvested 48 hours after sham or BCNI surgery to evaluate gene expression of nNOS and TH. Outcomes Gene expression of TNF-α signaling pathway, Schwann cell and macrophage markers, protein expression of TNF-α in MPGs, and penile smooth muscle function to electrical field stimulation (EFS) were evaluated. Results BCNI increased gene and protein expression of TNF-α in MPGs. Exogenous TNF-α inhibited MPG neurite outgrowth. MPGs cultured with TNF-α had decreased gene expression of nNOS (P Clinical Translation TNF-α inhibition may prevent ED after prostatectomy. Strength/Limitations TNF-α inhibition might prevent loss of Nitrergic Nerve apoptosis after BCNI and preserve corporal smooth muscle function but further investigation is required to evaluate protein expression of nNOS in MPGs of TNFKO mice. Conclusions TNF-α inhibited neurite outgrowth from MPGs by downregulating gene expression of nNOS and TNFRKO mice showed enhanced gene expression of nNOS and enhanced penile smooth-muscle relaxation. Matsui H, Sopko NA, Campbell JD, et al. Increased Level of Tumor Necrosis Factor-Alpha (TNF-α) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and Modulates Penile Smooth Tone. J Sex Med 2021;18:1181–1190.

  • galanin administration partially restores erectile function after cavernous Nerve injury and mediates endogenous Nitrergic Nerve outgrowth in vitro
    The Journal of Sexual Medicine, 2018
    Co-Authors: Emmanuel Weyne, Johanna L Hannan, Thomas Gevaert, Mohammad Ayodhia Soebadi, Hotaka Matsui, Fabio Castiglione, Koenraad Van Renterghem, Dirk De Ridder, Frank Van Der Aa, Trinity J Bivalacqua
    Abstract:

    Abstract Background Previously, we found that the neuropeptide galanin was strongly upregulated soon after bilateral cavernous Nerve injury (BCNI) and that galanin and its receptors were expressed in Nitrergic erectile innervation. Galanin has been observed to exert neuroregenerative effects in dorsal root ganglion neurons, but evidence for these effects in the major pelvic ganglion (MPG) after BCNI is lacking. Aim To evaluate the neurotropic effects of galanin receptor agonists and antagonists in vitro in Nitrergic neurons and MPG and in vivo in rats after BCNI. Methods Male Sprague-Dawley rats underwent BCNI and sham surgery. Organ culture and single-cell neuron culture of the MPG were performed. Osmotic pump treatment with the galanin agonist in vivo and measurement of erectile response to electrostimulation after BCNI, immunohistochemical localization of galanin and receptors in the human neurovascular bundle, and myographic analysis of rat corpus cavernosum smooth muscle relaxation to galanin receptor agonists were investigated. Outcomes Neurite outgrowth in vitro and erectile response to electrostimulation after BCNI in vivo, immunohistochemical localization of galanin and receptors, and penile muscle relaxation in vitro. Results Galanin showed neurotrophic action in vitro and inhibition of endogenous galanin significantly impaired neurite outgrowth in Nitrergic but not in sympathetic MPG neurons. In vivo administration of a selective galanin receptor-2 agonist, M1145, resulted in partial recovery of erectile function (EF) after BCNI. Galanin did not act as a direct vasodilator on corpus cavernosum muscle strips. Clinical Translation Endogenous neurotrophins such as galanin could be used as a strategy to improve EF for patients after BCNI from radical prostatectomy. Strengths and Limitations We evaluated the effect of galanin on Nerve regeneration and EF recovery in vivo and in vitro. Limitations include the lack of washout period for the in vivo experiment and absence of differences in the expression of neuronal markers between treatment groups. Conclusions We identified galanin as a potential endogenous mechanism for Nerve regeneration after BCNI, which could play a physiologic role in EF recovery after radical prostatectomy. In vivo treatment with exogenous galanin was beneficial in enhancing EF recovery after BCNI, but further research is necessary to understand the underlying mechanisms. Weyne E, Hannan JL, Gevaert T, et al. Galanin Administration Partially Restores Erectile Function After Cavernous Nerve Injury and Mediates Endogenous Nitrergic Nerve Outgrowth In Vitro. J Sex Med 2018;15:480–491.

  • posttranslational modification of constitutive nitric oxide synthase in the penis
    Journal of Andrology, 2009
    Co-Authors: Biljana Musicki, Ashley E Ross, Hunter C Champion, Arthur L Burnett, Trinity J Bivalacqua
    Abstract:

    Erectile dysfunction (ED) is a common men's health problem characterized by the consistent inability to sustain an erection sufficient for sexual intercourse. Basic science research on erectile physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin, neurogenic dysfunction, or both. The constitutive forms of nitric oxide synthase (NOS, endothelial [eNOS] and neuronal [nNOS]) are important enzymes involved in the production of nitric oxide (NO) and thus regulate penile vascular homeostasis. Given the effect of endothelial- and neuronal-derived NO in penile vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium and Nitrergic Nerve terminal in normal erectile physiology, as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, molecular mechanisms involved in dysregulation of these NOS isoforms in the development of ED are essential to discovering the pathogenesis of ED in various disease states. This communication reviews the role of eNOS and nNOS in erectile physiology and discusses the alterations in eNOS and nNOS via posttranslation modification in various vascular diseases of the penis.

M J Rand - One of the best experts on this subject based on the ideXlab platform.

  • effects of pyrogallol hydroquinone and duroquinone on responses to Nitrergic Nerve stimulation and no in the rat anococcygeus muscle
    British Journal of Pharmacology, 1999
    Co-Authors: M J Rand
    Abstract:

    The hypothesis that endogenous superoxide dismutase (SOD) protects the Nitrergic transmitter from inactivation by superoxide and that this explains the lack of sensitivity of the transmitter to superoxide generators was tested in the rat isolated anococcygeus muscle. Responses to Nitrergic Nerve stimulation or to NO were not significantly affected by exogenous SOD or by the Cu/Zn SOD inhibitor diethyldithiocarbamic acid (DETCA). Hydroquinone produced a concentration-dependent reduction of responses to NO with an IC50 of 27 μM, and higher concentrations reduced relaxant responses to Nitrergic Nerve stimulation with an IC50 of 612 μM. The effects of hydroquinone were only slightly reversed by SOD, so it does not appear to be acting as a superoxide generator. Pyrogallol produced a concentration-dependent reduction in responses to NO with an IC50 value of 39 μM and this effect was reversed by SOD (100–1000 u ml−1). Pyrogallol did not affect responses to Nitrergic Nerve stimulation. Treatment with DETCA did not alter the differentiating action of pyrogallol. Duroquinone produced a concentration-dependent reduction of relaxations to NO with an IC50 value of 240 μM and 100 μM slightly decreased Nitrergic relaxations. After treatment with DETCA, duroquinone produced greater reductions of relaxant responses to NO and to Nitrergic stimulation, the IC50 values being 8.5 μM for NO and 40 μM for Nitrergic Nerve stimulation: these reductions were reversed by SOD. The findings do not support the hypothesis that the presence of Cu/Zn SOD explains the greater susceptibility of NO than the Nitrergic transmitter to the superoxide generator pyrogallol, but suggest that it may play a role in the effects of duroquinone. British Journal of Pharmacology (1999) 126, 342–348; doi:10.1038/sj.bjp.0702277

  • role of potassium channels in the Nitrergic Nerve stimulation induced vasodilatation in the guinea pig isolated basilar artery
    British Journal of Pharmacology, 1998
    Co-Authors: Fan Jiang, M J Rand
    Abstract:

    We studied the effects of various K+ channel blockers on the vasodilator responses of guinea-pig isolated basilar arteries to Nitrergic Nerve stimulation, the nitric oxide (NO) donor sodium nitroprusside (SNP), and the membrane permeable guanosine-3′, 5′-cyclic monophosphate (cyclic GMP) analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP). In endothelium-denuded preparations which were contracted with prostaglandin F2α (1 μM), electrical field stimulation (EFS, 10 Hz for 30 s) produced a vasodilatation which was totally blocked by the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester L-NAME; 100 μM) (n=3) and by the selective NO-sensitive guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ; 1 μM) (n=4). The vasodilator response to SNP (100 nM) was not reduced by L-NAME but was abolished by ODQ (1 μM) (n=4). EFS-elicited vasodilatation was partly but significantly reduced by the non-selective K+ channel blockers tetraethylammonium (TEA, 1 and 3 mM) and 4-aminopyridine (4-AP, 3 mM), and by the large-conductance calcium-activated K+ channel (KCa channel) blockers charybdotoxin (ChTX, 150 nM) and iberiotoxin (IbTX, 30 and 100 nM). In contrast, the ATP-sensitive K+ channel (KATP channel) blocker glibenclamide (1–10 μM) and the small-conductance KCa channel blocker apamin (100–500 nM) did not affect EFS-induced vasodilatation. The vasodilator response elicited by SNP (10–100 nM) was significantly reduced by TEA (3 mM) and ChTX (150 nM) but not by apamin (500 nM) or glibenclamide (1 μM). The vasodilatation elicited by 8-Br-cyclic GMP (100 μM) was also reduced by TEA (3 mM) and ChTX (150 nM). The results indicate that the vasodilatations induced by Nitrergic Nerve stimulation and the NO donor SNP in endothelium-denuded guinea-pig basilar artery depend on the formation of intracellular cyclic GMP. The increased cyclic GMP level activates large-conductance KCa channels which partly mediate the vasodilator response. Neither KATP channels nor apamin-sensitive small-conductance KCa channels are involved in Nitrergic transmitter-mediated vasodilatation. British Journal of Pharmacology (1998) 123, 106–112; doi:10.1038/sj.bjp.0701552

  • inhibition of no mediated responses by 7 ethoxyresorufin a substrate and competitive inhibitor of cytochrome p450
    British Journal of Pharmacology, 1996
    Co-Authors: Chun Guang Li, M J Rand
    Abstract:

    1 . The effects of 7-ethoxyresorufin (7-ER), which is a substrate for and competitive inhibitor of cytochrome P450, were studied on responses to nitric oxide (NO), the NO donors sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), acetylcholine-induced endothelium-dependent relaxations of rat and rabbit aortic rings and Nitrergic Nerve stimulation-induced relaxations of rat anococcygeus muscles. 2 . In rat and rabbit aortic rings, 7-ER (2 μm) inhibited the relaxations to acetylcholine in endothelium-intact preparations and the relaxant action of NO in endothelium-denuded preparations. Relaxant responses to SNP and GTN were inhibited by 7-ER in the rat but not rabbit aortic rings. However, the relaxant actions of papaverine and 8-bromo-cyclic GMP were not affected by 7-ER. 3 . In rat anococcygeus muscles, 7-ER (2 μm) inhibited the relaxant action of NO, but relaxations elicited by Nitrergic Nerve stimulation were only partly inhibited by a higher concentration of 7-ER (10 μm). 4 . After inhibition by 7-ER, superoxide dismutase (100 u ml−1) restored NO-induced relaxations of the rat aortic rings, but not acetylcholine-, SNP or GTN-induced relaxations, and restored NO- and Nitrergic Nerve stimulation-induced relaxations of anococcygeus muscles. 5 . Another cytochrome P450 inhibitor, troleandomycin (10–30 μm), had no effect on NO- or acetylcholine-induced relaxations of rat aortic rings and NO- or Nitrergic Nerve stimulation-induced relaxations of anococcygeus muscles. However, resorufin, an analogue of 7-ER, inhibited responses to acetylcholine, NO and GTN in rat aortic rings. 6 . The results suggest that 7-ER inhibited responses to NO and Nitrergic Nerve stimulation through generation of superoxide radicals. However, an additional mechanism may be involved in the reduction in acetylcholine-induced responses in aortic rings. 7 . A 7-ER sensitive P450 system may be involved in the bioactivation of GTN and SNP in rat aortic rings, but not in rabbit aorta or rat anococcygeus muscles.

Tomio Okamura - One of the best experts on this subject based on the ideXlab platform.

  • Cigarette smoking impairs nitric oxide-mediated cerebral blood flow increase: Implications for Alzheimer's disease
    Elsevier, 2016
    Co-Authors: Noboru Toda, Tomio Okamura
    Abstract:

    Cerebral blood flow is mainly regulated by Nitrergic (parasympathetic, postganglionic) Nerves and nitric oxide (NO) liberated from endothelial cells in response to shear stress and stretch of vasculature, whereas sympathetic vasoconstrictor control is quite weak. On the other hand, peripheral vascular resistance and blood flow are mainly controlled by adrenergic vasoconstrictor Nerves; endothelium-derived NO and Nitrergic Nerves play some roles as vasodilator factors. Cigarette smoking impairs NO synthesis in cerebral vascular endothelial cells and Nitrergic Nerves leading to interference with cerebral blood flow and glucose metabolism in the brain. Smoking-induced cerebral hypoperfusion is induced by impairment of synthesis and actions of NO via endothelial nitric oxide synthase (eNOS)/neuronal NOS (nNOS) inhibition and by increased production of oxygen radicals, resulting in decreased actions of NO on vascular smooth muscle. Nicotine acutely and chronically impairs the action of endothelial NO and also inhibits Nitrergic Nerve function in chronic use. Impaired cerebral blood supply promotes the synthesis of amyloid β that accelerates blood flow decrease. This vicious cycle is thought to be one of the important factors involving in Alzheimer's disease (AD). Quitting smoking is undoubtedly one of the important ways to prevent and delay the genesis or slow the progress of impaired cognitive function and AD

  • Recent advances in research on Nitrergic Nerve-mediated vasodilatation
    Pflügers Archiv - European Journal of Physiology, 2015
    Co-Authors: Noboru Toda, Tomio Okamura
    Abstract:

    Cerebral vascular resistance and blood flow were widely considered to be regulated solely by tonic innervation of vasoconstrictor adrenergic Nerves. However, pieces of evidence suggesting that parasympathetic Nitrergic Nerve activation elicits vasodilatation in dog and monkey cerebral arteries were found in 1990. Nitric oxide (NO) as a neurotransmitter liberated from parasympathetic postganglionic neurons decreases cerebral vascular tone and resistance and increases cerebral blood flow, which overcome vasoconstrictor responses to norepinephrine liberated from adrenergic Nerves. Functional roles of Nitrergic vasodilator Nerves are found also in peripheral vasculature, including pulmonary, renal, mesenteric, hepatic, ocular, uterine, nasal, skeletal muscle, and cutaneous arteries and veins; however, adrenergic Nerve-induced vasoconstriction is evidently greater than Nitrergic vasodilatation in these vasculatures. In coronary arteries, neurogenic NO-mediated vasodilatation is not clearly noted; however, vasodilatation is induced by norepinephrine released from adrenergic Nerves that activates β_1-adrenoceptors. Impaired actions of NO liberated from the endothelium and Nitrergic neurons are suggested to participate in cerebral hypoperfusion, leading to brain dysfunction, like that in Alzheimer’s disease. Nitrergic neural dysfunction participates in impaired circulation in peripheral organs and tissues and also in systemic blood pressure increase. NO and vasodilator peptides, as sensory neuromediators, are involved in neurogenic vasodilatation in the skin. Functioning of Nitrergic vasodilator Nerves is evidenced not only in a variety of mammals, including humans and monkeys, but also in non-mammals. The present review article includes recent advances in research on the functional importance of Nitrergic Nerves concerning the control of cerebral blood flow, as well as other regions, and vascular resistance. Although information is still insufficient, the Nitrergic Nerve histology and function in vasculatures of non-mammals are also summarized.

  • nitroxidergic Nitrergic Nerve and erectile dysfunction
    Folia Pharmacologica Japonica, 2002
    Co-Authors: Kazuhide Ayajiki, Noboru Toda, Tomio Okamura
    Abstract:

    In vascular tissues including the corpus cavernosum, the organ function is reciprocally regulated by noradrenergic and non-adrenergic, non-cholinergic (NANC) Nerves. NANC Nerves innervating the corpus cavernosum is thought to be nitroxidergic (Nitrergic) Nerves which liberate nitric oxide (NO) produced by neuronal NO synthase, and liberated NO activates soluble guanylate cyclase (sGC) in cavernous smooth muscle cells. Intracellular increase in cyclic (c) GMP by activation of sGC dilates cavernous smooth muscle and then induces penile erection. Nitroxidergic (Nitrergic) vasodilator Nerves also innervate cavernous arteries and veins which regulate the blood volume in the corpus cavernosum. The order of potency of nitroxidergic Nerve functions in these tissues (cavernosum > artery >> vein) may be suitable for producing the erection. Therefore, obstruction of the arteries and impairment of nitroxidergic (Nitrergic) Nerve function are speculated to be one of the causes for erectile dysfunction (ED). On the other hand, NO derived from the cavernous endothelium may partly contribute to erectile function. Sildenafil (Viagra) is one of the potent therapeutics for ED. The agent is a selective phosphodiesterase type 5 (PDE-V) inhibitor that inhibits degradation of cGMP elevated by NO mainly derived from the Nerves. To develop more selective and safer therapeutics for ED, further systematic investigations are required.

  • effects of calcium antagonists on the Nitrergic Nerve function in canine corpus cavernosum
    Japanese Journal of Pharmacology, 2001
    Co-Authors: Tomio Okamura, Hideyuki Fujioka, Kazuhide Ayajiki
    Abstract:

    Effects of calcium antagonists on Nitrergic Nerve function were examined in the isolated canine corpus cavernosum. In the cavernous strips precontracted with phenylephrine, transmural electrical stimulation elicited frequency-dependent (2 – 5 Hz) relaxations that were abolished by NG-nitro-L-arginine (10−5 M), a nitric oxide (NO) synthase inhibitor; 1H[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ, 10−6 M), a soluble guanylate cyclase inhibitor; and tetrodotoxin (3 × 10−7 M). The relaxations were not affected by treatment with nifedipine or nicardipine (10−8 – 10 −6 M), L-type specific calcium channel inhibitors, but were significantly inhibited by amlodipine or cilnidipine, inhibitors of L- plus N-type calcium channels, in a concentration-related manner (10−7 – 10 −6 M). All of the inhibitors used did not affect the relaxations induced by exogenous NO (acidifed NaNO2). These findings suggest that N-type, but not L-type, calcium channels are responsible for increasing cytosolic free calcium, a prerequisite for the synthesis of NO, in the Nitrergic dilator Nerves innervating the corpus cavernosum.

  • effects of endothelial impairment by saponin on the responses to vasodilators and Nitrergic Nerve stimulation in isolated canine corpus cavernosum
    British Journal of Pharmacology, 1999
    Co-Authors: Tomio Okamura, Kazuhide Ayajiki, Hideyuki Fujioka, Megumi Toda, Mineko Fujimiya, Noboru Toda
    Abstract:

    Responsiveness to EDRF-releasing substances and inhibitory Nerve stimulation of canine isolated penile corpus cavernosum with and without saponin treatment were investigated. Histological studies demonstrated that saponin did not detach endothelial cells from underlying tissues, but induced degenerative changes in the endothelial cells selectively. In the cavernous strips contracted with phenylephrine, addition of acetylcholine, sodium nitroprusside, ATP and Ca2+ ionophore A23187 induced relaxations, but substance P and bradykinin did not change the muscle tone. Acetylcholine-induced relaxation was significantly attenuated but not abolished by NG-nitro-L-arginine (L-NOARG). L-arginine restored the response inhibited by L-NOARG. The L-NOARG resistant relaxation was not influenced by 1H[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) but was suppressed in the strips contracted with K+. Treatment with saponin abolished the relaxation elicited by acetylcholine and A23187 but did not influence the response to nitroprusside and ATP. The ATP-induced relaxation was attenuated by aminophylline. Transmural electrical stimulation at 2–20 Hz produced endothelium-independent relaxations which were abolished by tetrodotoxin and L-NOARG but unaffected by treatment with saponin. In saponin-treated cavernous strips, the neurogenic relaxation was not affected by acetylcholine, physostigmine, atropine and vasoactive intestinal peptide (VIP) but was abolished by ODQ. It is concluded that acetylcholine-induced relaxations are endothelium-dependent and mediated partly by NO and also by other substances from the endothelium. The endothelium-independent relaxation to ATP is likely to be mediated by P1 purinoceptors. The function of Nitrergic Nerve does not seem to be prejunctionally modulated by acetylcholine and VIP. British Journal of Pharmacology (1999) 127, 802–808; doi:10.1038/sj.bjp.0702623

De Nucci G - One of the best experts on this subject based on the ideXlab platform.

  • Effect Of Tityus Serrulatus Scorpion Venom On The Rabbit Isolated Corpus Cavernosum And The Involvement Of Nanc Nitrergic Nerve Fibres.
    2015
    Co-Authors: Teixeira C E, Bento A C, Lopes-martins R A, Teixeira S A, Von Eickestedt, Muscará M N, Arantes E C, Giglio J R, Antunes E, De Nucci G
    Abstract:

    1. The effect of Tityus serrulatus scorpion venom and its toxin components on the rabbit isolated corpus cavernosum was investigated by use of a bioassay cascade. 2. Tityus serrulatus venom (3-100 microg), acetylcholine (ACh; 0.3-30 nmol) and glyceryl trinitrate (GTN; 0.5-10 nmol) dose-dependently relaxed rabbit isolated corpus cavernosum preparations precontracted with noradrenaline (3 microM). The selective soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (ODQ; 30 microM) increased the basal tone of the rabbit isolated corpus cavernosum and abolished the relaxations induced by the agents mentioned above. Methylene blue (30 microM) also inhibited the relaxations induced by Tityus serrulatus venom but, in contrast to ODQ, the inhibition was irreversible. 3. The non-selective NO synthase (NOS) inhibitors Nomega-nitro-L-arginine methyl ester (L-NAME; 10 microM) and NG-iminoethyl-L-ornithine (L-NIO; 30 microM) also increased the tone of the rabbit isolated corpus cavernosum and markedly reduced both ACh- and Tityus serrulatus venom-induced relaxations without affecting those evoked by GTN. The inhibitory effect was reversed by infusion of L-arginine (300 microM), but not D-arginine (300 microM). The neuronal NOS inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM, 100 microM) did not affect either the tone of the rabbit isolated corpus cavernosum or the relaxations induced by ACh, bradykinin (Bk), Tityus serrulatus venom and GTN. TRIM was approximately 1,000 times less potent than L-NAME in inhibiting rabbit cerebellar NOS in vitro, as measured by the conversion of [3H]-L-arginine to [3H]-L-citrulline. 4. The protease inhibitor aprotinin (Trasylol; 10 microg ml[-1]) and the bradykinin B2 receptor antagonist Hoe 140 (D-Arg-[Hyp3,Thi5,D-Tic7, Oic8]-BK; 50 nM) did not affect the rabbit isolated corpus cavernosum relaxations induced by Tityus serrulatus venom. The ATP-dependent K+ channel antagonist glibenclamide (10 microm) and the Ca2+-activated K+ channel antagonists apamin (0.1 microM) and charybdotoxin (0.1 microM) also failed to affect the venom-induced relaxations. Similarly, the K+ channel blocker tetraethylammonium (TEA; 10 microM) had no effect on the venom-induced relaxations. 5. Capsaicin (3 and 10 nmol) relaxed the rabbit isolated corpus cavernosum in a dose-dependent and non-tachyphylactic manner. Ruthenium red (30 microM), an inhibitor of capsaicin-induced responses, markedly reduced the relaxations caused by capsaicin, but failed to affect those induced by Tityus serrulatus venom. L-NAME (10 microM) had no effect on the capsaicin-induced relaxations of the rabbit isolated corpus cavernosum. 6. The sodium channel blocker tetrodotoxin (TTX; 1 microM) abolished the relaxations of the rabbit isolated corpus cavernosum induced by Tityus serrulatus venom without affecting those evoked by capsaicin, ACh and GTN. Tetrodotoxin (1 microM) also promptly reversed the response to the venom when infused during the relaxation phase. 7. The bioassay cascade of the toxin components purified from Tityus serrulatus venom revealed that only fractions X, XI and XII caused dose-dependent relaxations of the rabbit isolated corpus cavernosum and these were markedly reduced by either TTX (1 microM) or L-NAME (10 microM). 8. Our results indicate that Tityus serrulatus scorpion venom (and the active fractions X, XI and XII) relaxes rabbit corpus cavernosum via the release of NO. This release is specifically triggered by the activation of capsaicin-insensitive cavernosal non-adrenergic non-cholinergic (NANC) fibres, that may possibly be Nitrergic neurones. Tityus serrulatus venom may therefore provide an important tool for understanding further the mechanism of NANC Nitrergic Nerve activation.123435-4

  • Effect of tityus serrulatus scorpion venom on the rabbit isolated corpus cavernosum and the involvement of NANC Nitrergic Nerve fibres
    'Springer Science and Business Media LLC', 2015
    Co-Authors: Teixeira C.e., Antunes E, De Nucci G, Muscara M.n., Teixeira S.a., Lopes-martins R.a.b., Bento A.c., Arantes E.c., Von Eickestedt
    Abstract:

    FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe effect of Tityus serrulatus scorpion venom and its toxin components on the rabbit isolated corpus cavernosum was investigated by use of a bioassay cascade. 2 Tityus serrulatus venom (3-100 mu g), acetylcholine (ACh; 0.3-30 nmol) and glyceryl trinitrate (GTN; 0.5-10 nmol) dose-dependently relaxed rabbit isolated corpus cavernosum preparations precontracted with noradrenaline (3 mu M). The selective soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3, alquinoxalin-1-one] (ODQ; 30 mu m) increased the basal tone of the rabbit isolated corpus cavernosum and abolished the relaxations induced by the agents mentioned above. Methylene blue (30 am) also inhibited the relaxations induced by Tityus serrulatus venom but, in contrast to ODQ, the inhibition was irreversible. 3 The non-selective NO synthase (NOS) N-omega-nitro-L-arginine methyl ester (L-NAME; 10 mu M) and N-G-iminoethyl-L-ornithine (L-NIO; 30 mu M) also increased the tone of the rabbit isolated corpus cavernosum and markedly reduced both Auckland Tityus serrulatus venom-induced relaxations without affecting those evoked by GTN. The inhibitory effect was reversed by infusion of L-arginine (300 mu M), but not D-arginine (300 mu M). The neuronal NOS inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM, 100 mu M) did not affect either the tone of the rabbit isolated corpus cavernosum or the relaxations induced by ACh, bradykinin (Bk), Tityus serrulatus venom and GTN. TRIM was approximately 1,000 times less potent than L-NAME in inhibiting rabbit cerebellar NOS in vitro, as measured by the conversion of [H-3]-L-arginine to [H-3]-L-citrulline. 4 The protease inhibitor aprotinin (Trasylol; 10 mu g ml(-1)) and the bradykinin Ba receptor antagonist Hoe 140 (D-Arg-[Hyp(3),Thi(5),D-Tic(7), Oic(8)]-BK; 50 nM) did not affect the rabbit isolated corpus cavernosum relaxations induced by Tityus serrulatus venom. The ATP-dependent K+ channel antagonist glibenclamide (10 mu M) and the Ca2+-activated K+ channel antagonists apamin (0.1 mu M) and charybdotoxin (0.1 mu M) also failed to affect the venom-induced relaxations. Similarly, the Kt channel blocker tetraethylammonium (TEA; 10 mu M) had no effect on the venom-induced relaxations. 5 Capsaicin (3 and 10 nmol) relaxed the rabbit isolated corpus cavernosum in a dose-dependent and non-tachyphylactic manner. Ruthenium red (30 mu M), an inhibitor of capsaicin-induced responses, markedly reduced the relaxations caused by capsaicin, but failed to affect those induced by Tityus serrulatus venom. L-NAME (10 mu M) had no effect on the capsaicin-induced relaxations of the rabbit isolated corpus cavernosum. 6 The sodium channel blocker tetrodotoxin (TTX; 1 mu M) abolished the relaxations of the rabbit isolated corpus cavernosum induced by Tityus serrulatus venom without affecting those evoked by capsaicin, ACh and GTN. Tetrodotoxin (1 mu M) also promptly reversed the response to the venom when infused during the relaxation phase. 7 The bioassay cascade of the toxin components purified from Tityus serrulatus venom revealed that only fractions X, XI and XII caused dose-dependent relaxations of the rabbit isolated corpus cavernosum and these were markedly reduced by either TTX (1 mu M) or L-NAME (10 mu M). 8 Our results indicate that Tityus serrulatus scorpion venom (and the active fractions X, XI and XII) relaxes rabbit corpus cavernosum via the release of NO. This release is specifically triggered by the activation of capsaicin-insensitive cavernosal non-adrenergic non-cholinergic (NANC) fibres, that may possibly be Nitrergic neurones. Tityus serrulatus venom may therefore provide an important tool for understanding further the mechanism of NANC Nitrergic Nerve activation1233435442FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

  • Pharmacological characterization of the presynaptic activity of Tityus serrulatus venom in the rat anococcygeus muscle
    Inglaterra, 2015
    Co-Authors: Ce Teixeira, De Nucci G, Priviero Fbm, Ce Okuyama, Antunes E
    Abstract:

    Scorpion venoms are known to cause peripheral Nerve stimulation with enhanced autonomic responses. This study, therefore, examined the effects of Tityus serrulatus venom (TSV) on adrenergic, cholinergic and Nitrergic Nerve fibers using the rat anococcygeus muscle. The contractile effects of TSV (1 mug/ml) and electrical field stimulation were markedly reduced by phentolamine (5 muM), prazosin (0.1 muM), guanethidine (30 muM) and tetrodotoxin (TTX, l muM), whereas imipramine (3 muM) enhanced these responses. The responses to tyramine (10 muM) were partially reduced by guanethidine and completely blocked by phentolamine, prazosin and imipramine. Atropine (1 muM) fully prevented carbachol (CCh, 30 muM)-induced contractions without affecting those mediated by TSV. Neostigmine significantly potentiated TSV-and ACh-evoked contractions, whereas hexamethonium had no effect. The relaxant responses induced by EFS and TSV (3 mug/ml) were completely blocked by L-NAME (100 muM), ODQ (1 muM) or TTX (1 muM). Addition of L-arginine (1 mM) reversed the effect of L-NAME. Thus, the motor and inhibitory responses of TSV in the rat anococcygeus muscle are mediated by prejunctional mechanisms dependent on Na+ channel activation, causing the stimulation of NA and NO release from adrenergic and Nitrergic Nerve fibers, respectively. (C) 2003 Published by Elsevier Ltd.42545146

  • Pharmacological characterization of the presynaptic activity of tityus serrulatus venom in the rat anococcygeus muscle
    'Elsevier BV', 2015
    Co-Authors: Teixeira C.e., Antunes E, De Nucci G, Priviero F.b.m., Okuyama C.e.
    Abstract:

    FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOScorpion venoms are known to cause peripheral Nerve stimulation with enhanced autonomic responses. This study, therefore, examined the effects of Tityus serrulatus venom (TSV) on adrenergic, cholinergic and Nitrergic Nerve fibers using the rat anococcygeus muscle. The contractile effects of TSV (1 mug/ml) and electrical field stimulation were markedly reduced by phentolamine (5 muM), prazosin (0.1 muM), guanethidine (30 muM) and tetrodotoxin (TTX, l muM), whereas imipramine (3 muM) enhanced these responses. The responses to tyramine (10 muM) were partially reduced by guanethidine and completely blocked by phentolamine, prazosin and imipramine. Atropine (1 muM) fully prevented carbachol (CCh, 30 muM)-induced contractions without affecting those mediated by TSV. Neostigmine significantly potentiated TSV-and ACh-evoked contractions, whereas hexamethonium had no effect. The relaxant responses induced by EFS and TSV (3 mug/ml) were completely blocked by L-NAME (100 muM), ODQ (1 muM) or TTX (1 muM). Addition of L-arginine (1 mM) reversed the effect of L-NAME. Thus, the motor and inhibitory responses of TSV in the rat anococcygeus muscle are mediated by prejunctional mechanisms dependent on Na+ channel activation, causing the stimulation of NA and NO release from adrenergic and Nitrergic Nerve fibers, respectively425451460FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçã

  • The role of nitric oxide on the relaxations of rabbit corpus cavernosum induced by Androctonus australis and Buthotus judaicus scorpion venoms
    Inglaterra, 2015
    Co-Authors: Ce Teixeira, Antunes E, Sa Teixeira, De Nucci G
    Abstract:

    In this study, we have investigated the relaxing effects of both Androctonus australis venom (AAV) and Buthotus judaicus venom (BJV) on the rabbit corpus cavernosum (RbCC) smooth muscle strips. The RbCC strips were mounted in a cascade system and superfused with warmed and gassed Krebs solution. The nitric oxide (NO) synthesis inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME, 10 muM), but not D-NAME (10 muM), significantly inhibited the RbCC relaxations induced by acetylcholine (ACh, 0.6 nmol), AAV (30 mug) and BJV (30 mug). Subsequent infusion of L-arginine (300 muM), but not of D-arginine (300 muM), partially restored the relaxations evoked by these agents. The brain NO synthase inhibitor 7-nitroinciazole (7-NI, 10 muM) also inhibited the relaxant responses elicited by the scorpion venoms. The guanylyl cyclase inhibitors methylene blue (MB, 30 muM) and 1H-[1.2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (ODQ, 10 muM) virtually abolished the relaxations induced by either AAV or BJV. The infusion of muscarinic receptor antagonists such as scopolamine and atropine (1 muM, each) completely abolished the ACh-induced relaxations but had no effect on those evoked by the scorpion venoms. The Na+ channel blocker tetrodotoxin (1 muM) prevented the relaxations evoked by both AAV and BJV, Thus, NO released from Nitrergic Nerve fibres mediates the relaxations elicited hy AAV and BJV in the rabbit cavernosal tissue. (C) 2000 Elsevier Science Ltd. All rights reserved.39563363