Neuronal Blocker Research Articles

Non‐adrenergic, non‐cholinergic, non‐purinergic contractions of the urothelium/lamina propria of the pig bladder

Acetylcholine, and to a lesser extent ATP, mediates neurogenic contractions of bladder smooth muscle. Recently, the urothelium and lamina propria have also been shown to have contractile properties, but the neurotransmitters involved in mediating responses to nerve stimulation have not been investigated. Isolated strips of porcine urothelium with lamina propria were electrically field stimulated and contractions recorded. Drugs interfering with neurotransmission were then employed to identify which neurotransmitters mediated responses. Strips of urothelium/lamina propria developed spontaneous contractions with a frequency of 3.5±0.1 cycles min⁻¹ and amplitude of 0.84±0.06 g. Electrical field stimulation at 5, 10, and 20 Hz resulted in frequency-related contractions (1.13±0.36 g, 1.59±0.46 g and 2.20±0.53 g, respectively, n=13), and these were reduced in the presence of tetrodotoxin (1 μm) by 77±20% at 5 Hz, 79±7% at 10 Hz and 74±12% at 20 Hz (all P<0.01), indicating they were predominantly neurogenic in nature. Neither the muscarinic antagonist atropine (10 μm), the adrenergic neurone blocker guanethidine (10 μm) nor desensitization of the purinergic receptors with α,β-methylene ATP (10 μm) affected the contractile amplitude. Similarly, responses were not affected by the nitric oxide synthase inhibitor L-NNA (100 μm) or drugs that interfere with peptide neurotransmission (capsaicin, NK2 antagonist GR159897, protease inhibitors). In conclusion, electrical depolarization of the nerves present in the porcine urothelium/lamina propria results in frequency-dependent contractions, which are predominantly neurogenic in nature. These contractions are resistant to drugs that inhibit the adrenergic, cholinergic and purinergic systems. The neurotransmitter involved in the responses of this tissue is therefore unknown but does not appear to be a peptide.

Adrenergic stimulation-released 5-HT stored in adrenergic nerves inhibits CGRPergic nerve-mediated vasodilatation in rat mesenteric resistance arteries

5-HT is taken up by and stored in adrenergic nerves and periarterial nerve stimulation (PNS) releases 5-HT to cause vasoconstriction in rat mesenteric arteries. The present study investigated whether PNS-released 5-HT stored in adrenergic nerves affects the function of perivascular calcitonin gene-related peptide-containing (CGRPergic) nerves. Rat mesenteric vascular beds without endothelium and with active tone were perfused with Krebs solution. Changes in perfusion pressure in response to PNS and CGRP injection were measured before (control) and after perfusion of Krebs solution containing 5-HT (10 µM) for 20 min. Distributions of 5-HT- and TH-immunopositive fibres in mesenteric arteries were studied using immunohistochemical methods. PNS (1-4 Hz) frequency dependently caused adrenergic nerve-mediated vasoconstriction followed by CGRPergic nerve-mediated vasodilatation. 5-HT treatment inhibited PNS-induced vasodilatation without affecting exogenous CGRP-induced vasodilatation, while it augmented PNS-induced vasoconstriction. Guanethidine (adrenergic neuron blocker), methysergide (non-selective 5-HT receptor antagonist) and BRL15572 (selective 5-HT1D receptor antagonist) abolished inhibition of PNS-induced vasodilatation in 5-HT-treated preparations. Combined treatment with 5-HT and desipramine (catecholamine transporter inhibitor), but not fluoxetine (selective 5-HT reuptake inhibitor), did not inhibit PNS-induced vasodilatation. Exogenous 5-HT inhibited PNS-induced vasodilatation, which was antagonized by methysergide. In immunohistochemical experiments, 5-HT-immunopositive nerves, colocalized with adrenergic TH-immunopositive nerves, were observed only in 5-HT-treated mesenteric arteries, but not in control preparations or arteries co-treated with desipramine. These results suggest that 5-HT can be taken up by and released from adrenergic nerves in vitro by PNS to inhibit CGRPergic nerve transmission in rat mesenteric arteries.

Spiking Neuron Computation With the Time Machine

The Time Machine (TM) is a spike-based computation architecture that represents synaptic weights in time. This choice of weight representation allows the use of virtual synapses, providing an excellent tradeoff in terms of flexibility, arbitrary weight connections and hardware usage compared to dedicated synapse architectures. The TM supports an arbitrary number of synapses and is limited only by the number of simultaneously active synapses to each neuron. SpikeSim, a behavioral hardware simulator for the architecture, is described along with example algorithms for edge detection and objection recognition. The TM can implement traditional spike-based processing as well as recently developed time mode operations where step functions serve as the input and output of each neuron block. A custom hybrid digital/analog implementation and a fully digital realization of the TM are discussed. An analog chip with 32 neurons, 1024 synapses and an address event representation (AER) block has been fabricated in 0.5 μm technology. A fully digital field-programmable gate array (FPGA)-based implementation of the architecture has 6,144 neurons and 100,352 simultaneously active synapses. Both implementations utilize a digital controller for routing spikes that can process up to 34 million synapses per second.

Prejunctional facilitatory effect of a thiol-alkylating agent N -Ethylmaleimide on neurogenic contractions in rat prostate smooth muscle

The effect of a non-specific thiol-alkylating agent N-ethylmaleimide (NEM) was studied on neurogenic contractile mechanisms in rat ventral prostate gland. Male Wistar albino rats were used. The rats were killed by cervical dislocation under sevoflurane anesthesia and ventral prostate gland was removed. Two preparations were obtained from each lobe. Neurally evoked isometric contractions were induced using trains of electrical field stimulation (EFS; 0.5, 1, 4, or 8 Hz). The effect of NEM on the contractions to EFS was examined in the absence or presence of adrenergic and/or purinergic antagonists. NEM enhanced the EFS-evoked contractions without altering the basal tone. These effects were significantly suppressed by an α(1) -adrenergic receptor antagonist (prazosin), a P2-purinergic antagonist (suramin), a specific P2X-receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), an ATP analog (α,β-methylene ATP), or a calcium channel blocker (verapamil). This facilitating effect of NEM did not occur following the administration of L-cysteine or glutathione which saturated NEM with excess thiols. However, a thiol-oxidant diamide failed to affect the contractions to EFS. An adrenergic neuron blocker (guanethidine) completely suppressed the responses to NEM. On the other hand, an α(2) -adrenergic receptor blocker (yohimbine), a nitric oxide synthase inhibitor (N(ω) -nitro-L-arginine) or a cholinergic muscarinic receptor antagonist (atropine) did not significantly affect the facilitatory response of NEM. These findings suggest that NEM has a prejunctional facilitatory action on the adrenergic nerves in rat prostate tissue to enhance release of transmitters, noradrenaline, and ATP. NEM sensitive proteins involved in transmitter release mechanisms can play a role in this effect.

Neurogenic Vascular Responses in Male Mouse Mesenteric Vascular Beds

Rat mesenteric arteries were maintained by both adrenergic vasoconstrictor nerves and calcitonin gene–related peptide (CGRP) vasodilator nerves. However, functions of these nerves in a pathophysiological state have not fully been analyzed. The use of disease models developed genetically in mice is expected to clarify neural function of perivascular nerves. Thus, we investigated basic mouse vascular responses. Mesenteric vascular beds isolated from male C57BL/6 mouse were perfused with Krebs solution and perfusion pressure was measured. Periarterial nerve stimulation (PNS, 8 – 24 Hz) induced frequency-dependent vasoconstriction, which increased flow rate–dependently. PNS-induced vasoconstriction was abolished by tetrodotoxin (neurotoxin) and guanethidine (adrenergic neuron blocker) and blunted by prazosin (α1-adrenoceptor antagonist). Injection of norepinephrine caused vasoconstriction, which was abolished by prazosin. In preparations with active tone, PNS (1 – 8 Hz) induced frequency-dependent vasodilation, which was inhibited by tetrodotoxin, capsaicin (CGRP depletor), and CGRP8-37 (CGRP-receptor antagonist). Injections of CGRP, acetylcholine, and sodium nitroprusside induced vasodilations. Vasodilator response to CGRP was inhibited by CGRP8-37. Immunohistochemical study showed innervation of tyrosine hydroxylase- and CGRP-immunopositive fibers in mesenteric arteries and veins. These results suggest that male mouse mesenteric vascular beds are useful for studying neural regulation of mesenteric arteries, which are innervated by adrenergic and CGRPergic nerves regulating vascular tone.

Abstract P081: Voltage-Gated TTX-Sensitive Nav1.1 Brain Sodium Channels Are Important for Cardiac Contractile Function

Background: Mutations in voltage gated brain sodium channel Nav1.1 have been linked to many disorders, including Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). Recent studies have identified TTX- sensitive Nav1.1 brain sodium channels in the SA node and ventricular T-tubules of the heart, though their role in cardiac function is still controversial. We tested the functional significance of Nav1.1 sodium channels in the heart by creating a novel knock-in of human epilepsy GEFS+ mutation SCN1A-R1648H at the Scn1a locus of a C57BL/6J X 129 mouse. Method: In vivo 2-D echocardiography was performed on 2 week old (juvenile) and 8 week old (adult) wild-type and heterozygote (Scn1aRH/+) mice after extracardiac neuronal block through intraperitoneal injections of atropine and propranolol (2.5mg/kg each). Calcium and contractility studies on adult ventricular cardiomyocytes isolated from the wild type and Scn1aRH/+ mice paced at 0.5Hz were followed by administration of TTX (100nM, a brain sodium channel inhibitor) and pacing at 2Hz. qRT-PCR and Western blot of the isolated cells and whole heart samples was also done. Results: A decrease in Nav1.1 gene expression in the Scn1aRH/+ juvenile (by 31%, 0.69 of 1) and adult (by 60%, 0.4 of 1) whole heart samples and isolated cells (p&lt;0.05) was seen. Echocardiography revealed concentric hypertrophy in the juvenile Scn1aRH/+ mice by a significant increase in LV mass, LV mass/body weight ratio, and relative wall thickness (p&lt;0.05). In the adult Scn1aRH/+ mice, systolic isovolumic contraction time (IVCT) was reduced (p=0.03) and decrease in diastolic function was evident through significant decreases in isovolumic relaxation time (IVRT) and E’/A’ ratio, and increase in E/E’ ratio. Isolated adult ventricular Scn1aRH/+ cardiomyocytes showed significant reduction in percent sarcomere shortening, maximum rate of contraction and relaxation, and time to peak contraction, exaggerated with TTX and pacing at 2Hz (p&lt;0.5). Conclusions: Our study demonstrates the importance of voltage gated TTX-sensitive Nav1.1 brain sodium channels in cardiac contractile function and their possible role in cardiac complications in epilepsy.

Proteinase activated receptor‐2 (PAR‐2) inhibits spontaneous activity in rat colon via adrenergic nerves

Rat colonic smooth muscle shows spontaneous contractile activity which is generated by pacemaker cells. We have investigated whether this spontaneous activity can be modulated by proteinase activated receptor-2 (PAR-2), a G-protein coupled receptor activated by proteolytic cleavage. Strips of rat colon longitudinal muscle were suspended in organ baths and increasing concentrations of the PAR-2 mimetic peptide f-LIGRL were applied. f-LIGRL induced concentration-dependent inhibition of spontaneous contractile activity of rat colon that was sensitive to apamin, an inhibitor of small conductance Ca2+-activated potassium channels. Tetrodotoxin, an inhibitor of neurotransmission, blocked the effects of f-LIGRL as did phentolamine, an α-adrenoceptor antagonist. Propanolol, a β-adrenoceptor antagonist, had only small inhibitory effect on f-LIGRL-evoked responses. The adrenergic neuronal blocker guanethidine reduced responses to f-LIGRL supporting our conclusion that PAR-2 activation inhibits spontaneous contractile activity in the rat colon by releasing noradrenaline from adrenergic neurons to act on α-adrenoceptors on pacemaker cells. Supported by NSERC

Regionalanästhesie und neurologische Erkrankungen

Modern anesthesia is handling an increasing number of patients with neurological diseases who require narcosis. Regional anesthesia techniques offer qualities which might be advantageous for this group particularly for childbirth. The number of pregnant women with neurological diseases has increased significantly in the recent years due to improved diagnostics and therapy. A more careful approach to regional anesthesia in patients with neurological diseases is necessary as the drugs themselves possess neurotoxic effects and the procedure might worsen the underlying neurological diseases. Additionally, performing regional anesthesia might be more complicated and the resulting blockade might be different from the expected neuronal block. Published data concerning regional anesthesia in this patient group are limited and mainly restricted to case reports. In this review general considerations regarding regional anesthesia, techniques, drugs and methods in these patient groups will be discussed. In the second part the practical approach to regional anesthesia for some of the most important neurological diseases is highlighted.

Systemic effects of ulna loading in male rats during functional adaptation

Functional skeletal adaptation is thought to be a local phenomenon controlled by osteoctyes. However, the nervous system also may have regulatory effects on adaptation. The aim of this study was to determine the effects of loading of a single bone on adaptation of other appendicular long bones and whether these responses were neuronally regulated. Young male Sprague-Dawley rats were used. The right ulna was loaded to induce a modeling response. In other rats, a second regimen was used to induce bone fatigue with a mixed modeling/remodeling response; a proportion of rats from each group received brachial plexus anesthesia to induce temporary neuronal blocking during bone loading. Sham groups were included. Left and right long bones (ulna, humerus, tibia, and femur) from each rat were examined histologically 10 days after loading. In fatigue- and sham-loaded animals, blood plasma concentrations of TNF-α, RANKL, OPG, and TRAP5b were determined. We found that loading the right ulna induced an increase in bone formation in distant long bones that were not loaded and that this effect was neuronally regulated. Distant effects were most evident in the rats that received loading without bone fatigue. In the fatigue-loaded animals, neuronal blocking induced a significant decrease in plasma TRAP5b at 10 days. Histologically, bone resorption was increased in both loaded and contralateral ulnas in fatigue-loaded rats and was not significantly blocked by brachial plexus anesthesia. In young, growing male rats we conclude that ulna loading induced increased bone formation in multiple bones. Systemic adaptation effects were, at least in part, neuronally regulated. © 2010 American Society for Bone and Mineral Research.

Inhibition of the Mechanical Activity of Mouse Ileum by Cactus Pear (Opuntia Ficus Indica, L, Mill.) Fruit Extract and Its Pigment Indicaxanthin

We investigated, using an organ bath technique, the effects of a hydrophilic extract from Opuntia ficus indica fruit pulp (cactus fruit extract, CFE) on the motility of mouse ileum, and researched the extract component(s) responsible for the observed responses. CFE (10-320 mg of fresh fruit pulp equivalents/mL of organ bath) reduced dose-dependently the spontaneous contractions. This effect was unaffected by tetrodotoxin, a neuronal blocker, N(omega)-nitro-l-arginine methyl ester, a nitric oxide synthase blocker, tetraethylammonium, a potassium channel blocker, or atropine, a muscarinic receptor antagonist. CFE also reduced the contractions evoked by carbachol, without affecting the contractions evoked by high extracellular potassium. Indicaxanthin, but not ascorbic acid, assayed at concentrations comparable with their content in CFE, mimicked the CFE effects. The data show that CFE is able to exert direct antispasmodic effects on the intestinal motility. The CFE inhibitory effects do not involve potassium channels or voltage-dependent calcium channels but rather pathways of calcium intracellular release. The fruit pigment indicaxanthin appears to be the main component responsible for the CFE-induced effects.

Cortistatin Inhibits Intestinal Secretion in the Guinea‐pig Ileum In Vitro

Background and AimsCortistatin (CST) is a novel neuropeptide with high structural homology with somatostatin. We previously found that CST is expressed by enteric neurons and acts as an inhibitory neurotransmitter in the submucosal plexus. The aim of the present study was to evaluate the effect of CST on neurogenic intestinal secretion.MethodsSubmucosal/mucosal preparations from guinea pig ileum were mounted in Ussing flux chambers for measurement of short‐circuit current (Isc) as an indicator of mucosal secretion. Transmural electrical field stimulation (EFS) was used to evoke neural‐mediated intestinal secretion.ResultsApplication of CST‐14 (rat), CST‐17 (human), CST‐29 (rat), or CST‐29 (human) to the submucosal side of the preparation decreased baseline Isc in a concentration‐dependent manner with an IC50 (in nM) of 90.5, 52.1, 102.9 or 71.6, respectively. The somatostatin‐2 receptor (SSTR‐2) antagonist CYN 154806 significantly suppressed CST‐14r, CST‐17h, CST‐29r, or CST‐29h‐evoked ΔIsc. The neuronal blocker tetrodotoxin significantly reduced CST‐14r, CST‐17h, CST‐29r, or CST‐29h‐evoked ΔIsc. CSTs produced a concentration‐dependent reduction of the EFS‐evoked secretory responses, which was antagonized by CYN 154806. Immunoreactivity (IR) of CST‐17 was found in submucosal neurons. CST‐17‐IR was localized in cholinergic secretomotor neurons but was absent from non‐cholinergic secretomotor neurons.ConclusionsThe results suggest that CSTs act at SST‐2 receptors in the submucosal plexus to suppress secretomotor neuronal excitability and neurogenic intestinal secretion.

Gastrin release: Antrum microdialysis reveals a complex neural control

We used microdialysis to monitor local gastrin release in response to food, acid blockade and acute vagal excitation. For the first time, gastrin release has been monitored continuously in intact conscious rats in a physiologically relevant experimental setting in a fashion that minimizes confounding systemic effects. Microdialysis probes were placed in the submucosa on either side of the antrum, 3 days before the experiments. The concentration of gastrin in the antral submucosal compartment was about 20 times higher than in the microdialysate and estimated to be 5–10 times higher than in serum regardless of the prandial state. The rats were conscious during microdialysis except when subjected to electrical vagal stimulation. Acid blockade (omeprazole treatment of freely fed rats for 4 days), or bilateral sectioning of the abdominal vagal trunks (fasted, 3 days post-op.), raised the gastrin concentration in blood as well as microdialysate. The high gastrin concentration following omeprazole treatment was not affected by vagotomy. Vagal excitation stimulated the G cells: electrical vagal stimulation and pylorus ligation (fasted rats) raised the gastrin concentration transiently in both serum and microdialysate. Food intake induced a 2- to 3-fold increase in serum gastrin, while gastrin in antral microdialysate increased 10- to 15-fold. In unilaterally vagotomized rats (fasted, 3 days post-op.), food evoked a prompt peak gastrin release followed by a gradual decline on the intact side. On the vagotomized side of the antrum, the peak response seemed to be reduced while the microdialysate gastrin concentration remained elevated. Thus, unilateral vagotomy surprisingly raised the integrated gastrin response to food on the denervated side compared to the intact side, indicating that vagotomy suppresses an inhibitory as well as a stimulating effect on the G cells. While local infusion of atropine was without effect, infusion of the neuronal blocker tetrodotoxin (TTX) (which had no effect on basal gastrin) virtually abolished the food-evoked gastrin response and lowered the high microdialysate gastrin concentration in omeprazole-treated rats by 65%. We conclude that activated gastrin release, unlike basal gastrin release, is highly dependent on a neural input: 1) Vagal excitation has a transient stimulating effect on the G cells. The transient nature of the response suggests that the vagus has not only a prompt stimulatory but also a slow inhibitory effect on gastrin release. 2) Although vagal denervation did not affect the gastrin response to anacidity, the TTX experiments revealed that both food-evoked and anacidity-evoked gastrin release depends on neural input.

Pouch colon associated with anorectal malformations fails to show spontaneous contractions but responds to acetylcholine and histamine in vitro

Purpose Congenital pouch colon (CPC) associated with anorectal malformation (ARM) is most commonly reported from Northern India. So far, no physiologic study comparing the detailed contractile status of CPC with non-CPC conditions are available. The present article deals with the contractile study and histopathologic observations in CPC, which may be useful for better surgical management. Methods Freshly excised 12 neonatal CPC and similar number of non-CPC (control) specimens were transferred to ice-cold (4°C-6°C) Krebs-Ringer solution bubbled with 100% oxygen. Longitudinally prepared 2 to 4 colonic strips were obtained from central part of each specimen and subjected to the contraction recording after exposure to cumulative concentrations of acetylcholine (ACh) and histamine. Acetylcholine-induced contractions were evaluated after application of atropine (muscarinic blocker), and histaminergic contractions were recorded after pheniramine (H 1 blocker), lignocaine (neuronal blocker), and atropine. Histopathologic observations were made by using H&E and Masson trichrome stains. Results Control specimens showed spontaneous contractions, but CPC strips did not. Both control and CPC responded to ACh and histamine. The response to histamine was greater ( P < .05) in CPC as compared to control, whereas the response to ACh was more ( P < .05) in control. In CPC, response of histamine (100 μmol/L) was blocked by pheniramine (0.32 mmol/L) and lignocaine (4 mmol/L) by 97% and 80%, respectively, and enhanced by 57% after preapplication of atropine (10 μmol/L). Acetylcholine (100 μmol/L)-induced contractions were attenuated (86%) in presence of atropine. Histopathologic examination showed fewer mature ganglion cells with various changes in muscle layers including fibrosis, disruption, hypertrophy, atrophy, and constriction bands. Conclusion Congenital pouch colon associated with ARM lacks normal spontaneous contractions but retains ACh and histamine-induced contractility. In view of the functional and histologic abnormalities, we propose that CPC associated with ARM is an abnormally functional and developed tissue. Therefore, resection of the pouch should be considered for better functional outcome of the remaining bowel.

Observation for antalgic effecls of different concentrations of ropivacaine on brachial plexus nerves

Objective To compare the antalgic effects of ropivacaine in various doses on brachial plexus nerves. Methods 87 patients undergoing upper arm surgery were enrolled in this study. The patients were unpremed-itated. The patients were randomized to receive ropivacaine of 0.30,0.25 or 0.20% (group Ⅰ,Ⅱ and Ⅲ) with mor-phine of 0.1mg/ml and Lidocaine of 10mg/ml. In order to analygesia of brachial plexus nerves,the rejecting of load dose is firstly 10ml,the total dose is 10ml/24h interval every time,the antalgic time is about 50 hours. To compare the antalgic effects of ropivacaine in various doses based on standard of VAS. Based on standard of Bromage to assess the situation of motor neuron blocking. Results According to standard of VAS in 6,12,24 and 48 hours after underwent surgery, the group Ⅲ is more effective than group Ⅰ and group Ⅱ ; according to standard of Bromage, the group Ⅰ is more effective than group Ⅱ and group Ⅲ. it has no adverse reactions to patients. Condusion 0. 25% of ropiva-eaine with morphine of 0.1mg/ml and lidocaine of 10mg/ml have obtained good antalgic effects for patients after un-dergoing upper arm surgery,it is fit for applying in clinic. Key words: Anestheisa and analgesia; Ropivacaine

Proton Acts as a Neurotransmitter for Nicotine-Induced Adrenergic and Calcitonin Gene-Related Peptide-Containing Nerve-Mediated Vasodilation in the Rat Mesenteric Artery

Nicotine stimulates presynaptic nicotinic acetylcholine receptors in perivascular adrenergic nerves and releases unknown transmitter(s) that activate transient receptor potential vanilloid-1 (TRPV1) located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves, resulting in vasodilation. The present study investigated a potential transmitter transmitting between perivascular adrenergic nerves and CGRPergic nerves. Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs' solution containing methoxamine, and the perfusion pressure and pH levels of the perfusate were measured. Nicotine perfusion for 1 min induced concentration-dependent vasodilation and lowered pH levels, which were abolished by cold-storage denervation of preparations, guanethidine (adrenergic neuron blocker), and mecamylamine (nicotinic alpha(3)beta(4)-acetylcholine receptor antagonist). Capsazepine (TRPV1 antagonist) blunted nicotine-induced vasodilation, but had no effect on the reduction of pH. Injection of hydrochloric acid (HCl) and perfusion of Krebs' solution at low pH (6.0-7.2) induced vasodilation. HCl-induced vasodilation was inhibited by cold-storage denervation, capsazepine, capsaicin (CGRP depletor), and CGRP(8-37) (CGRP receptor antagonist). Perfusion of adrenergic transmitter metabolites (normetanephrine and 3-methoxydopamine), but not of other metabolites, induced vasodilation, which was not inhibited by capsaicin treatment. Immunohistochemical staining of mesenteric arteries showed dense innervation of CGRP- and TRPV1-immunopositive nerves, with both immunostainings appearing in the same neuron. Mesenteric arteries were densely innervated by neuropeptide Y-immunopositive nerves, which coalesced with CGRP-immunopositive nerves. Scanning and immunoscanning electron microscopic images showed coalescence sites of different perivascular fibers before they intruded into smooth muscles. These results indicate that nicotine initially stimulates adrenergic nerves via nicotinic alpha(3)beta(4)-receptors to release protons and thereby induces CGRPergic nerve-mediated vasodilation via TRPV1.

Characterization of bradykinin‐induced endothelium‐independent contraction in equine basilar artery

We investigated the effect of bradykinin (BK) on isolated equine basilar arterial rings with and without endothelium. BK induced concentration-dependent contraction of resting arterial rings and no relaxation when the rings were precontracted by prostaglandin F(2alpha). The maximal response and pD(2) value were 161.2 +/- 28.1% (to 60 mm KCl-induced contraction) and 8.24 +/- 0.25 respectively. The cumulative concentration-response curve for BK was not shifted to the right by des-Arg(9)-[Leu(8)]-BK (a B(1)-receptor antagonist), HOE140 (a B(2)-receptor antagonist) or NPC567 (another B(2)-receptor antagonist). In four of six basilar arteries, NPC567 induced concentration-dependent contraction. Indomethacin (a cyclooxygenase inhibitor), nordihydroguaiaretic acid (a lipoxygenase inhibitor), quinacrine (a phospholipase A(2) inhibitor), tetrodotoxin (a selective blocker of Na(+) channels), guanethidine (a nor-adrenergic neuron blocking drug), phentolamine (an alpha-adrenoceptor antagonist), Nomega-nitro-L-arginine (L-NNA, a nitric oxide (NO) synthase inhibitor) and endothelial denudation did not affect the BK-induced contraction. L-NNA and indomethacin induced contraction and relaxation under resting vascular tone respectively. These results suggest that endothelial cells are not involved in BK-induced contraction and that the contraction is not mediated via activation of known B(1) and B(2) receptors. Arachidonic acid metabolites and neurotransmitters like norepinephrine and NO might not play a role in BK-induced contraction in equine basilar artery.

Sub-arachnoid ketamine administration combined with or without misoprostol/oxytocin to facilitate cervical dilation in ewes: A case study

The cervical anatomy limits the use of trans-cervical artificial insemination (AI) and embryo transfer in ewes. Thus, the objective of the study was to evaluate the sub-arachnoid administration of ketamine as a tool to be used in cervical dilation of the ewe. The following experimental treatments were used: in Experiment 1, animals ( n = 6) were treated with the sub-arachnoid administration of ketamine (KS, 1.5 mg kg −1); and in Experiment 2, one tablet of misoprostol was diluted in 1.5 ml saline and deposited near the cervical os, 5 h before the trial + oxytocin administered i.v. 5 min before the reproductive procedures (MO, 200 + 20 U.I., respectively). In Experiment 3, animals received sub-arachnoid ketamine + misoprostol/oxytocin (KSMO). The systemic effects, analgesia, sedation, and motor neuron block were evaluated before each experiment and at pre-determined time intervals thereafter. A subjective score system was used to assess pain and discomfort during the reproductive manipulations in the different experiments. The mean duration of analgesia in the sternal decubitus position without sedation was 30 ± 4 and 25 ± 7 min for the KS and KSMO treatments, respectively. All treatments provided sufficient cervical dilation for the passage of the insemination rod into the uterus. The ketamine sub-arachnoid treatment alone produced a complete cervical dilation, allowing easy passage of the rod. Further studies are needed to establish whether this anesthetic technique may interfere with fertility, pregnancy or lambing rate in ewes during AI or embryo transfer.

Investigation of the role of adrenergic and non‐nitrergic, non‐adrenergic neurotransmission in the sheep isolated internal anal sphincter

Nitric oxide is widely established as an important neurotransmitter in the control of anal sphincter tone; although, a number of other transmitters have also been tentatively implicated. Whilst alpha-adrenoceptor antagonists reduce anal sphincter pressure in man, the role of noradrenaline as a possible transmitter is poorly characterised. We have investigated the contribution of these transmitters to neurogenic relaxations, and evaluated the possible role of a non-nitrergic, non-adrenergic transmitter. The magnitude and duration of neurogenic responses were examined by measuring responses to electrical field stimulation (EFS) in segments of sheep internal anal sphincter following the development of spontaneous myogenic tone. Neurogenic relaxations induced by EFS were significantly reduced in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) suggesting major involvement of nitric oxide as a neurotransmitter. The duration of neurogenic relaxations was inversely related to the frequency of EFS, with contractile responses often manifest at higher frequencies. The duration of relaxations at high frequencies of EFS was increased by bretylium (adrenergic neurone blocker) and prazosin (alpha(1)-adrenoceptor antagonist). At higher frequencies of EFS, 60% of preparations also produced a residual non-nitrergic, non-adrenergic, apamin-sensitive relaxation which was unaffected by vasoactive intestinal polypeptide (VIP) and inhibitors of purinergic responses [suramin, pyridoxal-phosphate-6-azophenyl 2',4' disulfonic acid (PPADS) and alpha,beta-methylene adenosine triphosphate (ATP)]. However, MRS2179 (P2Y(1) receptor antagonist) showed a modest inhibitory effect. We conclude that endogenous noradrenaline acts via postjunctional alpha(1)-adrenoceptors to antagonize neurogenic relaxations that are largely mediated by nitric oxide. Our results indicate the involvement of a non-nitrergic, non-adrenergic, apamin-sensitive transmitter which is inhibited by MRS2179, suggesting a possible role for purines.

Two Novel Comments on the Treatment of Huntington's Disease

Back to table of contents Previous article Next article LETTERFull AccessTwo Novel Comments on the Treatment of Huntington’s DiseaseShahriar Gharibzadeh M.D., Ph.D.Yashar Sarbaz M.S.,Masood Banaie B.S.,Farzad Towhidkhah Ph.D.,Shahriar Gharibzadeh M.D., Ph.D.Search for more papers by this authorYashar Sarbaz M.S.Search for more papers by this author,Masood Banaie B.S.Search for more papers by this author,Farzad Towhidkhah Ph.D.Search for more papers by this author,Published Online:1 Jan 2009https://doi.org/10.1176/jnp.2009.21.1.98AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Huntington’s disease is a hereditary brain disorder that affects people of all races, all over the world. Until quite recently, little was known about Huntington’s disease. Yet in the last 20 years, much has been learned about the causes and effects of Huntington’s disease and about therapies and techniques for managing the symptoms. Huntington’s disease is a degenerative disease whose symptoms are caused by the loss of cells in the basal ganglia. This damage to cells affects cognitive ability (thinking, judgment, and memory), movement, and emotional control. Symptoms appear gradually, usually in midlife, between the ages of 30 and 50 years old. However, the disease can strike young children (juvenile form) and the elderly. 1 Despite the vast research on the anatomy and physiology of the basal ganglia, there is little agreement on the exact role the basal ganglia play in the behavior and motor control. While numerous models of basal ganglia have been proposed, few are computational in nature; thus, very few simulations of basal ganglia exist for testing the hypotheses and comparing the results to neurological and psychophysical data. The lack of computational models may, however, be partly due to the complexity of basal ganglia anatomy, multiplicity of physiological responses, and subtleties of behavioral responses. 2 We believe that the mathematical models of brain physiological performance have a great role in elucidating medical knowledge and have expanded our attitude about the illness states. The increase in effectiveness of mathematical models is manifested by two factors: the complexity of brain structure itself and greater complexity of pathological conditions. Certain neurological disorders such as Huntington’s disease have a particular importance and have gained the attention of many researchers. 3 We have implemented a computational model for gait disorder to show how GABA level variation and glutamate toxicity can cause the disease. 1 , 4 Then, in a new unpublished research, we tried to introduce a perfect model, based on recordings taken from Huntington’s disease patients. 5 This study shows the effect of changing neurotransmitters on movement symptoms of Huntington’s disease. We have considered most available physiological information about neuron basic features and basal ganglia. Basal ganglia are formed of some main parts, each of which is formed from many neurons that work together to do their job (i.e., control of movement). Similarly, our model has blocks that are formed in the same arrangement. In addition, the relation between blocks is modeled by proper gains, and inside each neuronal block we have put a related mathematical model. Each block has a threshold, firing rate, and a first order transfer function which simulates the neuron membrane.Our model was able to simulate the physiological behavior of basal ganglia in Huntington’s disease. In order to find out an effective new treatment, we ran our model with different amounts of gains (i.e., neurotransmitter amounts). Two important finding was obtained:1. Decreasing the level of glutamate to half its normal level reduces movement disorders. 2. Increasing GABA , together with increasing threshold, also decreases movement disorders. We propose that these two comments may be a good introduction to help ameliorate Huntington’s disease, though experimental research is needed to validate our hypotheses.Biomedical Engineering, Amirkabir University of TechnologyElectrical Engineering, Shahed UniversityBiomedical Engineering, Amirkabir University of TechnologyReferences1 . Sarbaz Y, Banaie M, Gharibzadeh S: A computational model for the Huntington disease. Med Hypotheses 2007; 68:1154–1158Google Scholar2 . Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science. McGraw-Hill Professional, 2000Google Scholar3 . Haeri M, Sarbaz Y, Gharibzadeh S: Modeling the Parkinson’s tremor and its treatments. J Theor Biol 2005; 236:311–322Google Scholar4 . Banaie M, Sarbaz Y: Modeling the Chorea on Huntington Disease. 12th Iranian Conference on Biomedical Engineering, Tabriz, Iran, Nov. 16–18, 2005Google Scholar5 . PhysioBank: Gait Dynamics in Neuro-Degenerative Disease Data Base. Available at http://www.physionet.org/physiobank/database/gaitndd/Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 21Issue 1 Winter, 2009Pages 98-99 Metrics PDF download History Published online 1 January 2009 Published in print 1 January 2009

Modulation of Noradrenergic Neurotransmission in Isolated Rat Radial Artery

The present study was designed to characterize the neurogenic contraction of rat radial artery. Electrical field stimulation (EFS) evoked frequency-dependent contraction that was abolished by tetrodotoxin (neuronal Na+ channel blocker), guanethidine (sympathetic neuron blocker), or phentolamine (α-adrenoceptor blocker). The α1-adrenoceptor antagonist prazosin inhibited endothelium-independent contractions to EFS, noradrenaline (NA), and the α1-adrenoceptor agonist phenylephrine. Rauwolscine, an α2-adrenoceptor antagonist, augmented nerve-mediated contractions and reduced sensitivity to NA and the α2-adrenoceptor agonist BHT-920. The β-adrenoceptor antagonist propranolol diminished EFS-elicited contractions, while sensitivity to NA was enhanced by propranolol. Relaxations evoked by isoproterenol, a β-adrenoceptor agonist, were abolished by propranolol. NG-Nitro-L-arginine (L-NOARG), a nitric oxide (NO) synthase inhibitor, increased both nerve-mediated and NA-induced responses in endothelium-intact, but not in endothelium-denuded arteries. Moreover, endothelium-dependent responses to BHT-920 and isoproterenol were modified by L-NOARG. Tetraethylammonium (TEA) or 4-amynopyridine, the Ca2+-activated (KCa) or voltage-dependent K+ (KV) channel blockers, respectively, enhanced the neurogenic contractions observed. TEA but not 4-amynopyridine increased NA-induced contractions. The ATP-sensitive K+ (KATP)–channel blocker glibenclamide failed to modify adrenergic contractions. Blockade of capsaicin-sensitive primary afferents increased EFS-induced contractions. In conclusion, adrenergic contractions are predominantly mediated by muscular α1-adrenoceptors, while endothelial α2- and β-adrenoceptors play a minor role. Presynaptic α2- and β-adrenoceptors cannot be precluded. Noradrenergic neurotransmission in rat radial artery seems to be modulated by both stimulation of endothelial NO, KCa, and KV channels and sensory C-fiber activation.