Pharmacological stimulation of the cholinergic antiinflammatory pathway.
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Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the "cholinergic antiinflammatory pathway," inhibition of TNF synthesis is dependent on nicotinic alpha-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock. (+info)
Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quino linone monomethanesulfonate).
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Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quino linone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits. (+info)
Effects of (+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a selective ligand for nicotinic acetylcholine receptors, in tests of visual attention and distractibility in rats and monkeys.
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Nicotine, a nonselective ligand for nicotinic acetylcholine receptors (nAChRs), has been shown to improve attention and reduce distractibility in humans. Although the numerous side effects induced by nicotine prevent its use as a therapeutic agent, it is hypothesized that subtype-selective nAChR ligands may offer a potential therapeutic benefit to humans with attention deficits. In this study, we evaluated the attention-enhancing properties of (+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a ligand selective for neuronal nAChRs with predominant activity at the human beta 4 subtype. SIB-1553A was evaluated in a test of attention (i.e., five-choice serial reaction time task or SRTT) and distractibility (i.e., delayed matching to sample task with distractor or DMTS-D) in adult rats and monkeys, respectively. SIB-1553A did not improve SRTT performance in normal rats, but reversed deficits induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine. In the DMTS-D, SIB-1553A improved accuracy across several doses at the short delay intervals, which were affected most by distracting stimuli in adult monkeys. Subsequent testing with optimal doses for each monkey was also associated with significant improvements in DMTS-D accuracy at short delays, indicating the reproducibility of the drug effect. In both species, SIB-1553A had no significant effects on latencies for sample or choice selection and was not associated with adverse effects at efficacious doses. Although it remains to be further demonstrated, SIB-1553A may act through combined nicotinic and non-nicotinic mechanisms. Collectively, the present data suggest that in specific conditions SIB-1553A may improve certain aspects of attentional function in young adult rats and nonhuman primates without adverse side effects. (+info)
Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury: studies on transgenic/knockout mice of adrenomedullin gene.
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Adrenomedullin (AM) is a potent depressor peptide whose vascular action is suggested to involve nitric oxide (NO) release. To explore the role of endogenous AM in vascular and renal function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists AM(22-52) and CGRP(8-37) on the renal perfusion pressure (RPP) of kidneys isolated from AM transgenic (TG)/heterozygote knockout (KO) mice and wild-type littermates (WT). Furthermore, we evaluated the renal function and histology 24 hours after bilateral renal artery clamp for 45 minutes in TG, KO, and WT mice. Baseline RPP was significantly lower in TG than in KO and WT mice (KO 93.4+/-4.6, WT 85.8+/-4.2, TG 72.4+/-2.4 mm Hg [mean+/-SE], P<0.01). ACh and AM caused a dose-related reduction in RPP, but the degree of vasodilatation was smaller in TG than that in KO and WT (%DeltaRPP 10(-7) mol/L ACh: KO -48.1+/-3.9%, WT -57.5+/-5.6%, TG -22.8+/-4.8%, P<0.01), whereas N(G)-nitro-L-arginine methyl ester (L-NAME) caused greater vasoconstriction in TG (%DeltaRPP 10(-4) mol/L: KO 33.1+/-3.3%, WT 55.5+/-7.2%, TG 152.6+/-21.2%, P<0.01). Both AM antagonists increased RPP in TG to a greater extent compared with KO and WT mice (%DeltaRPP 10(-6) mol/L CGRP(8-37): KO 12.8+/-2.6%, WT 19.4+/-3.6%, TG 41.8+/-8.7%, P<0.01). In mice with ischemic kidneys, serum levels of urea nitrogen and renal damage scores showed smaller values in TG and greater values in KO mice (urea nitrogen: KO 104+/-5>WT 98+/-15>TG 38+/-7 mg/dL, P<0.05 each). Renal NO synthase activity was also greater in TG mice. However, the differences in serum urea nitrogen and renal damage scores among the 3 groups of mice were not observed in mice pretreated with L-NAME. In conclusion, AM antagonists increased renal vascular tone in WT as well as in TG, suggesting that endogenous AM plays a role in the physiological regulation of the vascular tone. AM is likely to protect renal tissues from ischemia/reperfusion injury through its NO releasing activity. (+info)
Evaluation of the cholinomimetic actions of trimethylsulfonium, a compound present in the midgut gland of the sea hare Aplysia brasiliana (Gastropoda, Opisthobranchia).
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Trimethylsulfonium, a compound present in the midgut gland of the sea hare Aplysia brasiliana, negatively modulates vagal response, indicating a probable ability to inhibit cholinergic responses. In the present study, the pharmacological profile of trimethylsulfonium was characterized on muscarinic and nicotinic acetylcholine receptors. In rat jejunum the contractile response induced by trimethylsulfonium (pD2 = 2.46 +/- 0.12 and maximal response = 2.14 +/- 0.32 g) was not antagonized competitively by atropine. The maximal response (Emax) to trimethylsulfonium was diminished in the presence of increasing doses of atropine (P<0.05), suggesting that trimethylsulfonium-induced contraction was not related to muscarinic stimulation, but might be caused by acetylcholine release due to presynaptic stimulation. Trimethylsulfonium displaced [3H]-quinuclidinyl benzilate from rat cortex membranes with a low affinity (Ki = 0.5 mM). Furthermore, it caused contraction of frog rectus abdominis muscles (pD2 = 2.70 +/- 0.06 and Emax = 4.16 +/- 0.9 g), which was competitively antagonized by d-tubocurarine (1, 3 or 10 microM) with a pA2 of 5.79, suggesting a positive interaction with nicotinic receptors. In fact, trimethylsulfonium displaced [3H]-nicotine from rat diaphragm muscle membranes with a Ki of 27.1 microM. These results suggest that trimethylsulfonium acts as an agonist on nicotinic receptors, and thus contracts frog skeletal rectus abdominis muscle and rat jejunum smooth muscle via stimulation of postjunctional and neuronal prejunctional nicotinic cholinoreceptors, respectively. (+info)
Effects of scopolamine and physostigmine on acquisition of morphine-treated rats in Morris water maze performance.
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AIM: To investigate effects of morphine on acquisition process of rats a nd interactions of opioid and cholinergic systems by Morris water maze performance. METHODS: Morris water maze was used to measure the latency of rats with drug s treatment to find the covert platform. RESULTS: Chronic morphine administration (10 mg/kg) impaired the acquisition process of rats in Morris water maze task. Appreciable difference was identified with morphine 10 mg/k g group compared with morphine 3 mg/kg group. Co-administration of morphine (10 mg/kg) and scopolamine (3 mg/kg) aggravated acquisition impairment induced by morphine 1 0 mg/kg or scopolamine alone, though scopolamine itself induced no salient changes in acquisition capabilities of rats. In addition, physostigmine (0.1 mg/kg) could appreciably attenuate morphine-induced acquisition impairment. CONCLUSION: Morphine 10 mg/kg evidently impaired acquisition process of rats. There was a close relationship between the acquisition capabilities of morphine-treated rats and the functions of cholinergic system. (+info)
Usefulness of basal and pilocarpine-stimulated salivary flow in primary Sjogren's syndrome. Correlation with clinical, immunological and histological features.
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OBJECTIVES: To examine salivary function in patients with primary Sjogren's syndrome (SS) by assessing unstimulated and stimulated flows using 5 mg of pilocarpine in a 5% solution, in order to define their clinical usefulness in the evaluation of xerostomia in patients with primary SS as well as to identify those factors related to the increase in salivary flow after pilocarpine stimulation. METHODS: We investigated the clinical and immunological characteristics of 60 consecutive patients with primary SS. All patients fulfilled four or more of the preliminary diagnostic European criteria for SS. We measured unstimulated (basal) salivary flow (BSF) in all patients. In patients with BSF +info)
Presynaptic muscarinic M(2)-receptor-mediated inhibition of N-type Ca(2+) channels in cultured sphenopalatine ganglion: direct evidence for acetylcholine inhibition of cerebral nitrergic neurogenic vasodilation.
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Results of previous pharmacological studies suggested that presynaptic muscarinic M(2) receptors on cerebral perivascular nitric oxidergic (nitrergic) nerves mediated inhibition of nitric oxide release from these nerves. The inhibition was thought to be primarily attributable to a decreased Ca(2+) influx through N-type Ca(2+) channels on nitrergic nerves, but direct evidence supporting this hypothesis was not presented. In the present study, we used cultured rat sphenopalatine ganglion (SPG), a major source of nitrergic nerves to cerebral blood vessels, to investigate the role of muscarinic M(2) receptors in modulating voltage-dependent Ca(2+) channels. SPG neuronal soma and dendrites were immunoreactive for both N-type Ca(2+) channels and muscarinic M(2) receptors, indicating that muscarinic M(2) receptors were colocalized with N-type Ca(2+) channels. Using the whole-cell voltage-clamp technique, we found that voltage-dependent Ca(2+) currents in cultured SPG were largely blocked by omega-conotoxin, an N-type calcium channel antagonist, but were not affected by nifedipine, an L-type calcium antagonist. The Ca(2+) current was inhibited by acetylcholine (ACh) and arecaidine but-2-ynyl ester tosylate (ABET), a preferential muscarinic M(2)-receptor agonist, in a concentration-dependent manner. The inhibition was reversed by atropine and methoctramine (a muscarinic M(2)-receptor antagonist), but was not affected by muscarinic M(1)-, M(3)-, or M(4)-receptor antagonists. Consistent with this, preferential muscarinic M(1)-receptor agonists McN-A-343 and oxotremorine did not affect the Ca(2+) current. Furthermore, pretreatment with pertussis toxin and guanosine 5'-O-(3-thio)triphosphate prevented ACh and ABET inhibition of Ca(2+) currents. These results are consistent with pharmacological findings in the pig basilar arteries and provide direct evidence supporting our hypothesis that M(2)-receptor-mediated inhibition of cerebral nitrergic neurogenic vasodilation is due to a G(i)-protein-mediated suppression of Ca(2+) influx via voltage-dependent N-type Ca(2+) channels on perivascular nerves. (+info)