Autonomic and Autacoid Pharmacology最新文献

Preclinical and clinical studies show that gastrointestinal (GI) inflammation can evoke sensory changes occasionally far from the original inflammatory site. Animal models of colitis with either trinitrobenzenesulphonic acid (TNBS) or mustard oil (MO) produce distinct patterns of somatic and visceral sensory changes. We evaluated the effects of four doses of i.v. vincristine 150 μg kg⁻¹ (total of 600 μg kg⁻¹) treatment on the somatic (thermal nociceptive threshold) and colonic (morphological) changes induced by TNBS or MO in rats. TNBS and MO groups were further submitted to vincristine or saline pretreatments. TNBS induced somatic hypersensitivity, while MO induced somatic hyposensitivity (P < 0.05) when compared to the saline and ethanol control groups. Vincristine per se induced somatic hypersensitivity (P < 0.05). This effect was enhanced by TNBS and reversed by MO treatments. Although vincristine increased the colitis area (colonic weight length⁻¹ ratio) and the Morris' score in TNBS-treated rats, it did not alter the colitis area and even lowered the Morris' score in MO-treated rats. Compared to the saline (control) group, vincristine did not alter the colonic microscopic pattern. However, such lesions scores are higher (P < 0.05) in colitis groups induced by TNBS and MO, pretreated or not with vincristine. In conclusion, the somatic changes induced by different models of experimental colitis are diverse and modulated differently by vincristine.

1 A growing body of evidence suggests that the signalling molecule, noradrenaline (NA), plays a pathophysiological role in a broad range of psychiatric, neurological and peripheral disorders. Both preclinical and clinical data suggest that elevated NA signalling may be involved in the aetiology of major diseases such as depression, Alzheimer's disease and diabetes mellitus. 2 The molecular pathways by which NA may cause the manifestation of disease remain poorly understood, although they may include G protein-coupled receptor modulation of the Ras/MAP kinase, Stat3 and PI3K pathways, among others. In both individual animals and humans, NA tone may be elevated largely due to genetics, but also because of the exposure to marked psychological stress or trauma, or other environmental factors. 3 As NA is involved in the ‘fight or flight’ response by the sympathetic nervous system, this transmitter may be elevated in a large number of organisms due to evolutionary selection of enhancing responses to immediate environmental dangers. Likewise, acetylcholine signalling by the parasympathetic (‘rest and digest’) nervous system may be relatively diminished. This putative autonomic imbalance may result in diminished engagement in homeostatic processes, resulting in the emergence and progression of a number of diseases throughout the body. 4 In this scenario, a large number of individuals may benefit from chronic use of pharmacological agents – such as clonidine, guanfacine, propranolol or prazosin – that diminish NA signalling throughout the body. If so, NA transmission lowering drugs may protect against a wide range of diseases.

1. Considering the existence of cross-tolerance between clonidine and morphine besides the same interaction between morphine and WIN 55,212-2 persuaded us to verify this fact between WIN 55,212-2 and clonidine in guinea pig ileum, which is a well-known model to examine the mode of action of cannabinoids and α₂-adenoceptor agonists
2. The rectangular pulses were passed to the 0.5 g stretched ileum segments that were fixed in 20-ml organ bath. PowerLab system and Graphpad Prism were applied to record twitches and analyse the data. Electrically evoked contractions were dose-dependently inhibited by WIN 55,212-2 and clonidine (pD₂= 8.56 ± 0.41 and 7.65 ± 0.15, respectively).
3. Tolerance to this effect could be induced by 4-h incubation with WIN 55,212-2 (3 × IC₅₀) (pD₂ = 6.36 ± 0.26, degree of tolerance: 159.32) (P < 0.01) but not with clonidine (2 × IC₅₀ and 4 × IC₅₀) for different time courses. Dose–response curve for inhibitory action of WIN 55,212-2 was shifted to the right after 4-h incubation with clonidine (3 × 10⁻¹⁰m) comparing to the untreated tissues (pD₂ = 5.26 ± 0.69, degree of tolerance: 2000) (P < 0.001). This observation provides the evidence for the cannabinoid-noradrenergic systems interaction in the enteric nervous system as a simplified representative for central nervous system.

1. The three most common Cys-loop receptors expressed by myenteric neurons are nACh, 5-HT₃ and GABA_A. To investigate the function of these proteins researchers have used channel inhibitors such as hexamethonium (antagonist of nACh receptors), ondansetron (antagonist of 5-HT₃ receptors), picrotoxin and bicuculline (both antagonists of GABA_A receptors). The aim of this study was to investigate the specificity of these inhibitors on Cys-loop receptors of primary cultured neurons obtained from the guinea-pig small intestine. The whole-cell configuration of the patch clamp techniques was used to record membrane currents induced by ACh (I_ACh), 5-HT (I_5-HT) and GABA (I_GABA) in the absence and the presence of various concentrations of hexamethonium, ondansetron, picrotoxin or bicuculline.
2. The three Cys-loop receptors present in enteric neurons are expressed independently and they do not cross-desensitized. Hexamethonium inhibited I_ACh without affecting I_5-HT and I_GABA. Ondansetron inhibited I_5-HT and also I_ACh but did not affect I_GABA. Picrotoxin and bicuculline inhibited I_5-HT, I_ACh and I_GABA with different potency, being the lowest potency on 5-HT₃ receptors. All these inhibitory effects were concentration dependent and reversible.
3. Our observations showed that except for hexamethonium, all other inhibitors used here show different degrees of selectivity, which has to be considered when these antagonists are used in experimental studies aimed to investigate the functions of these receptors. In particular, in tissues expressing nACh receptors because these are the targets of all other inhibitors used here. The low potency of picrotoxin and bicuculline to inhibit 5-HT₃ receptors suggests that these receptors are heteromeric proteins.

1. We have investigated α₁-adrenoceptor subtypes mediating contractions to noradrenaline in epididymal portions of rat vas deferens.
2. Contractions to noradrenaline were investigated in the absence or presence of the noradrenaline transporter blocker cocaine.
3. In the absence of cocaine, contractions to noradrenaline were potently antagonized by RS100329, but not by BMY7378, and so are mediated mainly by α_1A-adrenoceptors.
4. In the presence of cocaine, noradrenaline potency was increased, particularly in terms of low concentrations and phasic contractions. Contractions to low concentrations of noradrenaline in the presence of cocaine were resistant to RS100329 but potently antagonized by BMY7378, demonstrating that α_1D-adrenoceptors are additionally involved in contractions amplified by cocaine.
5. In the absence of cocaine, prazosin exhibited relatively low potency as an antagonist against the α_1A-adrenoceptor-mediated component to the response. In the presence of cocaine, prazosin exhibited higher potency against the α_1D-adrenoceptor-mediated component.
6. In conclusion, prazosin has previously unreported selectivity for α_1D- over α_1A-adrenoceptors in functional studies of rat vas deferens. Contractions of rat vas deferens are mediated by α_1A- and α_1D-adrenoceptors. The range of prazosin potencies and of receptor subtypes previously reported in rat vas deferens may be explained by the presence of these two subtypes.

1. Fructose (F) overload produces elevated blood pressure (BP), hyperglycaemia, hypertriglyceridemia and insulin resistance, resembling human metabolic syndrome. Previously, we found altered vascular prostanoid (PR) production in this model.
2. Sodium molybdate (Mo), as well as sodium tungstate, causes insulin-like effects and normalizes plasma glucose levels in streptozotocin-treated diabetic rats. We studied the effects of Mo on BP, metabolic parameters and release of PR from the mesenteric vascular bed (MVB) in F-overloaded rats.
3. Four groups of male Sprague-Dawley rats were analysed: Control, tap water to drink; F, F solution 10% W/V to drink; CMo, Mo 100 mg kg day⁻¹ and FMo, both treatments. After 9 weeks, the animals were killed and MVBs removed and the released PRs measured.
4. F increased BP, glycemia, triglyceridemia and insulinemia. Mo treatment prevented the increases in BP and glycemia, but did not modify triglyceridemia or insulinemia. In addition, Mo decreased BP in controls.
5. Prostaglandins (PG) F₂alpha and E_2, PG 6-ketoF₁alpha and thromboxane (TX) B₂, as well as inactive metabolites of prostacyclin (PGI₂) and TXA₂ were detected. F decreased the production of vasodilator PRs PGI₂ and PGE₂ in MVB. Mo prevented these alterations and increased PGE₂ in controls. Vasoconstrict or PRs PGF₂alpha and TXA₂ release was not modified.
6. Mo treatment, beyond its known lowering effect on glycemia, prevents the reduction in the vascular release of vasodilator PR observed in this model. This could be one of the mechanisms by which Mo avoids the increase in BP caused by F overload in the rat.

1. We have investigated the ability of the 5HT₂-receptor antagonist ketanserin to affect the hyperthermia produced by methylenedioxymethamphetamine (MDMA) in conscious mice and examined whether α₁-adrenoceptor antagonist actions are involved.
2. Mice were implanted with intra-abdominal temperature probes under anaesthesia and allowed 2 weeks recovery. MDMA (20 mg kg⁻¹) was administered subcutaneously 30 min after vehicle or test antagonist and effects on body temperature monitored by telemetry.
3. Following vehicle, MDMA produced a slowly developing hyperthermia, reaching a maximum increase of 1.24 °C at 150 min postinjection. Ketanserin (0.5 mg kg⁻¹) revealed a significant and marked early hypothermia to MDMA, an effect that is mimicked by the α₁-adrenoceptor antagonist prazosin (0.1 mg kg⁻¹).
4. Functional studies revealed antagonist actions of ketanserin at α₁-adrenoceptors in rat aorta and rat vas deferens in vitro indicative of α₁-adrenoceptor antagonist actions at the concentration used in vivo.
5. In conclusion, ketanserin (0.5 mg kg⁻¹) modulates the hyperthermic actions of MDMA in mice. Although we cannot rule out additional actions at 5HT₂-receptors, the actions of ketanserin are consistent with α₁-adrenoceptor antagonism. There is no clear evidence from this study that 5HT₂-receptors mediate the hyperthermic response to MDMA.

1. The effects of local sensory blockade (topical anaesthesia) on eccrine sweat glands and cutaneous circulation are not well understood. This study aimed to determine whether topical lidocaine/prilocaine alters eccrine sweat gland and cutaneous blood vessel responses.
2. Sweating (capacitance hygrometry) was induced via forearm intradermal microdialysis of five acetylcholine (ACh) doses (1 × 10⁻⁴ to 1 × 10⁰ m, 10-fold increments) in control and treated forearm sites in six healthy subjects. Nitric oxide-mediated vasodilatory (sodium nitroprusside) and adrenergic vasoconstrictor (noradrenaline) agonists were iontophoresed in lidocaine/prilocaine-treated and control forearm skin in nine healthy subjects during blood flow assessment (laser Doppler flowmetry, expressed as% from baseline cutaneous vascular conductance; CVC; flux/mean arterial pressure).
3. Non-linear regression curve fitting identified no change in the ED₅₀ of ACh-induced sweating after sensory blockade (−1.42 ± 0.23 logM) compared to control (−1.27 ± 0.23 logM; P > .05) or in E_max (0.43 ± 0.08 with, 0.53 ± 0.16 mg cm⁻² min⁻¹ without lidocaine/prilocaine; P > .05). Sensory blockade did not alter the vasodilator response to sodium nitroprusside (1280 ± 548% change from baseline CVC with, 1204 ± 247% without lidocaine/prilocaine) or vasoconstrictor response to noradrenaline (−14 ± 4% change from baseline CVC with, −22 ± 14% without lidocaine/prilocaine; P > 0.05).
4. Cutaneous sensory blockade does not appear to alter nitric oxide-mediated vasodilation, adrenergic vasoconstriction, or cholinergic eccrine sweating dose-response sensitivity or responsiveness to maximal dose. Thus, lidocaine/prilocaine treatment should not affect sweat gland function or have blood flow implications for subsequent research protocols or clinical procedures.

1. As selective serotonin reuptake inhibitors have an inhibitory effect on nicotinic acetylcholine receptors, they may affect the neuromuscular transmission and interact with neuromuscular blockers. This study was designed to observe the effect of fluoxetine on neuromuscular transmission and its interaction with rocuronium using the rat phrenic nerve hemidiaphragm and rabbit head drop methods.
2. Rat phrenic nerve hemidiaphragms were mounted and stimulated using a train of four pulses (TOF). The effect of fluoxetine was studied on both indirectly and directly stimulated basal twitch responses by plotting cumulative dose response curves (DRCs). DRCs of rocuronium were obtained in the absence, and presence of 5 μm and 20 μm fluoxetine to study its interaction. ED₅, ED₅₀ and ED₉₅ values of rocuronium DRCs in absence and presence of fluoxetine were calculated.
3. Fluoxetine significantly inhibited twitch responses in both indirect and directly stimulated preparations. Fluoxetine (20 μm) caused an increase in the potency of rocuronium such that the ED₅₀ and ED₉₅ values of rocuronium DRCs were significantly decreased. Partially inhibited twitch responses by fluoxetine (100 μm) were not reversed by neostigmine (3.3 μm) or 3,4 diaminopyridine (0.25 μm).
4. Rabbits were given fluoxetine 0.25 mg kg⁻¹ and 1 mg kg⁻¹ orally for 15 days, and on 15th day, rocuronium infusion was given, and time for head drop was recorded. The time of head drop was significantly reduced in fluoxetine pretreated as compared to control group.
5. Fluoxetine blocks the neuromuscular transmission and increases the potency of rocuronium-induced neuromuscular block.

1. The nitrergic system modulates cardiovascular functions of the central nucleus of amygdala (CeA) and the posterior hypothalamus (PH) which are involved in the central regulation of the cardiovascular system. The aim of this study was to investigate the contribution of nitric oxide (NO) in the PH in eliciting cardiovascular responses produced through electrical stimulation (ES) of the CeA. Rats were implanted with a stimulation electrode and a parenchymal cannula system into the CeA and a parenchymal cannula or a microdialysis probe into the PH. The next day, the femoral artery was cannulated for haemodynamic measurement. The CeA was electrically stimulated to produce cardiovascular response. The nitric oxide synthetase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 400 nmol/100 nl) or artificial cerebrospinal fluid were injected into the PH or the CeA before the ES of the CeA. The dialysates were collected from the PH to determine the L-citrulline and the L-glutamic acid levels.
2. L-NAME injection into the CeA but not to the PH suppressed the increases in the mean arterial pressure produced by the ES of the CeA significantly; however, heart rate was not affected by L-NAME injection into either the PH or the CeA. L-citrulline and L-glutamic acid levels in the PH were shown to be increased by the ES of the CeA.
3. NO is involved between the PH and the CeA which has a considerable role in the central regulation of the cardiovascular system.