共查询到20条相似文献,搜索用时 125 毫秒
1.
The endothelium plays a fundamental role in the blood coagulation cascade and at the site of injury is important in the development, and sequela, of atheroma. It is also now firmly established that endothelial cells can produce both vasorelaxant and vasoconstrictor factors and thus directly influence vascular tone and blood flow. Prostacyelin and NO are both potent vasodilators, and endothelin is a highly potent 21 amino acid peptide vasoconstrictor, which have all been shown to be syn 相似文献
2.
《Acta pharmacologica Sinica》1999,(5)
Calcitonin gene-related peptide (CGRP), a 37-amino acid neuropeptide, is produced in dorsal root ganglia (DRG) neurons, which extend nerves peripherally to different organs and centrally to the spinal cord.We have previously reported that plasma levels of CGRP are significantly elevated in rats after injection of lipopolysaccharide (LPS) in vivo.LPS triggers CGRP release from capsaicin-sensitive sensory nerves in the isolated mesenteric arteial bed of the rats.In this work, we used the cultured DRG neurons of neonatal mrs to detemine whether or not LPS could trigger CGRP release and if it did so, what cellular signaling pathway was involved in the CGRP release.Neurons were disassociated from the DRG of 5- 7-d neonatal rat using 相似文献
3.
The vanilloid receptor and hypertension 总被引:4,自引:1,他引:3
Wang DH 《Acta pharmacologica Sinica》2005,26(3):286-294
Mammalian transient receptor potential (TRP) channels consist of six related protein sub-families that are involved in a variety of pathophysiological function, and disease development. The TRPV1 channel, a member of the TRPV sub-family, is identified by expression cloning using the “hot” pepper-derived vanilloid compound capsaicin as a ligand. Therefore, TRPV1 is also referred as the vanilloid receptor (VR1) or the capsaicin receptor. VR1 is mainly expressed in a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin-sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a “sensory-effector” function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to VR1. The most studied sensory neuropeptides are calcitonin gene-related peptide (CGRP) and substance P (SP), which are potent vasodilators and natriuretic/diuretic factors. Recent evidence using the model of neonatal degeneration of capsaicin-sensitive sensory nerves revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neurohormonal systems to maintain normal blood pressure when challenged with salt loading. The therapeutic utilities of vanilloid compounds, endogenous agonists, and sensory neuropeptides are also discussed. 相似文献
4.
Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the hippocampus, and nicotinic signaling plays an important role in neuronal function. In the context of learning and memory related behaviors associated with hippocampal function, a potentially significant feature of nAChR activity is the impact it has on synaptic plasticity. Synaptic plasticity in hippocampal neurons has long been considered a contributing cellular mechanism of learning and memory. These same kinds ofcellular mechanisms are a factor in the development of nicotine addiction. Nicotinic signaling has been demonstrated by in vitro studies to affect synaptic plasticity in hippocampal neurons via multiple steps, and the signaling has also been shown to evoke synaptic plasticity in vivo. This review focuses on the nAChRs subtypes that contribute to hippocampal synaptic plasticity at the cellular and circuit level. It also considers nicotinic influences over long-term changes in the hippocampus that may contribute to addiction. 相似文献
5.
D REMICK 《Acta pharmacologica Sinica》1999,(5)
A lot of data have been published to prove that neuro-endocrine polypeptide hormones and neuropeptides can regulate theimmune response in which all the major immune cell types appear to be influenced.The present review focuses on the immunomodulatory properties of calcitonin gene-related peptide (CGRP) and substance P (SP) which co-exist in primary afferent neurons.The sensory nerve endings are in close contact with 相似文献
6.
α-Synuclein (α-Syn) is a brain-enriched small protein that has been strongly implicated in the pathogenesis of Parkinson's disease (PD). However, the physiological function α-Syn remains poorly understood. It is recently reported that α-Syn is detectable in human cerebrospinal fluid, blood plasma and culture medium of neuroblastoma cells, indicating that this protein can be secreted into extracellular biological fluids. Whether or not the extracellular α-Syn will influence the function of neurons is an interesting issue that deserves extensive investigation. In order to explore the possible role of extracellular α-Syn in neuronal functions, 相似文献
7.
《Acta pharmacologica Sinica》1999,(5)
It has been reported that centrally or peripherally administered pro-inflammatory cytokines induce the expression of Fos in the central nervous system.However, little is known about the effects of antigen-induced immune response on the expression of immediate early gene in the brain. In the present study, using Fos protein as a marker of activated neurons, we first investigated the functional circuitry in the brain of xeogenitic antigen-challenged rats. Four days following ip immunization with 5× 10~9 sheep red blood cells (SRBC), a specific antibody to SRBC in blood was detected with plaque-forming cell assay (PFC), and a robust and widespread induction of Fos in the brain was 相似文献
8.
Shen Ying - Hua Wang Ze - Jian Yin Ming 《中国药理通讯》2006,23(4):24-25
The senile plaques in the brain are thought to contribute to the pathogenesis of Alzheimer's disease (AD) and are mainly consisted of β - amyloid peptide, which is the proteolytic product of amyloid precursor protein (APP). Previous work suggested that nicotine could effectively reduce β - amyloid peptide aggregation in the brain of animal models and improve the cognition impairment, indicating that the nicotinic acetylcholine receptors (nAChR) might play an important part in the function of memory and cognition and might be a target in the therapy of Alzheimer's disease. The α7 nicotinic acetylcholine receptors are highly expressed in hippocampus and in cholinergic neurons from the basal forebrain, structures that are particularly vulnerable to the ravages of Alzheimer's disease. To test whether the α7 nicotinic acetylcholine receptors can block the processing of amyloid precursor protein into β - amyloid peptide, we transfected human APP695 into the native nAChR - null SH - EP1 human epithelial cells which had been transfected with the gene of α7nAChR and confirmed their expression by RT - PCR and Western Blot. 相似文献
9.
《Acta pharmacologica Sinica》1999,(5)
Calcitonin gene-related peptide (CGRP), a neuropeptide contained in sensory neuron, has been demonstrated to be synthesized and released by rat lyrnphocytes in our previous studies.In this study, some release property and molecular 相似文献
10.
YoshT 《中国药理学与毒理学杂志》2002,16(6):407-408
It has been well known that inflammation leads to the decreased ability of drug metabolism in human and animals.Since many inflammatory and anti-inflammatory cytokines produced under the inflammatory conditions,their possible roles in the regulation of drug metabolizing enzymes,specifically cytochrome P450s(CYPs),have been examined to date.Lipopolysaccharide (LPS) produces many cryokines and decreases drug medabolism.LPS is also a potent inducer of heme oxygenase(HO-1).We found that LPS produced the induction of HO-1 via TNFα rather than IL-1,be employing each cytokine knockout mice.Additionally,arthritis model mice exhibited the increase in HO-1 without any changes in total CYP content.Effects of chemicals on HO-1 and CYPs in cytokine knockout mice will also be discussed. 相似文献
11.
The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts 总被引:8,自引:0,他引:8
Chai W Mehrotra S Jan Danser AH Schoemaker RG 《European journal of pharmacology》2006,531(1-3):246-253
Brief coronary artery occlusion can protect the heart against damage during subsequent prolonged coronary artery occlusion; ischemic preconditioning. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning is investigated in isolated perfused rat hearts, by measuring CGRP release during ischemic preconditioning and mimicking this by exogenous CGRP infusion, either in the absence or presence of the CGRP antagonist BIBN4096BS. CGRP increased left ventricular pressure and coronary flow in a concentration dependent manner, which was effectively antagonized by BIBN4096BS. Rat hearts (n=36) were subjected to 45 min coronary artery occlusion and 180 min reperfusion, which was preceded by: (1) sham pretreatment, (2) BIBN4096BS infusion (1 microM), (3) preconditioning by 15 min coronary artery occlusion and10 min reperfusion, (4) as 3, but with BIBN4096BS, (5) 15 min CGRP infusion (5 nM) and 10 min washout, (6) as 5, but with BIBN4096BS. Cardiac protection was assessed by reactive hyperaemia, creatine kinase release, infarct size related to the area at risk (%), and left ventricular pressure recovery. Preconditioning increased CGRP release into the coronary effluent from 88+/-13 to 154+/-32 pg/min/g, and significantly protected the hearts by decreasing reactive hyperaemia (35%), reducing creatine kinase release (53%), limiting infarct size (48%), and improving left ventricular pressure recovery (36%). Exogenous CGRP induced preconditioning-like cardioprotection. BIBN completely abolished the cardioprotection induced by preconditioning as well as by exogenous CGRP. In conclusion, since cardioprotection of preconditioning-induced CGRP release can be mimicked by exogenous CGRP, and both can be blocked by a CGRP antagonist, results indicate an important role for CGRP in ischemic preconditioning. 相似文献
12.
Kapoor K Arulmani U Heiligers JP Garrelds IM Willems EW Doods H Villalón CM Saxena PR 《British journal of pharmacology》2003,140(2):329-338
1. Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 microg kg-1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2. Infusions of capsaicin (0.3, 1, 3 and 10 microg kg-1 min-1, i.c.) did not alter the heart rate, but dose-dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3. Capsaicin infusion (10 microg kg-1 min-1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently blocked by BIBN4096BS. 4. Capsaicin infusion (10 microg kg-1 min-1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5. The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine. 相似文献
13.
Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist 总被引:19,自引:0,他引:19
Doods H Hallermayer G Wu D Entzeroth M Rudolf K Engel W Eberlein W 《British journal of pharmacology》2000,129(3):420-423
Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators known. This peptide is increased during migraine attacks and has been implicated in the pathogenesis of migraine headache. Here we report on the first small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an affinity (Ki) for human CGRP receptors of 14.4 +/- 6.3 (n = 4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 micrograms kg-1 (i.v.) inhibited the effects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood flow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist. 相似文献
14.
BIBN4096BS [[R-(R,(R*,S*)]-N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl] pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-,1-Piperidinecarboxamide] is a selective calcitonin gene-related peptide (CGRP) receptor antagonist with a picomolar affinity to the CGRP receptor in human neuroblastoma SK-N-MC cells. Here, we describe the characterisation of the binding properties of the tritiated radioanalogue of BIBN4096BS in SK-N-MC cells as well as in marmoset tissue. [(3)H]BIBN4096BS showed reversible and saturable binding to SK-N-MC cells with a K(D) of 0.045 nM. In competition experiments, [3(H)]BIBN4096BS is concentration-dependently displaced from SK-N-MC cell membranes by BIBN4096BS as well as by the endogenous ligand CGRP and its analogues with the rank order of affinity BIBN4096BS>human alpha-CGRP=human beta-CGRP>[Cys(Et)(2,7)]human alpha-CGRP>adrenomedullin (high affinity site)=human alpha-CGRP-(8-37)=human beta-CGRP-(8-37)>calcitonin=amylin. In the marmoset cortex, saturable [(3)H]BIBN4096BS binding was observed with a K(D) of 0.077 nM. CGRP showed biphasic competition of [(3)H]BIBN4096BS binding, whilst BIBN4096BS monophasically displaced its radioanalogue with a K(i) of 0.099 nM. These data, using [(3)H]BIBN4096BS, confirm the high affinity of this novel antagonist for the primate CGRP receptor and demonstrate furthermore that this radioligand is a useful tool to study CGRP receptor pharmacology. 相似文献
15.
Kapoor K Arulmani U Heiligers JP Willems EW Doods H Villalón CM Saxena PR 《European journal of pharmacology》2003,475(1-3):69-77
Calcitonin gene related peptide (CGRP) seems to be involved in the pathogenesis of migraine, since plasma CGRP levels increase during the headache phase. In the present study, we investigated the effects of a novel CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl] pentyl] amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [R-(R*,S*)]-), on the regional cardiac output distribution and on the carotid haemodynamic changes induced by alpha-CGRP in anaesthetised pigs. Treatment with BIBN4096BS (100, 300 and 1000 microg kg(-1), i.v.) did not affect the heart rate, mean arterial blood pressure or systemic vascular conductance, but a small decrease in cardiac output was noticed; the latter was, however, not significantly different from that in vehicle-treated animals. The highest dose of BIBN4096BS moderately decreased vascular conductance in the lungs, kidneys, spleen and adrenals. Vascular conductance in other tissues including the brain, heart, gastrointestinal system, skin and skeletal muscles remained unchanged. Intracarotid artery infusions of alpha-CGRP (10, 30 and 100 pmol kg(-1) min(-1) during 3 min) increased the total carotid blood flow and conductance, but decreased the arterial blood pressure. These responses were dose-dependently blocked by BIBN4096BS. The above results show that BIBN4096BS is a CGRP receptor antagonist in the porcine carotid and systemic circulations, but the endogenous CGRP does not seem to play an important physiological role in regulating basal vascular tone. These findings suggest that BIBN4096BS may have therapeutic usefulness in migraine. 相似文献
16.
Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat
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Petersen KA Birk S Doods H Edvinsson L Olesen J 《British journal of pharmacology》2004,143(6):697-704
Calcitonin gene-related peptide (CGRP) is believed to play a pivotal role in the pathogenesis of migraine via activation of CGRP receptors in the trigeminovascular system. The CGRP receptor antagonist, BIBN4096BS, has proven efficacy in the acute treatment of migraine attacks and represents a new therapeutic principle. We used an improved closed cranial window model to measure changes of the middle meningeal artery (MMA) and cortical pial artery/arteriole diameter (PA) and changes in local cortical cerebral blood flow (LCBF(Flux)) in anaesthetised artificially ventilated rats. The ability of BIBN4096BS (i.v.) to prevent the vasodilatatory actions of rat-alphaCGRP, betaCGRP and endogenously released CGRP following transcranial electrical stimulation (TES) was investigated. BIBN4096BS was per se without vasoactive effect on any of the measured variables and significantly inhibited the hypotension induced by both types of CGRP (P < 0.001). The alphaCGRP induced MMA dilatation was reduced from 97.4 +/- 14 to 2.1 +/- 1.3% (P < 0.001) and the betaCGRP induced dilatation was fully blocked by BIBN4096BS. ID(50) was 5.4 +/- 1.6 microg kg(-1) for alphaCGRP and 16.3 +/- 1.6 microg kg(-1) for betaCGRP. Transcranial electrical stimulation induced a 119.1 +/- 6.9% increase in MMA diameter. BIBN4096BS (333 microg kg(-1)) attenuated this increase (19.8 +/- 2.1%) (P < 0.001). Systemic CGRP and TES induced an increase in PA diameter that was not significantly inhibited by BIBN4096BS. The CGRP induced increase in LCBF(Flux) was similar not prevented by the antagonist. We suggest that systemic BIBN4096BS exerts its inhibitory action mainly on large dural blood vessels (MMA). 相似文献
17.
Endothelin-1-induced reduction of myocardial infarct size by activation of ATP-sensitive potassium channels in a rabbit model of myocardial ischaemia and reperfusion. 总被引:2,自引:1,他引:1
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1. This study examined whether endothelin-1 (ET-1) reduces infarct size in a rabbit model of acute coronary artery occlusion (60 min) and reperfusion (120 min). In addition, we investigated whether the observed cardioprotective effect of ET-1 was due to the activation of ATP-sensitive potassium (KATP) channels by using two selective antagonists, glibenclamide and sodium 5-hydroxydecanoate (5-HD). 2. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 2 h of reperfusion was 55 +/- 4% (n = 11). ET-1 (0.3 nmol kg-1), administered as a bolus injection into the left ventricle, had no effect on infarct size (62 +/- 2%, n = 4). A lower dose of ET-1 (0.03 nmol kg-1) resulted in a significant reduction in infarct size (infarct size 43 +/- 3%; P < 0.05, n = 16). The higher dose (0.3 nmol kg-1), but not the lower dose of ET-1 caused a significant rise in blood pressure, pressure rate index and hence, myocardial oxygen consumption. 3. The reduction in infarct size afforded by ET-1 (0.03 nmol kg-1) was abolished by pretreatment of rabbits with the KATP channel inhibitors, glibenclamide (0.3 mg kg-1) and 5-HD (5 mg kg-1), (infarct size 59 +/- 3 and 63 +/- 4% respectively; n = 4-9). 4. We propose that ET-1 reduces infarct size by opening KATP channels. 相似文献
18.
Free radicals may cause some of the irreversible injury which occurs during myocardial ischaemia and reperfusion. In the present study the effects of a cardioselective, free radical scavenger, MDL 74270, which is an analogue of alpha-tocopherol, on myocardial infarct size in an anaesthetised rat model of coronary artery ligation (60 min) and reperfusion (30 min) has been evaluated. Infusion of MDL 74270 (0.3-3.0 mg/kg per h) commencing 10 min before occlusion until the end of reperfusion significantly reduced infarct size. The highest dose also caused a significant reduction in serum creatine phosphokinase levels. Similar findings have been obtained with the bromide salt of MDL 74270. Tissue distribution studies with 14C-labelled MDL 74270 and its tertiary amine analogue (MDL 74366) showed heart/blood ratios of total radioactivity, 1-6 h after i.v. administration, greater than 20 after MDL 74270 and around 1 after MDL 74366. The importance of accumulation of total radioactivity in the heart after MDL 74270 is supported by the fact that MDL 74366 was 30 times less potent as a myocardial protector in the ligation/reperfusion studies. It is concluded that MDL 74270 has potential for cardioprotective use in conditions of acute reperfusion. 相似文献
19.
Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells. 总被引:4,自引:0,他引:4
Lars Edvinsson Rikard Alm Duncan Shaw Ruth Z Rutledge Kenneth S Koblan Jenny Longmore Stefanie A Kane 《European journal of pharmacology》2002,434(1-2):49-53
Several lines of evidence suggest that a calcitonin-gene related peptide (CGRP) receptor antagonist may serve as a novel abortive migraine treatment. Here we present data on a human cell line and isolated human vessels for such an antagonist, BIBN4096BS. On SK-N-MC membranes, radiolabelled CGRP was displaced by both CGRP-(8-37) and BIBN4096BS, yielding pK(i) values of 8.5 and 11.4, respectively. Functional studies with SK-N-MC cells demonstrated that CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and BIBN4096BS with pA(2) values of 7.8 and 11.2, respectively. Isolated human cerebral, coronary, and omental arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation that was antagonized by both CGRP-(8-37) and BIBN4096BS in a competitive manner. CGRP was a weaker agonist on coronary arteries as compared to intracranial arteries; however, BIBN4096BS was an equally effective antagonist. In human omental arteries, CGRP did not induce relaxation. BIBN4096 had a pA(2) value of 10.1 in cerebral and 10.4 in coronary arteries. The results of clinical trials with BIBN4096BS for acute migraine attacks are awaited with great interest. 相似文献
20.
1-Piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS), a calcitonin gene-related peptide (CGRP) receptor antagonist, can alleviate the symptoms of migraine and is highly selective for CGRP over adrenomedullin (AM) receptors. These receptors are heterodimers of the calcitonin receptor-like receptor (CL) and receptor activity modifying proteins (RAMPs), with the pharmacological properties determined by the RAMP subunit. BIBN4096BS-sensitive CGRP(1) receptors are CL/RAMP1, whereas BIBN4096BS-insensitive AM receptors are CL/RAMP2 or CL/RAMP3 (AM(1) and AM(2), respectively), implicating RAMP1 in conferring BIB-N4096BS sensitivity. Because calcitonin receptors [CT((a))] also interact with RAMP1 [AMY(1(a)) receptors], BIBN4096BS could also have affinity for these receptors. To test this, receptors were transfected into COS-7 cells and agonist-stimulated cAMP levels measured in the presence and absence of antagonists. We found that AMY(1(a)) receptors were approximately 150-fold less sensitive to BIBN4096BS antagonism than CGRP(1) receptors. In contrast, AMY(3(a)) [CT((a))/RAMP3] or AM(2) receptors were not sensitive to BIBN4096BS antagonism. We investigated Trp74 in RAMP1, a residue implicated in the species selectivity of BIBN4096BS. BIBN4096BS affinity was reduced at AMY(1(a)) and CGRP(1) receptors when this residue was mutated to lysine or alanine. The equivalent residue in RAMP3, Glu74, when mutated to tryptophan (E74W), induced BIBN4096BS sensitivity at AM(2) and AMY(3(a)) receptors. It is interesting that a selective reduction in AM potency was observed at E74W AM(2) receptors, implicating this residue in AM interactions with this receptor. These data support the importance of Trp74 in RAMP1 in the interaction of BIBN4096BS with CGRP(1) and AMY(1(a)) receptors and identified Glu74 in RAMP3 as the first amino acid in RAMP important for agonist interactions with calcitonin-family receptors. 相似文献