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1.
In an in vivo preparation of the exposed rat cranial dura mater electrical field stimulation causes increases in blood flow that are mainly due to the vasodilatory effect of calcitonin gene-related peptide (CGRP) released from meningeal afferents. In this preparation the effect of BIBN4096BS, a non-peptide competitive antagonist of CGRP receptors, was examined. Additionally, in an in vitro preparation of the hemisected rat skull the effect of BIBN4096BS on CGRP release stimulated by activation of meningeal afferents was analysed. Injection of BIBN4096BS at cumulative doses of 300 microg/kg and 900 microg/kg caused dose-dependent inhibition of the electrically evoked blood flow increases. The basal blood flow and vital parameters were not significantly changed by any dose. In the hemisected skull BIBN4096BS at 10(-6) M did not alter the CGRP release evoked by depolarizing K(+) concentrations or antidromic electrical stimulation of the trigeminal ganglion. We conclude that neurogenic increases in dural blood flow are reduced by BIBN4096BS without changing basal vascular parameters. This peripheral effect may be important with regard to CGRP receptor inhibition as an antimigraine strategy. 相似文献
2.
Arulmani U Schuijt MP Heiligers JP Willems EW Villalón CM Saxena PR 《Basic & clinical pharmacology & toxicology》2004,94(6):291-297
Several studies suggest that a calcitonin gene-related peptide (CGRP) receptor antagonist may have antimigraine properties, most probably via the inhibition of CGRP-induced cranial vasodilatation. We recently showed that the novel selective 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,(R*,S*)]), attenuated the CGRP-induced porcine carotid vasodilatation in a model predictive of antimigraine activity. In order to evaluate the potential safety of BIBN4096BS in migraine therapy, this study was designed to investigate the effects of intravenous BIBN4096BS on alpha-CGRP-induced systemic and regional haemodynamic changes in anaesthetised rats, using radioactive microspheres. In vehicle-pretreated animals, consecutive intravenous infusions of alpha-CGRP (0.25, 0.5 and 1 microg kg(-1) min.(-1)) dose-dependently decreased mean arterial blood pressure with an accompanying increase in heart rate and systemic vascular conductance whereas cardiac output remained unchanged. Alpha-CGRP also increased the vascular conductance to the heart, brain, gastrointestinal tract, adrenals, skeletal muscles and skin, whilst that to the kidneys, spleen, mesentery/pancreas and liver remained unaltered. The above systemic and regional haemodynamic responses to alpha-CGRP were clearly attenuated in BIBN4096BS (3 mg kg(-1) intravenously)-pretreated animals. These results indicate that exogenously administered alpha-CGRP dilates regional vascular beds via CGRP receptors on the basis of the antagonism produced by BIBN4096BS. Moreover, the fact that BIBN4096BS did not alter baseline haemodynamics suggests that endogenously produced CGRP does not play an important role in regulating the systemic and regional haemodynamics under resting conditions. 相似文献
3.
BACKGROUND AND OBJECTIVE: Migraine attacks are associated with release of the calcitonin gene-related peptide (CGRP) from trigeminal nerves. BIBN 4096 BS is the first CGRP receptor antagonist tested in humans showing response rates similar to those reported for triptans, together with very good safety and tolerability profiles. The objective of the current study is to develop a population pharmacokinetic/pharmacodynamic model resembling the mechanism of action of BIBN 4096 BS, and to extract by model-based simulations dosage formulations and pharmacodynamic properties that can assist in the development of CGRP receptor antagonists. METHODS: 126 patients with an acute moderate to severe migraine attack lasting not more than 6 hours were enrolled in this phase IIa study. BIBN 4096 BS was given as a single intravenous 10-minute infusion at different dose levels ranging from 0.25 to 10 mg. Severity of headache was measured up to 24 hours. Patients who did not show pain relief by 2 hours were allowed to take rescue medication. Severity of headache and time to rescue medication measurements were fitted simultaneously using logistic regression and time-to-event analysis with nonlinear mixed-effect modelling software NONMEM version V. RESULTS: Severity of headache and time to rescue medication were described as a function of the fraction of the CGRP receptors blocked by BIBN 4096 BS, and controlled by the second- and first-order rate constants representing the onset (k(on)) and offset (k(off)) of the anti-migraine effects. The model predicted a slow rate of offset of the anti-migraine effect (half-life of k(off) = 21 hours). The model developed described the data well and was validated properly. DISCUSSION: A semi-mechanistic population pharmacokinetic/pharmacodynamic model has been developed for the anti-migraine effects of BIBN 4096 BS, characterised by the severity of headache and time to rescue medication. Simulations exploring the effect of the rate of absorption, bioavailability after an extravascular administration and the rate of activation/inactivation of the anti-migraine effect were performed. The rate of absorption seems to play a minor role; however, at least bioavailability fractions of 0.2-0.3 should be obtained. With regard to the kinetics of the anti-migraine effect, and to achieve a response rate of 60% at 2 hours, values of k(on) should be > 0.081 mL/ng/h. At later times after administration higher values of k(off) are associated with faster offset of the response. The simulations showed that molecules with high k(on) and low k(off) values are the most promising. 相似文献
4.
降钙素基因相关肽和BIBN4096BS对麻醉大鼠心肌缺血的作用 总被引:5,自引:1,他引:4
WuDM ZwiePA 《Acta pharmacologica Sinica》2001,22(7):588-594
INTRODUCTION Calcitonin gene-related peptide (CGRP) is a 37amino acid peptide that is predominantly synthesized andstored in sensory neurons. It can be released from boththe central and peripheral axons of these neurons.CGRP-containing nerve fibers have been identifiedthroughout the cardiovascular system, in association withblood vessels, in particular the coronary arteries, andaround the sinoatrial and atrioventricular nodes.CGRP is a potent vasodilator peptide and it exerts positivechronotropic and inotropic effects in rats and hu-mans. It has been shown to exert extremely potent 相似文献
5.
CGRP is an important neuropeptide found throughout the cardiovascular system. However, until recently it has been difficult to define its pharmacology or physiological role because of the lack of suitable antagonists. BIBN4096BS is a high-affinity, nonpeptide antagonist that shows much greater selectivity for human CGRP1 receptors compared to any other drug. Its pharmacology has been defined with studies on transfected cells or cell lines endogenously expressing receptors of known composition. These have allowed confirmation that in many human blood vessels, CGRP is working via CGRP1 receptors. However, it also interacts with other CGRP-activated receptors, of unknown composition. In vivo, clinical studies have shown that BIBN4096BS is likely to be useful in the treatment of migraine. It has also been used to define the role of CGRP in phenomena such as plasma extravasation and cardioprotection following ischemia. 相似文献
6.
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
7.
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
8.
I?aki F Trocóniz Jan-Markus Wolters Hans Guenter Schaefer Willy Roth 《European journal of pharmaceutical sciences》2004,22(4):287-295
Pharmacokinetics (PK) of the calcitonin gene-related (CGRP) peptide receptor antagonist BIBN 4096 BS, the first compound of this new class tested in humans, has been evaluated combining the data from a phase I study performed in healthy volunteers and a phase IIa study conducted in migraine patients. A total of 94 individuals with a total of 556 plasma samples contributed to the analysis. Subjects received a single dose of 0.25, 0.5, 1, 2.5, 5 or 10 mg BIBN 4096 BS administered in a 10 min i.v. infusion. Blood samples were obtained at selected times up to 12 h. Disposition of BIBN 4096 BS was best described with a three compartment body model with first order elimination. BIBN 4096 BS showed a moderate degree (between 30 and 50%) of inter-subject variability in the apparent volume of distribution of the central compartment (V1), total plasma clearance (CL), distribution clearance between the central and deep compartment, and the apparent volume of distribution of the shallow compartment. Typical estimates of V1 were significantly (P <0.01) lower in healthy volunteers (7.16 versus 9.95 L), and typical estimates of CL were significantly lower in subjects receiving oral contraceptives (11.4 versus 17.1 L/h), although the absolute reduction in the unexplained inter-subject variability was negligible (4%). Computer simulations showed that the above mentioned covariates lack clinical significance. In conclusion, the pharmacokinetics of BIBN 4096 BS was independent of the dose and not altered by the tested covariates to a clinically significant degree. 相似文献
9.
Edvinsson L 《CNS drug reviews》2005,11(1):69-76
Basal studies have shown that calcitonin gene-related peptide (CGRP) is a major sensory neuronal messenger in the trigeminovascular system, the pathway conveying intracranial pain. In migraine and cluster headache attacks, CGRP is released in parallel with the pain and successful treatment of the attacks abort both the associated pain and the CGRP release. The search for a potent small molecule CGRP antagonist has been successful and such an agent has been tested in preclinical and clinical studies. The aim of the present study was to examine current knowledge on the clinical pharmacology of systemic BIBN4096BS, which has been shown in man to abort acute migraine attacks as well or better than oral sumatriptan. BIBN4096BS is a specific and potent CGRP receptor antagonist in humans. In safety and tolerability studies the substance is well tolerated with no or only mild side effects. In acute migraine attacks the overall response was 66% with the drug and 27% with placebo. A difference as compared to placebo was seen at 30 min; the response was still rising at 4 h suggesting a long duration of action. At 24 h the pain-free rate was better than that with triptans, suggesting a lower grade of rebound and perhaps even a prophylactic possibility. 相似文献
10.
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
11.
A calcitonin gene-related peptide (CGRP) antagonist (CGRP8-37) inhibits microvascular responses induced by CGRP and capsaicin in skin. 下载免费PDF全文
1. The effect of the calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 on responses to CGRP and other mediators was investigated in rabbit dorsal skin. 2. Blood flow changes at intradermally-injected sites were measured by a multiple site 133xenon clearance technique. CGRP8-37 had little effect on blood flow at doses up to 0.3 nmol/site, when injected alone, although a significant increase in blood flow was observed at the highest dose tested (1 nmol/site). 3. CGRP8-37 dose-dependently inhibited the increased blood flow induced by human alpha CGRP and human beta CGRP, but had no effect on equivalent vasodilator responses induced by vasoactive intestinal peptide (VIP) and prostaglandin E1 (PGE1). CGRP8-37 showed a preferential ability to inhibit alpha CGRP (IC50 0.04 nmol), when compared with beta CGRP (IC50 greater than or equal to 0.3 nmol). 4. Capsaicin, which selectively activates sensory nerves, caused a dose-dependent increase in blood flow when injected intradermally into rabbit skin. The effects of capsaicin (0.01-0.1 mumol/site) were inhibited by CGRP8-37 (0.3 nmol/site), with a partial but significant attenuation of blood flow induced by the highest dose of capsaicin. 5. Oedema formation, induced by intradermal histamine injection (3 nmol/site), was measured in rabbit skin by the local accumulation of intravenously-injected 125I-labelled albumin. Vasodilator doses of CGRP, PGE1 and capsaicin potentiated, in a synergistic manner, oedema formation induced by histamine. GRP8-37 totally inhibited the potentiating effect of CGRP, partially inhibited the synergistic effect of capsaicin, but did not affect PGE1-induced responses.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
12.
Calcitonin gene-related peptide (CGRP) is a potent vasodilator in brain vessels and it has been implicated in the pathogenesis of migraine headache. Blocking post-junctional CGRP receptors, mediators of trigeminal-induced vasodilation, has been suggested as a potential antimigraine strategy. In this study, we tested the ability of a new non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the CGRP-induced dilation in human and/or bovine brain vessels and compared it to that of the antagonist alpha-CGRP(8-37). BIBN4096BS and alpha-CGRP(8-37) both blocked the alpha-CGRP-induced dilation in bovine middle artery segments with respective potency (pK(B) values) of 6.3 and 7.8. In human pial vessels, BIBN4096BS was particularly potent. When tested at 10(-14)-10(-9) M concentrations, it induced a rightward shift in the alpha-CGRP concentration-response curve and yielded a biphasic Schild plot suggesting interaction with more than one receptor population, as was also indicated by the significant best fit of the alpha-CGRP-induced dilation in human brain vessels with a two receptor site interaction. Schild plot analysis in the linear portion of the BIBN4096BS inhibition curve revealed interaction with one high affinity site (pA(2) value approximately 14). In bovine vessels, both alpha-CGRP(8-37) and BIBN4096BS concentration-dependently reversed a pre-established CGRP-induced dilation ( approximately 59 and 85%, respectively), BIBN4096BS being approximately tenfold more potent than alpha-CGRP(8-37) (respective pIC(50) values of 7.5 and 6.75). In human middle cerebral and middle meningeal arteries, BIBN4096BS reversed the alpha-CGRP-induced dilation (> or =70%) by interaction with two different receptor populations: it exhibited a high affinity for one population (pIC(50) value approximately 13) and a lower affinity for the other (pIC(50) value approximately 8). The present data demonstrate that BIBN4096BS is a very potent antagonist that could, depending on its bioavailability and in vivo affinity, be of potential benefit in the acute treatment of migraine headache by blocking and/or reversing the CGRP-mediated dilation of intracranial vessels induced by activation of trigeminovascular afferents. 相似文献
13.
A Cadieux F Pomerleau S St-Pierre A Fournier 《The Journal of pharmacy and pharmacology》1990,42(7):520-521
The effect and mechanism of action of calcitonin gene-related peptide (CGRP) have been investigated on the mouse distal colon. CGRP caused a concentration-dependent relaxation which was not blocked by classical pharmacological antagonists. The response pattern was characterized by a relatively rapid onset and long sustained duration. The results suggest that CGRP itself may contribute to regulating the muscular tone of the mouse colon. 相似文献
14.
Hay DL Howitt SG Conner AC Doods H Schindler M Poyner DR 《British journal of pharmacology》2002,137(1):80-86
1. The ability of the CGRP antagonist BIBN4096BS to antagonize CGRP and adrenomedullin has been investigated on cell lines endogenously expressing receptors of known composition. 2. On human SK-N-MC cells (expressing human calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1)), BIBN4096BS had a pA(2) of 9.95 although the slope of the Schild plot (1.37 +/- 0.16) was significantly greater than 1. 3. On rat L6 cells (expressing rat CRLR and RAMP1), BIBN4096BS had a pA(2) of 9.25 and a Schild slope of 0.89 +/- 0.05, significantly less than 1. 4. On human Colony (Col) 29 cells, CGRP(8-37) had a significantly lower pA(2) than on SK-N-MC cells (7.34 +/- 0.19 (n = 7) compared to 8.35 +/- 0.18, (n = 6)). BIBN4096BS had a pA(2) of 9.98 and a Schild plot slope of 0.86 +/- 0.19 that was not significantly different from 1. At concentrations in excess of 3 nM, it was less potent on Col 29 cells than on SK-N-MC cells. 5. On Rat 2 cells, expressing rat CRLR and RAMP2, BIBN4096BS was unable to antagonize adrenomedullin at concentrations up to 10 microM. CGRP(8-37) had a pA(2) of 6.72 against adrenomedullin. 6. BIBN4096BS shows selectivity for the human CRLR/RAMP1 combination compared to the rat counterpart. It can discriminate between the CRLR/RAMP1 receptor expressed on SK-N-MC cells and the CGRP-responsive receptor expressed by the Col 29 cells used in this study. Its slow kinetics may explain its apparent 'non-competitive' behaviour. At concentrations of up to 10 micro M, it has no antagonist actions at the adrenomedullin, CRLR/RAMP2 receptor, unlike CGRP(8-37). 相似文献
15.
- Experiments were performed in anaesthetized rabbits to examine the effects of calcitonin gene-related peptide (CGRP) and the CGRP antagonist CGRP8–37 on blood flow to the medial collateral ligament of the knee joint.
- Topical application of CGRP (10−13 to 10−9 mol) to the exposed external surface of eight knee joints resulted in dose-dependent dilatation of vessels in both the ligament and the joint capsule. The magnitude of this response varied significantly in different regions of the medial collateral ligament, with the 10−9 mol dose of CGRP giving the maximum response (101.5±25.3% increase) at the femoral insertion site of the medial collateral ligament and lowest (23.1±8.8%) at the tibial insertion site.
- Topical application of CGRP8–37 (0.1, 1 and 10 nmol) produced dose-dependent constriction of vessels in the ligament and the joint capsule in five knees, with a trend towards the greatest effect occurring at the femoral insertion site (45.8±8.1% reduction in blood flow). With the 10 nmol dose, the vasoconstrictor response at the femoral insertion site differed significantly (P<0.05) from the responses obtained at the tibial insertion and joint capsule sites.
- Topical application of CGRP8–37 (0.1, 1 and 10 nmol) to four chronically denervated knees produced substantially smaller vasoconstrictor responses at all sites. At the femoral insertion site, where 10 nmol CGRP8–37 normally produces a 45.8±8.1% reduction in blood flow (n=8), ten days following denervation this response was reduced to 6.5±6.1%, this difference being significant (P=0.01).
- Adrenaline was applied topically to augment blood vessel tone, in order to establish how effectively co-administration of CGRP would offset this increase in tone. Adrenaline (10−10 mol) produced vasoconstriction at all sites (n=6). In the capsule this vasoconstriction was virtually abolished when CGRP (10−9 mol) was co-administered with adrenaline but in the ligament vasodilatation occurred at all sites. This vasodilatation was significantly greater at the femoral insertion site compared to the tibial insertion and mid ligament sites (P<0.05 for both) and the capsule (P<0.01).
- Topical application of substance P (10−10 or 10−9 mol) failed to elicit dilatation of ligament blood vessels.
- These results suggest that endogenous CGRP may play an important role in regulating blood flow to different structures in and around the knee joint.
16.
Release of CGRP during migraine may produce harmful dilatation of cranial arteries, thereby possibly causing pain. We have compared the antagonism by BIBN4096BS and CGRP(8-37) of the relaxant effects of alpha-CGRP on rings of human temporal artery. alpha-CGRP relaxed the arteries precontracted with 9 - 24 mM KCl (-logEC50=9.4) nearly as efficaciously as sodium nitroprusside (10 microM). BIBN4096BS (0.1 - 100 nM) antagonized the effects of alpha-CGRP in surmountable manner with slopes of Schild-plots not different from unity. -LogKB values of 10.1 and 10.4 were estimated for BIBN4096BS when administered before or during the KCl-contracture respectively. BIBN4096BS (1 microM) did not modify the relaxant effects of papaverine and sodium nitroprusside. CGRP(8-37) (1 - 10 microM) antagonized the effects of alpha-CGRP in a surmountable manner with slopes of Schild-plots not different from unity. -LogKB values of 6.6 and 6.7 were estimated for CGRP(8-37) administered before or during the KCl-contracture respectively. The high affinity of BIBN4096BS for CGRP receptors of human temporal artery makes it an excellent tool to explore the hypothesis of CGRP-evoked cerebral vasodilation in migraine. 相似文献
17.
Characterization of calcitonin gene-related peptide (CGRP) receptors in guinea pig lung 总被引:1,自引:0,他引:1
Receptors for calcitonin gene-related peptide (CGRP) in the lung membranes of guinea pig were characterized by using a millititer plate precoated with polyethylenimine. Specific binding of 125I-CGRP was time-dependent, rapid, and reversible, and the binding increased linearly with increasing concentrations of membrane protein. Scatchard analysis revealed two classes of CGRP binding sites: high affinity sites with a KD value of 7.17 x 10(-11) M and a Bmax of 364 fmol/mg protein and low affinity sites with a KD value of 1.7 x 10(-8) M and a Bmax of 39594 fmol/mg protein. Furthermore, the specific binding of 125I-CGRP was dissociated in the presence of GTP or Gpp(NH)p, suggesting that CGRP receptors in guinea pig lung membranes were coupled to the guanine nucleotide regulatory protein. Scatchard analysis of CGRP binding in the presence of GTP revealed selective inhibition of the binding to high affinity binding sites. Unlabeled CGRP displaced the binding of 125I-CGRP to guinea pig lung membranes with an IC50 value of 3.1 x 10(-10) M. In contrast, salmon calcitonin and human calcitonin displaced the binding at 600-fold higher concentrations. We suggest that both low and high affinity binding sites for CGRP exist in the lung membranes of the guinea pig, and the high affinity binding sites for CGRP may be coupled to GTP binding regulatory protein. 相似文献
18.
Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat 下载免费PDF全文
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
19.
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
20.
Characterization and effects on cAMP accumulation of adrenomedullin and calcitonin gene-related peptide (CGRP) receptors in dissociated rat spinal cord cell culture 下载免费PDF全文
Takhshid MA Poyner DR Chabot JG Fournier A Ma W Zheng WH Owji AA Quirion R 《British journal of pharmacology》2006,148(4):459-468
Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) have structural similarities, interact with each others receptors (calcitonin receptor-like receptor (CLR)/receptor-activity-modifying proteins (RAMPs)) and show overlapping biological activities. AM and CGRP receptors are chiefly coupled to cAMP production. In this study, a method of primary dissociated cell culture was used to investigate the presence of AM and CGRP receptors and their effects on cAMP production in embryonic spinal cord cells. Both neuronal and non-neuronal CLR immunopositive cells were present in our model. High affinity, specific [(125)I]-AM binding sites (K(d) 79 +/- 9 pM and B(max) 571 +/- 34 fmol mg(-1) protein) were more abundant than specific [(125)I]-CGRP binding sites (K(d) 12 +/- 0.7 pM and B(max) 32 +/- 2 fmol mg(-1) protein) in embryonic spinal cord cells. Specific [(125)I]-AM binding was competed by related molecules with a ligand selectivity profile of rAM > hAM(22-52) > rCGRPalpha > CGRP(8-37) > [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 (BIBN4096BS). Specific [(125)I]-CGRP binding was competed by rCGRPalpha > rAM > or = CGRP(8-37) > or = BIBN4096BS > hAM(22-52). Cellular levels of cAMP were increased by AM (pEC(50) 10.2 +/- 0.2) and less potently by rCGRPalpha (pEC(50) 8.9 +/- 0.4). rCGRPalpha-induced cAMP accumulation was effectively inhibited by CGRP(8-37) (pA(2) 7.63 +/- 0.44) and hAM(22-52) (pA(2) 6.18 +/- 0.21) while AM-stimulation of cAMP levels was inhibited by CGRP(8-37) (pA(2) 7.41+/- 0.15) and AM(22-52) (pA(2) 7.26 +/- 0.18). BIBN4096BS only antagonized the effects of CGRP (pA(2) 8.40 +/- 0.30) on cAMP accumulation. These pharmacological profiles suggest that effects of CGRP are mediated by the CGRP(1) (CLR/RAMP1) receptor in our model while those of AM are related to the activation of the AM(1) (CLR/RAMP2) receptor subtype. 相似文献