[Methysergide-induced fibrosis. Directives for preventive treatment of migraine with methysergide].
Explore the source record for details and available documents.
Endomyocardial Fibrosis↗
SEARCH · PubMed Health
Results for “Methysergide”
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Inhibitory effect of methysergide on calcitonin gene-related peptide-induced vasodilatation and ocular irritative changes in the rabbit.
1. Calcitonin gene-related peptide (CGRP) is involved in ocular neurogenic inflammation in the rabbit, causing vasodilatation in the anterior uvea, breakdown of the blood-aqueous barrier, increase in the intraocular pressure (IOP) and rise in the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content in the aqueous humour. So far there is no means of preventing these CGRP-induced ocular effects. 2. In the present study, the effect of intravenous methysergide (1-10 mg kg-1, b.w.) on CGRP-induced changes in the IOP, blood-aqueous barrier and cyclic AMP content in the aqueous humour was studied in vivo. The effect of methysergide on CGRP-induced vasodilatation both in vivo and in vitro was also investigated. 3. Methysergide decreased intraocular pressure but had only a transient effect on blood pressure. Methysergide decreased the regional blood flow in ocular tissues by 53-65%, but did not have such a vasoconstrictor effect in most extra-ocular tissues studied. 4. Methysergide inhibited CGRP-induced vasodilatation, increase in the IOP, breakdown of the blood-aqueous barrier and increase in the cyclic AMP content in the aqueous humour in vivo. 5. In vitro, methysergide alone did not have effects on the vascular tone in isolated ophthalmic artery of rabbit. However, it potentiated noradrenaline (NA)-induced contraction. There were no differences in the IC50 values for CGRP on the NA-induced contraction in the presence and absence of methysergide, indicating that methysergide has no direct effect on the vasorelaxant effect of CGRP in vitro. 6. The present study demonstrates that in the rabbit eye methysergide inhibits CGRP-induced changes.One inhibitory mechanism of methysergide may be to enhance the effect of a vasoconstrictor (NA) to antagonize the vasodilator effect of CGRP. The present findings suggest that a methysergide-sensitive mechanism may be used to limit some pathophysiological conditions in the eye that involve neurogenic inflammation and the release of CGRP.
Animals↗
Responses of isolated canine intermediate auricular arteries to 5-hydroxytryptamine and methysergide.
The responses of the isolated canine intermediate auricular arteries to 5-hydroxytryptamine (5-HT), methysergide, norepinephrine (NE) and potassium chloride (KCl) were examined by means of the 'cannula inserting' method. 5-HT produced dose-dependent vasoconstriction more potently than did NE. The effect was blocked by methysergide, i.e. a small dose of methysergide competitively inhibited the 5-HT-induced effect, and a large amount of methysergide inhibited it non-competitively. The 5-HT-induced constriction was slightly but significantly suppressed by phentolamine in doses which markedly blocked NE-induced effects. KCl-induced effects were not significantly affected by methysergide and phentolamine treatment. Methysergide induced vasoconstriction by itself in about half out of all preparations. In cases in which methysergide induced vasoconstriction, the dose-response curves were bell-shaped and the constriction became smaller with large doses. At small doses, methysergide induced reproducible vasoconstriction but at large doses it readily caused tachyphylaxis. The methysergide-induced constriction was not blocked by 1 microgram of phentolamine which inhibited NE-induced constriction. It is concluded that the canine intermediate auricular artery is very sensitive to 5-HT and methysergide, and that the action of 5-HT may partially involve alpha-adrenergic mechanisms.
Animals↗
A paradox: the 5-HT2-receptor antagonist ketanserin restores the 5-HT-induced contraction depressed by methysergide in large coronary arteries of calf. Allosteric regulation of 5-HT2-receptors.
Methysergide depresses the contractile effects of 5-hydroxytryptamine (5-HT) in bovine large coronary arteries devoid of endothelium. The IC50 of methysergide for depression of the response to 5-HT was (-log mol/l) 9.8. A low sensitivity contractile effect of 5-HT was not influenced by 1-1,000 nmol/l methysergide. The maximum force of this residual response is approximately 1/3 of the maximum force elicited by 5-HT in the absence of methysergide. Ketanserin restored the 5-HT-induced contraction depressed by methysergide. In the presence of 0.1 mumol/l ketanserin, methysergide caused depression of the 5-HT-induced effects with an IC50 (-log mol/l) of 6.5 without affecting the residual response. We propose that methysergide depresses 5-HT-induced contractions by acting on an allosteric site. The effect of binding of methysergide to the allosteric site would lead to a conformational change of the 5-HT2-receptor, thereby only allowing the production of a residual 5-HT-induced contraction. Ketanserin competes with high affinity not only with 5-HT for the 5-HT2-receptor but also with methysergide for the allosteric site, thus shifting the receptor back into its original conformation. The affinity estimate of ketanserin for the allosteric site yielded a KB (-log mol/l) of 10.3. Ketanserin (1-1,000 nmol/l) antagonized the contractile effects of 5-HT with a potency expected from its affinity for 5-HT2-receptors (-log KB, mol/l 9.4). However, micromolar concentrations of ketanserin antagonized the effects of 5-HT less than expected from its affinity for 5-HT2-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Allosteric Regulation↗
Allosteric properties of the 5-HT2 receptor system of the rat tail artery. Ritanserin and methysergide are not competitive 5-HT2 receptor antagonists but allosteric modulators.
We present an analysis of the interactions of 5-hydroxytryptamine (5-HT) and antagonists (methysergide, ketanserin, ritanserin) with the 5-HT2 receptor system of strips of rat tail artery. The mode of action of ritanserin was also studied on strips of calf coronary arteries. 1. Ketanserin competitively antagonized 5-HT-induced effects in rat tail artery with an affinity (pKB = 9.4 nmol/l) consistent with the assumption of an interaction of 5-HT and ketanserin at 5-HT2-receptors. 2. Methysergide reduced to 50-60% the maximum response to 5-HT in rat tail artery. Concentration-effect curves for 5-HT became biphasic in the presence of methysergide with quickly and slowly developing contractions at low and high concentrations of 5-HT, respectively. 100 nmol/l ketanserin completely restored effects of 5-HT depressed by low concentrations of methysergide (less than 10 nmol/l). Higher concentrations of methysergide in the presence of 100 nmol/l ketanserin again depressed the effects of 5-HT. 3. Ritanserin resembles methysergide by causing insurmountable antagonism of 5-HT-induced contractions which can be prevented by ketanserin in both rat tail artery and calf coronary artery. These results are inconsistent with competition between ritanserin and 5-HT for the 5-HT2 receptor. 4. The findings are consistent with the assumption of an interaction of ketanserin and methysergide or ritanserin with an allosteric site near the 5-HT2-receptor. Both methysergide and ritanserin appear to antagonize the effects of 5-HT through an allosteric site which is distinct from the 5-HT2 receptor.
Allosteric Regulation↗
Pharmacokinetics of methysergide and its metabolite methylergometrine in man.
Five healthy men were given 1.0 mg methysergide maleate intravenously and 2.7 mg methysergide maleate orally in a cross-over study. The systemic availability of methysergide was only 13%, most probably due to a high degree of first-pass metabolism to methylergometrine. We also found evidence of extrahepatic clearance of methysergide. After oral administration the plasma concentrations of the metabolite were considerably higher than those of the parent drug and the area under the plasma concentration curve (AUC) for methylergometrine was more than ten times greater than for methysergide. Our findings may be relevant to the treatment of migraine if methylergometrine contributes to the effect of methysergide. Methylergometrine had a significantly longer elimination half-life than methysergide (223 +/- 43 min vs 62.0 +/- 8.3 min and 174 +/- 35 min vs 44.8 +/- 8.1 min in the oral and intravenous studies respectively).
Administration, Oral↗
Modification of the vasomotor actions of methysergide in the femoral arterial bed of the anaesthetized dog by changes in sympathetic nerve activity.
1 Methysergide has been shown to have a remarkably selective vasoconstrictor action in the carotid arterial bed of the anaesthetized dog following intravenous administration. However we have now shown that under conditions which produce sympathetic blockade methysergide will also constrict the femoral arterial bed and the mechanism involved has been investigated. 2 Methysergide (10.100 microgram/kg i.v.) produced small but variable effects on femoral arterial blood flow in the anaesthetized dog. However following ganglion blockade (mecamylamine 5 mg/kg i.v.), section of the lumbar sympathetic chain between L4-L5 or catecholamine depletion with syrosingopine, methysergide consistently caused dose-related decreases in femoral arterial flow which were associated with increases in femoral arterial vascular resistance. 3 Intravenous infusion of methysergide (10 microgram/kg/min) or 5-hydroxytryptamine (5-HT, 10 microgram/kg/min) inhibited the increases in femoral arterial vascular resistance produced by stimulation of the lumbar sympathetic chain by 70% and 44% respectively whilst increases in vascular resistance produced by close intra-arterially administered noradrenaline were potentiated by 25% and 11% respectively 4 Our results show that the vasomotor actions of methysergide in the dog femoral arterial bed are dependent on the degree of sympathetic activity. This suggests that in the dog the post-junctional vasoconstrictor action of methysergide can be masked by a pre-junctional inhibitory effect on sympathetic nerves which may be mediated through stimulation of a specific pre-junctional receptor for 5-HT.
Anesthesia↗
Enhancement of reflex vagal bradycardia following intracerebroventricular administration of methysergide in cats.
Metehysergide in total doses of 100, 200 and 400 micrograms injected into the fourth cerebral ventricle of cats potentiated the reflex bradycardic responses which were evoked by i.v. pressor doses of norepinephrine. Methysergide (400 micrograms) injected i.v., or intracerebroventricularly in vagotomized cats did not affect the reflex bradycardia. These results suggest that the enhancement of reflex vagal activation is due to an action of methysergide in the central nervous system. Intracerebroventricular methysergide significantly reduced the resting arterial pressure and heart rate, while i.v. administration caused only significant bradycardia. Carotid occlusion responses were depressed following both i.v. and intracerebroventricular methysergide. The magnitude of reductions in arterial pressure and heart rate following the injection of methysergide into the fourth cerebral ventricle were the same in vagotomized cats and in intact vagus preparations. It is suggested that depression of cardiovascular function is due to a central action of methysergide and is mediated by reduction in sympathetic outflow.
Animals↗
The effects of ketanserin, methysergide and LY 53857 on sympathetic nerve activity.
Preganglionic sympathetic nerve activity, blood pressure, heart rate and femoral arterial conductance were recorded in anaesthetised, paralysed cats. Three 5-HT2 antagonists, ketanserin, methysergide and LY 53857, were infused separately over 1 h periods. Ketanserin caused a fall in, methysergide a rise followed by a fall and LY 53857 only a rise in preganglionic sympathetic nerve activity. The sympathoexcitation caused by both LY 53857 and methysergide was not associated with any changes in blood pressure and heart rate. The sympathoinhibition caused by ketanserin and methysergide was accompanied by a fall in blood pressure and heart rate. Both ketanserin and LY 53857 caused increases in femoral arterial conductance, while methysergide caused a transient decrease. These differences are explained on the basis that ketanserin possesses alpha 1-adrenoceptor antagonist and methysergide 5-HT receptor agonist properties. It is suggested that 5-HT2 sympathoinhibitory receptors are involved in central cardiovascular control.
Anesthesia↗
5-Hydroxytryptamine agonistic action of methysergide and the absence of supersensitivity to 5-HT agonists in spinal flexor reflexes in rats.
The intravenous administration of L-5-hydroxytryptophan (5-HTP), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), p-chloroamphetamine (PCA), LSD and methysergide to acute spinal rats, transected at C1, stimulated the flexor reflexes induced by electrical stimulation applied to the skin of the toe. The enhancement produced by 5-HTP, 5-MeODMT and PCA, was not antagonized by the prior administration of a dose of LSD or methysergide, although the enhancement produced by 5-MeODMT, LSD and methysergide, but not that produced by 5-HTP and PCA, was antagonized by cyproheptadine. In rats treated with 5,6-dihydroxytryptamine (intracisternal administration, 2 weeks previously) supersensitivity was observed to the effects of 5-HTP, a precursor of 5-HT, while subsensitivity was observed for the effects of PCA, a releaser of 5-HT. However, no supersensitivity was observed for the effects of 5-MeODMT, LSD and methysergide. These results suggest that methysergide may have an agonistic action on the 5-HT receptors in spinal cord and that supersensitivity to 5-HTP in rats treated with 5,6-dihydroxytryptamine was due to the lack of uptake of 5-HT into terminals of descending 5-HT fibres or to the change in 5-HT receptors which were not sensitive to 5-MeODMT, LSD, methysergide or cyproheptadine.
5,6-Dihydroxytryptamine↗
Methysergide induces selective potentiation in cholinergic contractions of the guinea-pig vas deferens by facilitating acetylcholine release.
Methysergide (3 x 10(-6) M) enhanced the contractile responses of the isolated stripped vas deferens of guinea-pig to acetylchline(ACh) and arecoline, but not those to noradrenaline, tyramine and bradykinin. Methysergide (3 x 10(-5) M) suppressed the contraction elicited by noradrenaline or histamine. The methysergide-induced potentiation of the response to ACh was prevented by pre-addition of hemicholinium but not by tetrodotoxin or morphine. The augmentation of the response to ACh by physostigmine was unaffected by hemicholinium. The phasic contraction of the tissue elicited by 30 mM KCl was also enhanced by methysergide, and this enhancement was prevented by the pre-addition of atropine (1.4 x 10(-7) M). In the depolarized vas deferens after exposure to 30 mM KCl, methysergide occasionally induced a sustained tonic contraction which was inhibited by atropine. These findings suggest that methysergide facilitates a release of ACh by acting on the cholinergic nerve terminals and selectively potentiates the cholinergic response.
Acetylcholine↗
[Inhibitory action of methysergide bimaleate on the collagenase of Clostridium histolyticum].
Inhibitory effects of methysergide bimaleate on the collagenase of the Clostridium histolyticum have been established. Having previously shown the inhibitory action of serotonin on this bacterial collagenase, the authors have tested methysergide bimaleate as another inhibitor. After injection in the peritoneum of the rats of methysergide bimaleate and collagenase together, lesions are minimal or absent, in contrast with the dramatic effects of collagenase alone. This shows the antagonist role of methysergide bimaleate in regard to collagenase and suggest that methysergide bimaleate reduce the collagenolysis and may elucidate the possible occurrence of fibrotic lesions after treatment of migraine by methysergide bimaleate in man.
Animals↗
Non-reversal of scopolamine- or age-related EEG changes by ondansetron, methysergide or alaproclate.
The present studies investigates the effects of a 5HT3-antagonist (ondansetron: 0.01, 0.1, 1, 10 micrograms), a 5HT2-antagonist (methysergide: 2, 10, 20 mg/kg) and a serotonin uptake inhibitor (alaproclate: 2, 10, 20 mg/kg) on the neocortical electrical activity of young scopolamine-treated and aged rats. The scopolamine (0.2 and 0.8 mg/kg)-induced increase in EEG spectral components was not reversed by ondansetron, methysergide or alaproclate. The scopolamine (0.8 mg/kg)-induced EEG amplitude increase reversing potency of a subthreshold dose of the muscarinic agonist pilocarpine (2 mg/kg) was not potentiated by ondansetron, methysergide or alaproclate. A higher dose of pilocarpine (10 mg/kg) reversed scopolamine-induced EEG slowing. Age-related increase in high voltage spindles (HVS) was not alleviated by either ondansetron, methysergide or alaproclate. The HVS activity stabilizing effect of pilocarpine (2 mg/kg) was not enhanced by ondansetron, methysergide or alaproclate. These results suggest that the serotonergic agents investigated could not alleviate cortical cholinergic activation deficit and once again implicate the role of cholinergic system in both the neocortical electrical activation and age-related cortical electrical arousal deficit.
Aging↗
Effects of intrathecally administered methysergide and yohimbine on microstimulation-produced antinociception in the rat.
This study examined whether intrathecal (i.t.) administration of the serotonergic antagonist methysergide, of the alpha 2 noradrenergic antagonist yohimbine, or of both drugs antagonized stimulation-produced antinociception (SPA) evoked from the nucleus raphe magnus (NRM) and the nucleus reticularis paragigantocellularis (NRPG) of lightly anesthetized rats. The increase in tail flick latency (TFL), but not the increase in paw pinch withdrawal threshold (PWT), evoked from NRM sites was antagonized by i.t. administration of methysergide. Intrathecal administration of yohimbine antagonized both the increase in TFL and the increase in PWT produced by stimulation of NRM sites. Stimulation of sites in the NRPG also increased TFL and PWT; these increases were not antagonized by i.t. administration of methysergide. Although i.t. administration of yohimbine antagonized the increase in TFL evoked from the NRPG, the increase in PWT was not antagonized. When coadministered intrathecally, methysergide and yohimbine antagonized the increases in TFL and PWT produced by stimulation of NRM and of NRPG sites. In contrast, i.v. administration of the same doses of methysergide and yohimbine did not antagonize either the increase in TFL or the increase in PWT evoked from either set of sites. These results support the concept that activation of serotonergic and noradrenergic bulbospinal neurons mediates SPA and additionally suggest that the noradrenergic component involves an alpha 2 noradrenergic receptor.
Animals↗
Centrally mediated hypotension and bradycardia by methysergide in anesthetized dogs.
In anesthetized dogs, methysergide (1 and 3 mg/kg i.v.) caused reductions in systolic and diastolic blood pressure, heart rate, left ventricular pressure and peripheral resistance. Caardiac output was unchanged because of an increase in stroke volume. Methysergide exhibited no alpha-receptor, ganglion, or adrenergic neuron-blocking properties nor did it have marked direct vasocilator action. The BCO, but not the orthostatic, reflex was severely inhibited by the drug, evidence for a central inhibitory action. Atropine, vagotomy or carotid sinus debuffering had little or no effect on the hypotension and bradycardia produced by methysergide, whereas guanethidine pretreatment essentially abolished these effects. Direct intracerebronventricular administration of small doses of methysergide (0.2 mg/kg) caused significant hypotension and bradycardia. It is concluded that methysergide causes centrally mediated hypotension and bradycardia, the mechanism of which is not clearly understood.
Animals↗
Potentiating effect of methysergide on norepinephrine-induced constriction of the isolated internal carotid artery of the dog.
The stainless steel cannula inserting method was used to examine the effects of methysergide on 5-hydroxytryptamine (5-HT)- and norepinephrine-induced vasoconstriction in the isolated internal carotid artery of the dog. 5-HT, at a dose of 0.3 microgram, induced a marked increase in perfusion pressure, usually over 100 mm Hg. On the other hand, norepinephrine produced a relatively small increase in perfusion pressure (20-40 mm Hg) at a large dose of 10 micrograms. Methysergide inhibited 5-HT-induced vasoconstriction. Norepinephrine-induced vasoconstriction was significantly potentiated by treatment with methysergide and blocked by phentolamine. Methysergide also enhanced the vasoconstrictor response to potassium chloride. Thus, it is suggested that the potentiating effect of methysergide on norepinephrine-induced vasoconstriction may partially be due to activation of the inward calcium channel of the internal carotid artery.
Animals↗
Antagonism by methysergide of neurogenic vasoconstriction in the dog forelimb.
In the flow-regulated dog forelimb, electrical stimulation of the efferent median nerve produced frequency-dependent increases in perfusion pressure. These vasoconstrictor effects were attenuated by a large dose of phentolamine, an alpha 1 and alpha 2 blocking drug. Administration of methysergide after phentolamine completely reversed the vasoconstrictor responses to vasodilation at most frequencies of stimulation. In the absence of phentolamine pretreatment, even a lower dose of methysergide reversed or caused biphasic responses (attenuated constriction followed by dilatation) during the nerve stimulation at the lower frequencies (0.5-4.0 Hz). This lower dose of methysergide completely abolished vascular effects of exogenous 5-hydroxytryptamine (5-HT) and potentiated those of norepinephrine; hence, the antagonism by methysergide of neurally mediated vasoconstriction is not caused by an action on alpha-adrenergic receptors. Unlike methysergide, selective 5-HT2 antagonists ketanserin and ritanserin have no modifying effect on exogenous 5-HT responses. These studies have provided pharmacological evidence that suggests that 5-HT may be the neurotransmitter mediating neurogenic vasoconstriction in the dog forelimb, and that this effect does not involve activation of 5-HT2 receptors.
Animals↗
Methysergide in the treatment of narcolepsy.
Five patients with narcolepsy (four with the allied symptom of cataplexy) were treated with the serotonin antagonist methysergide. All patients had as good control of their sleep attacks while on methysergide therapy as on a control period of dextroamphetamine therapy. The cataplexy was less well controlled by methysergide than by dextroamphetamine, but improved when compared to a period without medication. Two patients developed severe calf claudication while on methysergide.
Adult↗