[Methysergide-induced fibrosis. Directives for preventive treatment of migraine with methysergide].
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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↗
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↗
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↗
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↗
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↗
Behavioral supersensitivity to 5-hydroxytryptophan induced by chronic methysergide pretreatment.
The administration of 5-hydroxytryptophan to intact guinea pigs results in rhythmic myoclonic behavior. This behavior is blocked acutely by methysergide, but is intensified in animals chronically pretreated with methysergide. Brain serotonin concentrations of guinea pigs pretreated with methysergide did not differ from saline-treated animals. These results are compatible with the hypothesis that prolonged methysergide administration can result in pharmacologically-induced denervation hypersensitivity at central serotonin receptors.
5-Hydroxytryptophan↗
Centrally mediated antihypertensive and bradycardic effects of methysergide in spontaneously hypertensive rats.
Methysergide caused dose-dependent reductions in systolic blood pressure and heart rate of unanesthetized SHR, whereas cyproheptadine was ineffective. In pithed SHR pretreated with methysergide or cyproheptadine, pressor responses to 5-HT were abolished. Responses to sympathetic nerve stimulation were unaltered by methysergide, whereas cyproheptadine slightly reduced them. Both drugs enhanced pressor responses to norepinephrine. Failure to identify a peripheral mechanism for the antihypertensive action of methysergide suggests that the effect may be centrally mediated but not reliant upon serotonin receptor blockade.
Animals↗
Reduction in blood pressure, sympathetic nerve discharge and centrally evoked pressor responses by methysergide in anesthetized cats.
Methysergide (1 and 3 mg/kg i.v.) caused dose-dependent reductions in blood pressure and heart rate of anesthetized cats. In addition, sympathetic nerve discharges of the postganglionic renal nerve were also markedly reduced by the same doses of drug. Pressor responses to electrical stimulation of the diencephalon were inhibited by 3 mg/kg but not 1 mg/kg of methysergide. These results suggest that methysergide acts to decrease blood pressure by a centrally mediated reduction in sympathetic nervous outflow and, at higher doses, can additionally prevent pressor changes caused by electrical activation of suprabulbar central structures. These results are in agreement with previous reports that methysergide has little or no peripheral effects on the cardiovascular system.
Action Potentials↗
The effects of methysergide on the constrictor response to serotonin on the isolated, perfused rabbit ear artery.
On the isolated, perfused rabbit ear artery methysergide 10(-9) mol.1(-1) only potentiated the constrictor response to serotonin while at a concentration of 2.5 x 10(-8) mol.1(-1) it only blocked the response. At an intermediate concentration (2.5 x 10(-9) mol.1(-1)) it produced initial potentiation followed by subsequent blockade. In contrast, at all three concentrations it only potentiated the constrictor response to noradrenaline. The results thus show that methysergide can exert a dual effect on the constrictor response to serotonin with the actual effect produced being dependent not only on the concentration of methysergide used but also on the period of time the artery is exposed to methysergide.
Animals↗
Evidence for a dopaminergic activity of methysergide in humans.
The acute administration of 2 mg of methysergide significantly reduced plasma prolactin levels in nine normal subjects and in seven hyperprolactinaemic patients. The prolactin lowering effect of this drug was abolished by sulpiride. Morever methysergide lowered plasma GH levels in four out of nine acromegalic patients, who were also responsive to a dopaminergic drug such as bromocriptine. Although methysergide did not significantly blunt the TRH-induced prolactin release, our data suggest that this drug may affect GH and prolactin release through a dopaminergic mechanism of action. This effect should be taken into account when methysergide is employed as antiserotoninergic drug in neuroendocrinological studies.
Acromegaly↗
A proposed mechanism for the biphasic vasoconstrictor responses to 5-hydroxytryptamine and methysergide in the rabbit ear artery.
Rabbit ear arteries were isolated and perfused at a constant flow rate so that the perfusate flowed into the fluid bathing the adventitial surface of the artery. Submaximal doses of intraluminally applied noradrenaline injected as a bolus into the perfusion fluid produced transient monophasic vascoconstrictor responses. In contrast, similarly administered 5-hydroxytryptamine (5-HT) or methysergide caused prolonged biphasic vascoconstrictor responses. The extraluminal/intraluminal potency ratios for noradrenaline, 5-HT and methysergide were 230, 15 and 6 respectively, which indicates that 5-HT methysergide are relatively more potent when administered extraluminally than noradrenaline. Cocaine (3-0 X 10(-5) mol litre-1) markedly increased the potency of extraluminally administered noradrenaline and converted the monophasic responses produced by noradrenaline to biphasic responses. It is concluded that under the experimental conditions used 5-HT and methysergide produced biphasic responses by an action on the medial smooth muscle firstly via the intraluminal surface and secondly an additional direct action via the adventitial surface. Noradrenaline's extraluminal potency is low because of its neuronal uptake and hence the responses are normally monophasic.
Animals↗
The influence of methysergide on 5-hydroxytryptamine-induced changes in regional distribution of blood flow.
Systemic and regional haemodynamic variables were measured at the baseline and after saline or 5-HT infusions (5 microgram kg-1 min-1, i.v.) or methysergide injections (0.5 mg kg-1, i.v.). Cardiac output and its complete distribution were measured by the radioactive microsphere (15 micrometer diam) technique. Although 5-HT did not change the systemic variables, methysergide caused a moderate increase in systolic and mean blood pressure and heart rate. 5-HT caused a substantial increase in gastric and a moderate increase in cerebral and myocardial blood flow at the expense of that to the lungs (arteriovenous shunt + bronchial flows), kidneys and skin. While methysergide was able to reduce the vascular responses to 5-HT in stomach, skin, kidneys, heart, lungs and brain, the drug itself, like 5-HT, decreased the number of microspheres reaching the lungs. Since a large number of 15 micron microspheres can escape through the arteriovenous anastomoses to lodge in the lungs it seems likely that both 5-HT and methysergide can reduce the 'non-nutrient' flow through these anastomoses.
Animals↗
Improvement of sexual behavior in aged rats by p-chlorophenylalanine and methysergide.
The effects of methysergide, a serotonin antagonist, and p-chlorophenylalanine (PCPA), a serotonin synthesis blocker on the sexual behavior of intact old male rats at 19-23 months of age and female rats at 17-18 months of age were studied. Female rats with prolonged vaginal cornification and a lordosis quotient (LQ) of less than 50%, and male rats displaying no ejaculation were selected as experimental animals. The receptivity of aged female rats, but not the approach behavior to males nor proceptivity was improved by PCPA or methysergide. The LQ of intact aged female rats in non-exit tests was improved by the i.p. administration of 50 mg/kg B.W. of PCPA 2 to 4 hours prior to the sexual behavior test or 3 mg/kg B.W. of methysergide 4 hours prior to the test. Total mount frequency and mount latency of intact aged male rats were improved by the administration of methysergide (3 mg/kg B.W.), while total mount frequency and intromission latency were improved by the administration of PCPA (20 mg/kg B.W. for 4 days). The present results together with the finding from our previous study suggest that the increase of serotonin (5-HT) activity per se plays an important role in the decline of receptivity of aged female rats and the copulatory activity of aged male rats.
Aging↗
Effects of combined methysergide and mecamylamine/scopolamine treatment on spatial navigation.
In the present study, we investigated the effects of a 5-HT2 receptor antagonist, methysergide (2.5, 7.5 and 20 mg/kg), on spatial learning in saline, mecamylamine (10 mg/kg) and scopolamine (0.8 mg/kg) treated rats. Methysergide had no effect on water-maze (WM) spatial learning in rats subjected to saline or mecamylamine pretreatments. However, scopolamine-induced WM learning deficit was augmented by methysergide at doses of 7.5 and 20 mg/kg. These results further suggest (A) that cholinergic and serotonergic systems may interact in the regulation of spatial learning, and (B) that the cholinergic component of this interaction with serotonin2 receptors is mediated by muscarinic receptors, but not by nicotinic receptors.
Animals↗
Effects of methysergide, pizotifen and ergotamine in the monkey cranial circulation.
Internal and external carotid vascular resistances were measured, in anaesthetized monkeys, to asses the direct cranial vascular effects of i.v. methysergide, pizotifen and ergotamine, and their effects on the cranial vascular responses to the constrictors 5-hydroxytryptamine and noradrenaline and the dilators histamine, prostaglandin E1 and bradykinin. Methysergide reduced responses to 5-HT, and tended to potentiate the external carotid responses to noradrenaline. Pizotifen blocked responses to histamine; it tended to reduce internal carotid responses to 5-HT, but it potentiated external carotid 5-HT responses. Ergotamine reduced responses to 5-HT and noradrenaline, but this was probably related to its cranial vasoconstrictor effects, especially in the external carotid circulation. Methysergide induced weak transient cranial vasoconstriction and pizotifen had no direct effects. These findings may be relevant to the therapeutic actions of these drugs in migraine, since the doses used approximated to those used clinically.
Animals↗
Biphasic effects of the antiserotonergic methysergide on lordosis in rats.
As also reported by other workers, the antiserotonergic drug methysergide was found to facilitate lordotic responding in estrogen primed, ovariectomized rats. A second dose of methysergide 24 hr after the first, however, failed to produce any increment in responding. Animals received daily estrogen injections in order to maintain a relatively constant level of priming. After several days of methysergide, a progesterone injection facilitated lordosis to the same degree as in controls receiving only saline and estrogen. When a second injection of progesterone was given 24 hr later, however, the animals failed to respond. In contrast, saline controls with this estrogen paradigm responded equally well to both progesterone injections. These results are discussed in terms of their bearing on possible serotonergic and non-serotonergic mechanisms by which progesterone may control lordosis.
Animals↗
Effect of topical and intracameral methysergide on calcitonin gene-related peptide-induced irritative changes in the rabbit eye.
Calcitonin gene-related peptide (CGRP) is a neuropeptide localized in the ocular sensory nerves. It is responsible for most of the irritative changes in the rabbit eye in neurogenic inflammation, namely vasodilation in the anterior uvea, breakdown of the blood-aqueous barrier and increase in the intraocular pressure. In the present study, intracameral methysergide inhibited the CGRP-induced irritative changes in the rabbit eye. Provided that sufficient concentration of methysergide could be reached in the anterior chamber after topical application, it might be possible to use locally administered methysergide to limit different pathophysiological conditions in the eye in which CGRP is involved.
Administration, Topical↗