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PubMed1979

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↗
PubMed1995

Effects of methysergide administration on edema formation at the site of scald.

Femoral blood flow (Qa), hind paw lymph flow (Qlym), and lymph-to-plasma protein concentration ratio (Clym/Cp) were monitored before and 4 h after 1) 5-s 100 degrees C paw scald, 2) methysergide (1 mg/kg iv) 20 min before scald, 3) methysergide 30 min after scald, and 4) methysergide only. Before experimentation, hind paw venous pressure was elevated and maintained until steady-state Qa, Qlym, and minimal Clym/Cp levels were reached. The reflection coefficient (sigma d) was determined as 1 - minimal Clym/Cp; the filtration coefficient (Kf) was calculated. Methysergide alone caused no changes. Increases in Qa, Qlym, Clym/Cp, and Kf were identified in all scald groups. Compared with scald only animals, pre- and postscald methysergide blunted the increases in Qa, Qlym, Kf, and paw weight gain without an effect on sigma d. These data demonstrate that methysergide reduces edema formation at the site of scald, perhaps by modulating the burn-induced vasodilator response and/or by limiting the burn-induced increase in microvascular surface area.

Animals↗
PubMed1987

[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↗
PubMed1996

Burn edema reduction by methysergide is not due to control of regional vasodilation.

To determine the extent to which edema modulation by methysergide is due to a blunting of the regional vasodilator response to scald and/or local reduction of transvascular fluid flux, a canine hind limb lymphatic was cannulated. Femoral blood flow (Qa; ml/min), lymph flow (QL; microliter/min/100 g), and lymph-to-plasma protein ratios (CL/CP) were monitored in groups of five dogs before and 4 hr after 5-sec, 100 degrees C foot paw scald; high (1.0 mg/kg) or low (.5 mg/kg) dose of methysergide 30 min before scald. The compression on a clamp placed around the femoral artery in other dogs was adjusted after scald to simulate the blunting effect on Qa observed in methysergide treated dogs. Hind leg venous pressure was elevated to approximately = 40 mm Hg before experimentation until steady state QL and (CL/CP)min were reached. Protein reflection coefficient (sigma d; 1-C1/ CP) and fluid filtration coefficient (Kf) were calculated. Compared to preburn values, all groups showed significant (P < 0.002, analysis of variance) increases in CL/CP and Kf. Contrasted with the burn only group, methysergide blunted increases in Qa, Kf and paw weight gain in a dose-dependent fashion, with no effect on the reflection coefficient. Compression clamp control of femoral Qa caused no effects on permeability. Methysergide limits burn edema in a dose-related fashion, though not due to a blunting of the regional vasodilator response. Local, not regional, mechanism(s) likely mediate this response.

Animals↗
PubMed1991

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↗
PubMed1985

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↗
PubMed1975

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↗
PubMed1982

Methysergide releases locomotion without support in lateral hypothalamic akinesia.

Rats made profoundly akinetic by large bilateral electrolytic partial transections of the lateral hypothalamus were released from their akinesia by methysergide maleate (45 mg/kg, IP). When tested as soon as 24 hr postoperatively, lateral hypothalamic rats treated with methysergide displayed vigorous forward locomotion without postural support for as long as an hour and a half. By postoperative day 5, the locomotion elicited by methysergide was integrated with postural support to produce a more normal form of walking. Although atropine sulfate (50 mg/kg, IP) releases excessive walking in akinetic rats treated with 6-hydroxydopamine [53] it did not release locomotion lateral hypothalamic rats. Similarly, apomorphine, clonidine and phentolamine did not do so. Assuming that methysergide in the dose used exerts its effects primarily via the blockade of serotonin systems, we suggest that, in addition to an inhibitory cholinergic system, an independent inhibitory serotonergic system may also exaggerate the akinesia seen following treatments that diminish the action of brain catecholamine systems. Furthermore, the type of locomotion released by methysergide is a fractional form not previously isolated.

Animals↗
PubMed1984

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↗
PubMed1987

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↗
PubMed1975

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↗
PubMed1975

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↗
PubMed1982

Methysergide blocks the sleep suppressant action of quipazine in rats.

The aim of the present study was to examine the effect of methysergide, a 5-hydroxytryptamine (5-HT) receptor antagonist, on the sleep suppression produced by the 5-HT receptor agonist, quipazine. Treatment with methysergide maleate (5 mg/kg, IP) 15 min before the administration of quipazine blocked quipazine-induced suppression of flow-wave sleep (SWS), but failed to prevent the decrease in rapid-eye-movement sleep (REMS) produced by quipazine. Treatment with methysergide also prevented the head-shaking behavior induced by quipazine, a phenomenon associated with increased activity of the central serotonergic system. Furthermore, it was shown that administration of methysergide alone (1 or 5 mg/kg, IP) had little effect on sleep or head-shaking behavior. The present data provide pharmacological evidence that the suppression of SWS but not REMS by quipazine may be a result of stimulation of 5-HT receptors.

Animals↗
PubMed1983

The effects of aspirin and methysergide on responses to clot-induced pulmonary embolism.

This study reports the effect of pretreatment of rabbits with aspirin and methysergide on pulmonary vascular and other responses to clots introduced into the lobar pulmonary artery. Pretreatment with 250 mg/kg aspirin significantly (p less than 0.01) reduced the pulmonary artery pressure, the heart rate, and the systemic blood pressure changes induced by embolization. Pretreatment with methysergide 3 mg/kg also significantly (p less than 0.005) reduced the pulmonary artery pressure rise but had no effect on heart rate, systemic blood pressure, or ventilation rate. Pretreatment with a combination of aspirin and methysergide produced an additive effect and reduced the pulmonary artery pressure rise at 2 minutes post embolization from 10 +/- 2 mm Hg in control subjects to 1.3 +/- 0.9 mm Hg. There were no significant alterations in heart rate, systemic blood pressure, or ventilation rate following combined treatment. Responses to arachidonic acid and serotonin were virtually abolished by aspirin and methysergide, respectively. These results suggest a positive role for more than one mediator in the response to clot-induced pulmonary embolism.

Animals↗
PubMed1982

Selective inhibition by methysergide of the monosynaptic reflex discharge in the isolated spinal cord of the newborn rat.

In the isolated spinal cord of the newborn rat, methysergide and LSD-25 depressed the monosynaptic reflex discharge selectively. Cyproheptadine and dimethothiazine did not inhibit the monosynaptic reflex. The selective inhibitory effect of methysergide on the monosynaptic reflex was not due to a presumptive low safety factor of this reflex. The inhibition was restored under a condition such as the compound action potential in the dorsal root was enhanced by 4-aminopyridine. Methysergide did not decrease the sensitivity of the motoneuron to substance P and L-glutamic acid. It is suggested that methysergide acts at the presynaptic terminal of Ia afferent fibers and depresses evoked transmitter release.

Action Potentials↗
PubMed1976

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↗
PubMed1977

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↗
PubMed1985

Methysergide and spinal inhibition from electrical stimulation in the periaqueductal grey.

In barbiturate anaesthetized cats, electrical stimulation in the periaqueductal grey (PAG) selectively inhibited the excitation of multireceptive dorsal horn neurons by noxious heating of the skin or by electrical stimulation of unmyelinated primary afferents. Intravenous methysergide (0.2-1.0 mg/kg) had opposing effects on uninhibited responses, increasing excitation by noxious heat but reducing responses to C fibre stimulation. Evidence was obtained that the increases to noxious heat resulted from increased firing of peripheral nociceptors secondary to decreased cutaneous blood flow. Intravenous methysergide reduced inhibition from PAG stimulation. When administered electrophoretically from micropipettes however, methysergide did not reduce such inhibition. The mechanism whereby systemic methysergide reduces PAG spinal inhibition is unknown and cannot necessarily be related to a blockade of spinally released 5-hydroxytryptamine.

Animals↗