The animal pharmacology of drugs used in the treatment of migraine

Fozard, John R.

doi:10.1111/j.2042-7158.1975.tb09448.x

Cited by 71 publications

(15 citation statements)

References 102 publications

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“…We believe that our findings with cyproheptadine and methysergide implicate a receptor mechanism mediated via the so-called D-receptor for 5-HT (Gaddum & Picarelli 1957: see also Apperley et al 1980). Both compounds, although chemically distinct, share the property of being potent specific D-receptor blocking drugs in vitro (Fozard 1975;Apperley et a1 1976) and in this study in vivo they had a similar profile of activity being potent and specific antagonists of the vasopressor action of 5-HT. The existence of specific receptors for a naturally occurring substance like 5-HT on adrenal medullary cells is not unprecedented.…”

Section: Effect Of Acute Bilateral Adrenalectomysupporting

confidence: 61%

An analysis of the mechanism of 5-hydroxytrypt-amine-induced vasopressor responses in ganglion-blocked anaesthetized dogs

Feniuk

Hare

Humphrey

1981

Journal of Pharmacy and Pharmacology

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5‐Hydroxytryptamine (5‐HT) administered intravenously (i.v., 1–30 μg kg−1) to ganglion‐blocked anaesthetized dogs produced dose‐related increases in diastolic blood pressure and we have analysed the mechanism involved. Cyproheptadine and methysergide (10–100 μg kg−1 i.v.) were potent and specific antagonists of the 5‐HT induced rise in blood pressure, while the α‐adrenoceptor blocking agent phentolamine (0·3–3 mg kg−1 i.v.) also caused dose‐related inhibition. Syrosingopine pretreatment converted the vasopressor action of 5‐HT to a vasodepressor action and acute bilateral adrenalectomy caused a marked reduction in the 5‐HT‐induced rise in blood pressure. In two dogs, 5‐HT (30 μg kg−1 i.v.) markedly increased the venous plasma concentrations of noradrenaline and adrenaline. We concluded that the 5‐HT‐induced rise in diastolic pressure in the ganglion blocked anaesthetized dog is due largely to the release of catecholamines of which a substantial component is from the adrenal gland. The rise in diastolic blood pressure is specifically blocked by low doses of cyproheptadine and methysergide suggesting that the release of catecholamines is mediated by specific 5‐HT receptors located mainly within the adrenal medulla.

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Section: Effect Of Acute Bilateral Adrenalectomysupporting

confidence: 61%

An analysis of the mechanism of 5-hydroxytrypt-amine-induced vasopressor responses in ganglion-blocked anaesthetized dogs

Feniuk

Hare

Humphrey

1981

Journal of Pharmacy and Pharmacology

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“…However, in several publications it has been obvious that methysergide also possesses agonistic actions. For example, the drug contracts isolated blood vessels (Fozard, 1975;Muller-Schweinitzer & Weidmann, 1978;Apperley et al, 1980;Muller-Schweinitzer, 1983), and it selectively increases resistance in the carotid vascular bed (Saxena, 1974), probably via 5-HT receptors. Moreover, methysergide and the related anti-5-HT drugs, cyproheptadine and mianserin, are not very effective in antagonizing the carotid vasoconstrictor effects of 5-HT (Saxena et al, Correspondence: Professor Pramod R. Saxena.…”

Section: Introductionmentioning

confidence: 99%

Effects of methysergide and 5‐hydroxytryptamine on carotid blood flow distribution in pigs: further evidence for the presence of atypical 5‐HT receptors

Saxena

Verdouw

1984

British J Pharmacology

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1 The effects of acute (50-350 gg kg-, i.v.) and subacute (350 gg kg-l orally per day for six days) administration of methysergide, and of intra-arterial infusions of 0.5 and 2.0 gkg-min-1 5-hydroxytryptamine (5-HT) on the distribution of carotid blood flow into the capillary (nutrient) and arterio-venous anastomotic (AVA) fractions were studied in anaesthetized pigs. 2 The acute, but not the subacute, administration of methysergide caused a moderate reduction of carotid blood flow. This reduction, noticed only in the AVA fraction, was due to a constriction of the arterio-venous anastomoses (AVAs). 3 Both doses of 5-HT reduced total carotid blood flow but its nutrient fraction -particularly that distributed to the skin and ears -increased substantially. The AVA fraction was greatly diminished. 4 After treatment with methysergide, 5-HT no longer reduced the total carotid blood flow, but increased it. Despite this reversal the constriction of AVAs by the amine was only slightly diminished. On the other hand, the vasodilatation of the nutrient channels was enhanced. 5 The results of the interaction between methysergide and 5-HT provide further evidence for the presence of 'atypical' 5-HT receptors (probably corresponding to 5-HT1 binding sites) mediating AVA contraction and nutrient vasodilatation. The 5-HT2 receptors mediate vasoconstriction and are located in the large conducting arteries and possibly, in smaller numbers, in the AVAs and arterioles.

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“…Thus, the concentrations required to elicit these effects (1.0 X 10-6 g/ml) were high by therapeutic standards. Moreover, both ergotamine and methysergide display important pharmacological properties which, because they occur at very much lower concentrations than those re quired to produce the effects seen in the present experiments, present a prior claim for therapeutic relevance (5).…”

Section: Discussionmentioning

confidence: 57%

“…It is this 'free' concentration and any changes in it that is relevant to the migraine syndrome, possibly as a factor controlling normal vascular tone (8) or as a modulator of vascular reactivity (4) or as a potential stimulant of prosta glandin generation and release (5,11).…”

Section: Discussionmentioning

confidence: 99%

Interactions between Antimigraine Drugs and a High Affinity Uptake and Storage Mechanism for 5-Hydroxytryptamine

Fozard¹,

Berry²

1976

Pharmacology

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Rabbit hearts removed ³H-5-hydroxytryptamine (³H-5-HT) from a perfusion concentration of 2.6 X 10^–9 g/ml. 15.8 % of the extractable cardiac total radioactivity consisted of metabolites, mainly 5-hydroxyindoleacetic acid, and metabolites appeared in the perfusion fluid during the course of the perfusion. Ergotamine tartrate (1.0 X 10^-6 g/ ml) caused a small increase in ³H-5-HT uptake by the heart. Methysergide bimaleate (1.0 x 10^–6 g/ml) slowed the appearance of metabolites in the perfusion fluid. Because of the high concentrations required, neither observation seems likely to be of clinical significance to migraine. The results do, however, suggest that the frequently observed sensitisation of tissues to 5-HT by ergotamine and methysergide is not the result of inhibition of its tissue uptake.

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The animal pharmacology of drugs used in the treatment of migraine

Cited by 71 publications

References 102 publications

An analysis of the mechanism of 5-hydroxytrypt-amine-induced vasopressor responses in ganglion-blocked anaesthetized dogs

An analysis of the mechanism of 5-hydroxytrypt-amine-induced vasopressor responses in ganglion-blocked anaesthetized dogs

Effects of methysergide and 5‐hydroxytryptamine on carotid blood flow distribution in pigs: further evidence for the presence of atypical 5‐HT receptors

Interactions between Antimigraine Drugs and a High Affinity Uptake and Storage Mechanism for 5-Hydroxytryptamine

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