sumatriptan, Imitrex
Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig.

den Boer MO, Somers JA, Saxena PR.

Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.

1. In anaesthetized animals, the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine, reduce carotid arteriovenous anastomotic shunting. Within the carotid vascular bed arteriovenous anastomoses are located, amongst other places in the dura mater, which is a putative site of the pain during a migraine attack. 2. In this investigation, we have localized and measured the arteriovenous shunting within the carotid vascular bed of the pig by using simultaneous intracarotid injections of radiolabelled microspheres of three different sizes (10, 15 and 50 microns), which provides an index of blood flow via arteriovenous anastomoses larger than approximately 14, 27 and 90 microns diameter, respectively. The effects of sumatriptan (0.3 mg kg-1), ergotamine (0.02 mg kg-1), dihydroergotamine (0.1 mg kg-1) and saline were studied by repeating the injections of 15 and 50 microns spheres after the treatments. 3. There was no difference in shunting or entrapment between the 10 and 15 microns microsphere, indicating the absence of arteriovenous anastomoses with a diameter between 14 and 27 microns. 4. Arteriovenous anastomoses with a diameter between 27 and 90 microns, as indicated by the difference in blood flow measured by 15 and 50 microns spheres, were located in the dura mater, ears, skin, fat and, to a lesser extent, in the skeletal muscles and eyes. 5. Sumatriptan, ergotamine and dihydroergotamine reduced the overall flow in the smaller arteriovenous anastomoses (diameter between 27 and 90 microns), and even more in larger shunts (wider than 90 microns). 6. Locally, blood flow in the smaller arteriovenous shunts was reduced in the skin and fat, but not in the dura mater, ears, eyes and muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

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sumatriptan, Imitrex
Agonist-directed trafficking explaining the difference between response pattern of naratriptan and sumatriptan in rabbit common carotid artery.

Akin D, Onaran HO, Gurdal H.

Department of Pharmacology and Clinical Pharmacology, Medical Faculty of Ankara University, Sihhiye, Ankara 06100 Turkey.

1. Sumatriptan or eletriptan produced vasocontraction in common carotid artery (CCA) by stimulating 5HT(1B) receptors (see also Akin & Gurdal, this issue). 2. Naratriptan as a 5HT(1B/D) agonist, was unable to produce vasocontraction in this artery, but inhibited the vasocontractile response induced by sumatriptan or eletriptan. 3. All these agonists inhibited forskolin-stimulated cyclic AMP production with comparable potencies and maximal responses. This inhibition was mediated by 5HT(1B) receptors: 5HT(1B) antagonist SB216641 (1 microM) completeley antagonized sumatriptan-, eletriptan- or naratriptan-induced cyclic AMP inhibition, but 5HT(1D) antagonist BRL15572 (1 microM) did not affect this response. 4. Naratriptan-induced stimulation of 5-HT(1B) receptors resulted only in adenylate cyclase inhibition, whereas stimulation of these receptors by sumatriptan or eletriptan produced vasocontraction as well. Hence, we concluded that the 5HT(1B)-mediated inhibition of adenylate cyclase was not a sufficient condition to couple the receptor stimulation to vasocontraction. 5. We discussed agonist-induced trafficking as a plausible mechanism for the observed phenomenon.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12010764&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Agonist activity of sumatriptan and metergoline at the human 5-HT1D beta receptor: further evidence for a role of the 5-HT1D receptor in the action of sumatriptan.

Miller KJ, King A, Demchyshyn L, Niznik H, Teitler M.

Department of Pharmacology and Toxicology, Albany Medical College, NY 12208.

We have recently cloned a novel human 5-HT1D receptor subtype termed 5-HT1D beta. CHO K1 cells expressing the human serotonin 5-HT1D beta receptor were assayed to determine the second messenger system of this receptor. Cyclic AMP radioimmunoassays revealed that the 5-HT1D beta receptor is negatively coupled to adenylate cyclase in this cell system. A maximum of 50% inhibition of forskolin stimulated cAMP production was obtained with 5-HT1 receptor agonists which was blocked by the non-selective 5-HT receptor antagonist methiothepin (pKB = 100 nM). The novel anti-migraine drug sumatriptan, a putative 5-HT1D selective compound, acted as an agonist at the 5-HT1D beta receptor. Most notably metergoline, a putative 5-HT1 receptor antagonist, did not block the effects of 5-HT and was found to be acting as a full agonist at the 5-HT1D beta receptor. The ability of metergoline to act as an agonist at the 5-HT1D beta receptor may explain why it does not inhibit 5-HT and sumatriptan induced contraction of dog saphenous vein and other large conducting arteries. These results suggest that the 5-HT1D beta receptor may be the site of action of sumatriptan in preventing migraine, and that metergoline's actions on the dog saphenous vein are not contradictory to that hypothesis, as previously reported.

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sumatriptan, Imitrex
Sumatriptan contracts large coronary arteries of beagle dogs through 5-HT1-like receptors.

Parsons AA, Stutchbury C, Raval P, Kaumann AJ.

Smith Kline Beecham Pharmaceuticals, Welwyn, Herts, United Kingdom.

The effects of 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), methysergide and sumatriptan were studied on endothelium-denuded rings of beagle dog large coronary arteries. Submicromolar concentrations of the compounds contracted the rings with the order of potency 5-CT > 5-HT > sumatriptan = methysergide. Concentrations greater than 2 microM of both 5-HT and 5-CT, and 60 mumol/l methysergide also caused concentration-dependent relaxation. Sumatriptan did not cause relaxation. Peak intrinsic activities relative to the plateau contraction to sumatriptan (1.00), were 5-CT 0.47, 5-HT 0.87 and methysergide 0.51. Ketanserin 1 mumol/l affected neither contractile responses nor relaxant responses to 5-CT, methysergide and sumatriptan and only caused marginal blockade of the contractile effects of 5-HT. Methiothepin 200 nM shifted the concentration-contractile response curves by around 2 log units, as expected from its affinity for 5-HT1-like receptors. The rank order of contractile potency of the agonists, the antagonism by methiothepin and the resistance to blockade by ketanserin are consistent with a nearly exclusive involvement of 5-HT1-like receptors. Isolated large coronary arteries from beagle dogs may be a suitable model for the study of human coronary artery 5-HT1-like receptors that are involved in the spasm observed with 5-HT and sumatriptan.

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sumatriptan, Imitrex
Involvement of 5-HT1B and 5-HT1D receptors in sumatriptan mediated vasocontractile response in rabbit common carotid artery.

Akin D, Gurdal H.

Department of Pharmacology and Clinical Pharmacology, Medical Faculty of Ankara University, Sihhiye, Ankara 06100, Turkey.

1. In this study we examined the involvement of 5-HT(1B) and 5-HT(1D) receptors in the vasocontractile response induced by 5-HT(1B/D)-receptor agonist sumatriptan in rabbit common carotid artery (CCA). 2. Immunoblotting experiments using specific antisera against 5-HT(1B) or 5-HT(1D) receptors revealed the presence of one weak (at 93 kD for 5-HT(1B) or at 105 kD for 5-HT(1D)) and one strong band (at 46 kD for 5-HT(1B) or at 52 kD for 5-HT(1D)) in CCA. 3. Sumatriptan-mediated vasocontractile response was antagonized by SB216641 with an apparent pKb value of 8.6, which was consistent with its affinity for 5-HT(1B) receptor. Antagonism by BRL15572 was weak and calculated apparent pKb (6.0) value was consistent with its affinity for 5-HT(1B) subtype (but not for 5-HT(1D) subtype). This result indicates insignificant or no involvement of 5-HT(1D) receptor in the vasocontractile response. 4. The vasocontractile response induced by sumatriptan was highly sensitive to pertussis toxin treatment of CCA. Nicardipine, a calcium channel blocker, also potently antagonized vasocontractile response induced by sumatriptan. 5. 5-HT, but not sumatriptan, stimulated inositol phosphate accumulation in CCA. 6. These results indicate that stimulation of 5-HT(1B) subtype activate a pertussis toxin (PTX) sensitive G protein (Go/Gi) and mediate vasocontraction, in which L-type voltage dependent calcium channels are involved.

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sumatriptan, Imitrex
[Angina pectoris after sumatriptan (Imigran)]

[Article in Danish]

Abrahamsen B, Christiansen BD.

Medicinsk afdeling, Varde Sygehus.

Developed for the treatment of migraine, sumatriptan is an agonist of 5-hydroxytryptamine-1-receptors. Though a pressure sensation is a common complaint, significant ECG changes have not been reported after subcutaneous administration of sumatriptan. A case history is given where angina pectoris after sumatriptan self-administration was experienced on two occasions by a 61-year old man with a history of minor myocardial infarction--without post-infarction angina--two years previously. The angina after sumatriptan was accompanied on both occasions by significant ST-segment depression on ECG-monitoring. An extracranial vasoconstrictor action of sumatriptan in patients with ischaemic heart disease is suggested.

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sumatriptan, Imitrex
The effect of i.v. sumatriptan, a selective 5-HT1-receptor agonist on central haemodynamics and the coronary circulation.

Macintyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS.

Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, University of Glasgow.

1. Sumatriptan (GR43175) is a selective 5-HT1-receptor agonist effective in the acute treatment of migraine. Vasoactive properties in other vascular beds have been suggested by recent in vitro studies. 2. Its effects on coronary artery dimensions and central haemodynamics were assessed in 10 patients undergoing diagnostic coronary arteriography using digital subtraction angiography and invasive haemodynamic monitoring. 3. Following a 10 min i.v. infusion of sumatriptan to a total dose of 48 micrograms kg-1 there was a significant increase (P < 0.05) in systemic and pulmonary arterial pressures. There was a significant reduction in coronary artery diameter from 4.3 +/- 1.6 mm to 3.6 +/- 1.6 mm 12.9 +/- 6.9% (P < 0.001). There was no significant change in heart rate or ECG morphology. 4. Sumatriptan, a 5-HT1-receptor agonist, causes a vasopressor response in the systemic and pulmonary arterial circulations and coronary artery vasoconstriction; in this study there were no clinical sequelae.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1337261&dopt=Abstract sumatriptan Imitrex