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W Feniuk

Publications and source records attributed to W Feniuk.

At least 55 records · Page 3Linked to original sources
PubMed1993

Extracellular recordings of membrane potential from guinea-pig isolated trigeminal ganglion: lack of effect of sumatriptan.

The aim of this study was to investigate the effect of the anti-migraine drug and selective 5-HT1 receptor agonist, sumatriptan, on membrane potential of guinea-pig isolated trigeminal ganglion. Ganglia were divided into three longitudinally, placed in two-compartment baths and the d.c. potential between compartments was recorded extracellularly. Drugs were applied to the Krebs superfusion fluid of one compartment. KCl (3 mmol/l) and GABA (0.1 mmol/l) caused depolarization (0.30 +/- 0.05 and 0.55 +/- 0.08 mV respectively, n = 11-19). 5-HT (1-10 mumol/l) caused small depolarizations (0.06 +/- 0.02 mV, n = 8) but sumatriptan (0.1-10 mumol/l) had no effect on trigeminal ganglion membrane potential. Collagenase pretreatment, to enhance desheathing, or modification of the composition of the Krebs solution failed to reveal any effect of sumatriptan. These data provide no evidence to suggest that sumatriptan inhibits neurotransmission in trigeminal ganglion. However, 5-HT1 receptors may be present in insufficient numbers in the trigeminal ganglion to elicit a change in membrane potential. Further studies are required to investigate the effect of sumatriptan at the level of the sensory nerve terminals within the intracranial vasculature, where 5-HT1 receptors may be concentrated.

Animals↗
PubMed1993

Neurokinin-induced changes in pial artery diameter in the anaesthetized guinea-pig.

1. The effects of selective neurokinin agents on pial artery diameter, measured with an on-line image analyser, have been studied in anaesthetized guinea-pigs in order to characterize the neurokinin receptors present on pial arteries. 2. Perivascular injection of either substance P (0.01-1 microM) or the selective NK1 receptor agonists, substance P methyl ester (SPOMe, 0.01-1 microM) and GR73632 (0.1 microM), increased pial artery diameter. 3. In contrast, the selective NK2 receptor agonist, GR64349 (1 microM), produced a small vasoconstriction while the NK3 receptor-selective agonist, senktide (1 microM) was inactive. 4. Co-administration of GR82334 (1 microM), a selective NK1 receptor antagonist, inhibited the vasodilatation produced by SPOMe (0.1 microM) but not that caused by calcitonin gene-related peptide (CGRP, 0.01 microM). 5. The results are consistent with an involvement of NK1 receptors in the neurokinin-induced increase in guinea-pig pial artery diameter.

Animals↗
PubMed1993

Antagonist effects of seglitide (MK 678) at somatostatin receptors in guinea-pig isolated right atria.

Somatostatin (SS) exerts a negative inotropic effect in isolated atria. Here we report that in guinea-pig isolated right atria, seglitide, a potent cyclic hexapeptide somatostatin agonist, behaves as a competitive somatostatin receptor antagonist with pA2 values against SS14, SS25 and SS28, of 6.50 +/- 0.40, 6.24 +/- 0.08 and 6.09 +/- 0.06, respectively. Seglitide had little or no effect on the negative inotropic action of carbachol or N6-cyclohexyladenosine. Our findings indicate that the receptor-response coupling characteristics of guinea-pig atria are such that in this preparation seglitide has low intrinsic activity and behaves specifically as a somatostatin receptor antagonist.

Adenosine↗
PubMed1993

Characterization of somatostatin receptors in guinea-pig isolated ileum, vas deferens and right atrium.

1. Somatostatin14 (SS14) inhibits neurogenically mediated contractile responses in guinea-pig ileum and vas deferens and exerts a direct negative inotropic action in guinea-pig spontaneously beating right atrium. In this study, the receptors mediating these inhibitory effects have been characterized by comparing the potencies of several cyclic somatostatin analogues. 2. In the guinea-pig ileum, SS14, somatostatin28 (SS28), somatostatin25 (SS25) and several smaller cyclic somatostatin analogues including octreotide, angiopeptin and CGP 23996, inhibited neurogenically mediated contractile responses, each being of similar potency. 3. In contrast, in the guinea-pig vas deferens and right atrium, SS28 was about 30 times more potent than SS14. However, although angiopeptin was nearly as potent as SS14 as an agonist in the vas deferens, in guinea-pig atrium angiopeptin had low intrinsic activity and antagonized the negative inotropic action of both SS14 and SS28 (pKB values of 7.4 and 7.2, respectively). CGP 23996 was 2-7 times weaker than SS14 in guinea-pig vas deferens and atria. 4. Phosphoramidon (1 microM) and amastatin (10 microM) did not influence the potency of SS14 or SS28 in either the guinea-pig ileum or right atrium. In the guinea-pig vas deferens, phosphoramidon and amastatin did not affect the potency of SS28, but enhanced the potency of SS14 about 5 fold. Despite the presence of phosphoramidon and amastatin, SS28 was still more potent than SS14 in the vas deferens. 5. The putative somatostatin receptor blocking drug, cyclo(7-aminoheptanoyl Phe-D-Trp-Lys-Thr[Brl]) (CPP; 1 microM), did not antagonize the effects of either SS14 or SS28 in ileum, vas deferens or atrial preparations. 6. Somatostatin14 did not modify the contractile action of carbachol or alpha,beta-methylene ATP in the ileum and vas deferens respectively, suggesting that the site of the inhibitory effects on neurogenically mediated contractile responses in both preparations was pre-junctional. Consistent with this conclusion was the observation that the inhibitory effect of SS14 was markedly and inversely related to the external Ca2+concentration. The inhibitory effect of SS14 in guinea-pig atrium was only partly dependent on the external Ca2+ concentration.7. The somatostatin receptors mediating the inhibitory effect of SS14 in the ileum and vas deferens can be distinguished by the differential relative potencies of SS14 and SS28. In the former, SS14 and SS28 have similar potency whilst in the latter SS28 is much more potent. In this respect, the somatostatin receptor mediating negative inotropy in the guinea-pig right atrium appears similar to that identified in the vas deferens.8. We suggest that the somatostatin receptor mediating inhibition of neurogenic contraction in the ileum is similar to the recently cloned SSTR2 receptor. In contrast, the somatostatin receptor mediating negative inotropy in the atrium and inhibition of neurotransmission in the vas deferens appears similar to the SSTR4 receptor which recognises SS28 with higher affinity than SS14.

Amino Acid Sequence↗
PubMed1992

Effect of sumatriptan, a selective 5-HT1-like receptor agonist, on pial vessel diameter in anaesthetised cats.

The action of sumatriptan, a selective 5-HT1-like receptor agonist that is effective for the acute treatment of migraine, was compared on pial vessel diameter following perivascular or intravenous administration to anaesthetised cats. Sumatriptan (0.01-10 microM), when microinjected perivascularly, caused a decrease in pial artery diameter (maximum change of -19 +/- 9%; mean +/- SD) but had no effect on the diameter of pial veins. Sumatriptan (1 microM)-induced pial artery vasoconstriction was unaffected by coadministration of ketanserin (1 microM) or ondansetron (1 microM) but was significantly (p less than 0.01) attenuated by methiothepin (1 microM). Intravenous infusion of a clinically effective dose of sumatriptan (64 micrograms/kg/10 min) caused selective carotid vasoconstriction (22 +/- 6% increase in carotid vascular resistance with little or no change in blood pressure or heart rate) and no change in pial artery diameter, although sumatriptan (1 microM) administered perivascularly in these animals before and after the infusion caused pial artery vasoconstriction. These results demonstrate that perivascularly administered sumatriptan causes pial artery vasoconstriction via activation of 5-HT1-like receptors. However, intravenously administered sumatriptan does not cause pial artery vasoconstriction, which suggests that sumatriptan does not readily penetrate the cerebrovascular intima.

Animals↗
PubMed1992

Studies on the mechanism of 5-HT1 receptor-induced smooth muscle contraction in dog saphenous vein.

1. We have investigated the mechanism of smooth muscle contraction evoked by activation of 5-HT1-like receptors in dog isolated saphenous vein. 2. In the presence of the 5-HT2 receptor antagonist, ritanserin (0.1 microM), concentration-effect curves (10 nM-300 microM) for 5-hydroxytryptamine (5-HT)-induced smooth muscle contraction were biphasic. This could be attributed to a direct action on 5-HT1-like receptors at low concentrations of 5-HT (10 nM-10 microM) and an indirect (through the release of noradrenaline from sympathetic neurones) activation of postjunctional alpha-adrenoceptors at higher 5-HT concentrations. In contrast, concentration-effect curves (100 nM-100 microM) for sumatriptan-induced contractions were not biphasic, and were due solely to activation of 5-HT1-like receptors. 3. Smooth muscle contractions evoked either by low concentrations of 5-HT or by sumatriptan were abolished by removal of extracellular calcium and were markedly inhibited, but not abolished, by the calcium channel blocker, verapamil (1-30 microM). In contrast, contractions evoked by high concentrations of 5-HT were markedly less sensitive to removal of extracellular calcium or to verapamil. 4. 5-HT and sumatriptan also inhibited (to a maximum of about 50%) prostaglandin E2 (PGE2, 5 microM)-stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. This effect was mimicked by the alpha 2-adrenoceptor agonist, azepexole (B-HT933) but not by the alpha 1-adrenoceptor agonist, methoxamine.5. In contrast to mediation of smooth muscle contraction, the 5-HT1-like receptor-mediated inhibition of PGE2-stimulated cyclic AMP formation evoked by 5-HT or sumatriptan was not attenuated by removal of extracellular calcium or by verapamil (1 microM).6. A directly-acting inhibitor of adenylyl cyclase, 2',3'-dideoxyadenosine (1 mM) inhibited PGE2-stimulated cyclic AMP formation but did not produce smooth muscle contraction.7. These results suggest that contractile responses of dog isolated saphenous vein arising through activation of 5-HT1-like receptors are associated with both an influx of extracellular calcium ions (to a large extent via voltage-dependent channels) and an inhibition of adenylyl cyclase. However, although these two responses are coupled to the same receptor, they appear to be independent.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation.

1. The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel. 2. Substance P caused concentration-related, endothelium-dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2 alpha. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P. 3. The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 microM) had no effect on the response to substance P. 4. Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2 alpha, caused neurogenically mediated, non-adrenergic non-cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 microM) or by capsaicin (10 microM) treatment. However, the nitric oxide synthesis inhibitor, L-NG-monomethyl arginine methyl ester (L-NMMA) (100 microM) markedly attenuated the response to electrical stimulation. 5. These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission. In contrast, the marked inhibitory effect of L-NMMA on NANC relaxations implicates nitric oxide in NANC neurotransmission in this vessel.

Animals↗
PubMed1992

Rabbit isolated renal artery contractions by some tryptamine derivatives, including 2-methyl-5-HT, are mediated by a 5-HT1-like receptor.

1. Despite the fact that 5-hydroxytryptamine (5-HT)-induced contractions of the rabbit isolated renal artery are mediated by a receptor belonging to the heterogeneous 5-HT1-like category, we observed that the so-called selective 5-HT3 receptor agonist, 2-methyl-5-HT, caused a concentration-dependent contraction of this vessel. This study was therefore undertaken to analyze the effects of 2-methyl-5-HT in the renal artery segments, either quiescent or precontracted with U46619 (10(-7) M). alpha-Methyl-5-HT and 5-methoxytryptamine, which have high affinities for 5-HT2 and 5-HT4 receptors, respectively, were used for comparison. 2. In the precontracted vessel segments, the maximum contractile responses obtained with 2-methyl-5-HT, alpha-methyl-5-HT, 5-methoxytryptamine and 5-HT were similar to those in the quiescent segments. However the pD2 values were higher in the precontracted segments, making them about 4-100 fold more sensitive. 3. Neither MDL 72222 (10(-6) M) nor tropisetron (3 x 10(-6) M) suppressed renal artery contractions elicited by 5-HT, 2-methyl-5-HT, alpha-methyl-5-HT or 5-methoxytryptamine, thus ruling out the involvement of 5-HT3 as well as 5-HT4 receptors. 4. On the other hand, both methiothepin (10(-8) and 10(-7) M) and ketanserin (10(-7) and 10(-6) M) caused a rightward shift of agonist concentration-effect curves.The two antagonists had similar pA2 values against the different agonists tested on either quiescent or precontracted vessels, but ketanserin (apparent pA2: 6.6 to 7.0) was between 20-100 fold less potent than methiothepin (apparent pA2: 8.4 to 8.8).5. The results of this functional study permit us to conclude that the contractile effects of 2-methyl-5-HT as well as ct-methyl-5-HT and 5-methoxytryptamine on the rabbit isolated renal artery are mediated by a 5-HT1-like receptor. Since, in addition, the reported ligand binding affinity of 2-methyl-5-HT at 5-HT3 receptors is similar to both the ligand binding affinity and the functional pD2 at 5-HTI sites, this compound cannot be regarded as a selective 5-HT3 receptor agonist. Similarly, a-methyl-5-HT and 5-methoxytryptamine have only a limited selectivity for 5-HT2 and 5-HT4 receptors, respectively.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

BMY 7378 is an agonist at 5-HT1A receptors mediating hypotension and renal sympatho-inhibition in anaesthetised cats.

The putative 5-HT1A receptor antagonist BMY 7378 (3-100 micrograms.kg-1 i.v.) caused reductions in blood pressure, heart rate and efferent renal nerve activity in anaesthetised cats. Similar effects were produced by the selective 5-HT1A receptor agonist, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT 1-10 micrograms.kg-1 i.v.). The sympatho-inhibitory effects of BMY 7378 and 8-OH-DPAT, but not those of clonidine were reversed by the non-selective 5-HT1A receptor antagonist, spipirone (1 mg.kg-1 i.v.). It is concluded that BMY 7378 is an agonist at 5-HT1A receptors mediating hypotension and renal sympatho-inhibition in anaesthetised cats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Rationale for the use of 5-HT1-like agonists in the treatment of migraine.

Migraine headache is thought to be associated with a dilatation of cranial blood vessels, particularly those in the dura mater, and an accompanying localized sterile inflammatory response. Sumatriptan is a highly selective 5-HT1-like receptor agonist which selectively constricts cranial blood vessels (including those in the dura mater). It also inhibits neurogenically-mediated plasma protein extravasation in the dura mater. Haemodynamic studies in anaesthetized animals have shown that sumatriptan selectively constricts the carotid arterial circulation and this effect appears to be restricted to an effect on carotid arteriovenous anastomoses. Sumatriptan has a much more selective pharmacological profile than ergot preparations which are also used in the acute treatment of migraine. The development of sumatriptan has been based on a vascular theory of migraine and its high degree of efficacy in the treatment of migraine strengthens the argument that dilatation of cranial blood vessels is the cause of vascular headache.

Animals↗
PubMed1991

Vasodilator effect of 8-OH-DPAT in the isolated perfused mesenteric bed of the rat: no evidence for involvement of 5-HT1A receptors.

1. In the isolated perfused mesenteric bed of the rat, bolus administration or infusion of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT; bolus 0.3-90 nmoles, infusion 0.03-30 microM) caused dose-related decreases in phenylephrine-induced tone. 2. These vasodilator responses were not modified by the 5-HT1A receptor antagonists BMY7378 (0.3 microM) or cyanopindolol (0.1 microM). 3. A number of compounds, having a range of affinities for 5-HT1A receptors, were tested in the mesentery and also for antagonist activity at alpha 1-adrenoceptors in the rabbit isolated aorta. 4. The potency of 8-OH-DPAT, flesinoxan, ipsapirone, sumatriptan and phentolamine, at decreasing phenylephrine-induced tone in the mesentery correlated closely with antagonist potency at alpha 1-adrenoceptors (r = 0.99) but not with affinity at 5-HT1A binding sites (r = -0.2). 5. It is concluded that the vasodilator effect of 8-OH-DPAT in the mesenteric bed of the rat most probably reflects alpha 1-adrenoceptor antagonist activity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Vascular 5-HT1-like receptors that mediate contraction of the dog isolated saphenous vein and carotid arterial vasoconstriction in anaesthetized dogs are not of the 5-HT1A or 5-HT1D subtype.

1. There is controversy about whether 5-HT1A receptors mediate contraction of isolated cerebral blood vessels. We have therefore compared the vascular actions of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) with those of the 5-HT1-like receptor agonist, sumatriptan, on the dog isolated saphenous vein, which contains a 5-HT1-like receptor similar to those on cerebral blood vessels, and in the carotid circulation of the anaesthetized dog. 2. 5-Hydroxytryptamine (5-HT), sumatriptan and 8-OH-DPAT each caused contraction of dog isolated saphenous vein with a rank order of agonist potency of 5-HT greater than sumatriptan greater than 8-OH-DPAT and EC50 values (95% confidence limits) of 0.06 (0.04-0.08), 0.3 (0.1-0.8) and 3.9 (2.0-7.5) microM respectively. The maximum contractile effect produced by each agonist was similar. 3. The contractile effects of 5-HT, sumatriptan and 8-OH-DPAT in the dog isolated saphenous vein were resistant to antagonism by the 5-HT1A receptor antagonists spiperone, spiroxatrine and pindolol (all 1 microM). The 5-HT1D receptor ligands, metergoline (0.1 microM) rauwolscine (1 microM) and yohimbine (1 microM) had little or no antagonist activity. In contrast, the non-selective 5-HT1-like receptor blocking drug, methiothepin (0.03-0.3 microM) potently antagonized the contractile effects of 5-HT, sumatriptan and 8-OH-DPAT to a similar degree, suggesting that all three agonists act at the same receptor. 4. In ganglion-blocked, anaesthetized dogs, intra-carotid administration of 8-OH-DPAT (0.3-3 pggkg-1) and sumatriptan (0.1l-1 pgkg -), caused dose-dependent carotid arterial vasoconstriction. The two agonists were approximately equipotent in this respect. 5. The carotid arterial vasoconstrictor actions of 8-OH-DPAT and sumatriptan were not modified by spiperone (1 mgkg- , i.v.) but were antagonized to a similar extent by the subsequent administration of methiothepin (1 mgkg- 1, i.v.). 6. These results suggest that 8-OH-DPAT contracts the dog isolated saphenous vein and constricts the carotid arterial circulation of anaesthetized dogs by activation of 5-HT1-like receptors which are not of the 5-HTlA subtype, nor, on the basis of data with metergoline in the dog isolated saphenous vein, of the 5-HTID subtype. The receptor involved in these actions appears to be the same as that mediating the vasoconstrictor effects of sumatriptan. This receptor does not appear to be like any known 5-HT1 ligand binding site; hence the current description, 5-HT1-like, remains the most appropriate.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Analysis of the 5-HT receptors mediating contractions in the rabbit isolated renal artery.

1. Using a number of agonist and antagonist compounds, we have attempted to characterize the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT) in the rabbit isolated renal artery. 2. In vessel segments precontracted with the thromboxane-mimetic agent, U46619 (100 nM), neither 5-HT (10(-8) to 10(-4) M) nor 5-carboxamidotryptamine (5-CT; 10(-8) to 3 x 10(-4) M) caused relaxations like those observed with methacholine. Both 5-HT and 5-CT further increased the tone of the vessels, with pD2 values of 7.1 and 7.9, respectively. 3. In the absence of U46619, both 5-HT (10(-7) to 3 x 10(-3) M) and 5-CT (10(-7) to 10(-3) M) contracted the rabbit renal artery, but with reduced potencies. The contractions to 5-HT were reproducible and the rank order of potency (pD2) of the agonists was: alpha-methyl-5-HT (5.7), sumatriptan (5.3), 5-HT (5.1), 8-hydroxy-2(di-n-propylamino)tetralin (5.0), 5-CT (4.7) and 5-methoxytryptamine (4.3). 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, flesinoxan and RU 24969 elicited either only small contractions or none at all. 4. The contractile effect of 5-HT was unaffected by MDL 72222 (10(-6) M) and metergoline (10(-8) and 10(-7) M), was weakly antagonized by ketanserin and phentolamine (pKB: 6.6 and 6.8, respectively), but was effectively antagonized by methiothepin (pKB: 8.6). Responses to 5-CT and sumatriptan were affected by ketanserin, phentolamine and methiothepin similarly to 5-HT-induced responses. 5. Ketanserin was ineffective against noradrenaline-induced contractions, which were antagonized by phentolamine with a pKB of 7.3. The pKB values of phentolamine against 5-HT, 5-CT or sumatriptan were about half a log unit lower than against noradrenaline.6. In vascular preparations treated with cocaine (3 x 10- I M), the potency (pKB) of phentolamine as an antagonist of the responses to noradrenaline (7.6) and 5-HT (6.7) did not differ significantly from the values in untreated preparations. However, the difference between the pKB values of phentolamine against the two agonists was now about one log unit.7. Pretreatment of the vascular strips with 6-hydroxydopamine (1.5 x 10- 3M) did not significantly affect responses to 5-HT or 5-CT, but almost eliminated those to tyramine. Cocaine (3 x 10- 5M) slightly potentiated noradrenaline-induced contractions, but did not significantly affect those induced by 5-HT.8. These data suggest that: (i) 5-HT receptors mediating vasodilatation are not present in the rabbit renal artery smooth muscle or endothelium; (ii) the contractile effect of 5-HT does not involve the release of noradrenaline from sympathetic nerve stores; (iii) the 5-HT receptor in the rabbit renal artery is not of the 5-HT2, 5-HT3 or 5-HT4 type. The pharmacological properties of this receptor most closely resemble those described for the heterogeneous 5-HT1-like category.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Preclinical studies on the anti-migraine drug, sumatriptan.

Sumatriptan is believed to constrict selectively the cranial vessels that are distended and inflamed during migraine. The action is mediated by activation of a 5-HT1 receptor subtype which has been shown in animals to be localized in cranial vessels. Further studies to elaborate sumatriptan's precise clinical mode of action have focused on the human meningeal circulation and should lead to a better understanding of the pathogenesis of migraine. Administering [14C]sumatriptan, drug-related material was shown to be well absorbed. Following absorption there was some first-pass metabolism resulting in oral bioavailabilities of 37, 58 and 23% in rat, dog and rabbit, respectively. In all species, circulating sumatriptan was cleared rapidly by metabolic and renal clearance with a half-life of 1-2 h. The indoleacetic acid metabolite is the primary metabolic product; however, rats, mice and rabbits also N-demethylate the methylaminosulphonylmethyl side-chain. The passage of sumatriptan and its metabolites across the blood-brain barrier appeared to be very limited, although some drug could be detected in the cerebrospinal fluid after administration of high intravenous doses. Safety studies in various animal species showed that sumatriptan produced few adverse pharmacodynamic effects when administered acutely, except at high doses, although it was less well tolerated in dogs. No findings of toxicological significance were observed in rats and dogs after chronic dosing for 1 year or more.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Serotonin and migraine.

Migraine has long been considered as a "vascular headache" but clearly neurological mechanisms are involved. The pathophysiology appears to somehow involve serotonin, both peripherally and centrally, but its involvement may be just epiphenomenal. Adding to the enigma it is apparent that many of the presently available drugs for the treatment of migraine interact in one way or another with serotonin receptors. However, they tend to have a number of other unrelated actions and they are only of limited clinical value. Interestingly a promising new drug for the treatment of the acute attack, sumatriptan, has a very selective action as an agonist at a specific 5-HT1-like receptor sub-type, mediating vasoconstriction, which is localized on cranial blood vessels. Its action may, or may not, be independent of any involvement of serotonin in the genesis of migraine. Hopefully though, current attempts to determine sumatriptan's mechanism of action will shed further light on the pathology of migraine itself and the putative involvement of serotonin.

Brain↗