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PubMed1997

Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor.

1. The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 micrograms kg-1, i.v.). 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3-30 micrograms min-1), 5-carboxamidotryptamine (5-CT; 0.01-0.3 microgram min-1), 5-methoxytryptamine (1-100 micrograms min-1) and lisuride (3-1000 micrograms min-1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT > > 5-HT > or = 5-methoxytryptamine > lisuride, whereas cisapride (100-1000 micrograms min-1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85 +/- 7 micrograms kg-1, i.c.), but not cisapride (mean dose of 67 +/- 7 micrograms kg-1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (3-3000 micrograms min-1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200 +/- 33 micrograms kg-1, i.c.) the agonist-induced vasodilator responses. 3. The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (+/-)-pindolol (4 mg kg-1) or ritanserin (100 micrograms kg-1) plus granisetron (300 micrograms kg-1), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30 micrograms kg-1, given after ritanserin plus granisetron), mesulergine (10 and 30 micrograms kg-1), metergoline (1 and 3 mg kg-1), methysergide (1 and 3 mg kg-1) or clozapine (0.3 and 1 mg kg-1). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine. 4. Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-ht7 receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat.

5-Methoxytryptamine↗

PubMed1998

Pharmacological analysis of G-protein activation mediated by guinea-pig recombinant 5-HT1B receptors in C6-glial cells: similarities with the human 5-HT1B receptor.

1. The guinea-pig recombinant 5-hydroxytryptamine1B (gp 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by monitoring G-protein activation in a membrane preparation with agonist-stimulated [35S]-GTPgammaS binding. The intrinsic activity of 5-HT receptor ligands was compared with that determined previously at the human recombinant 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2. Membrane preparations of C6-glial/gp 5-HT1B cells exhibited [3H]-5-carboxamidotryptamine (5-CT) and [3H]-N-[4-methoxy-3,4-methylpiperazin-1-yl) phenyl]-3-methyl-4-(4-pyridinyl)benzamide (GR 125743) binding sites with a pKd of 9.62 to 9.85 and a Bmax between 2.1 to 6.4 fmol mg(-1) protein. The binding affinities of a series of 5-HT receptor ligands determined with [3H]-5-CT and [3H]-GR 125743 were similar. Ligand affinities were comparable to and correlated (r2: 0.74, P<0.001) with those determined at the recombinant h 5-HT1B receptor. 3. [35S]-GTPgammaS binding to membrane preparations of C6-glial/gp 5-HT1B cells was stimulated by the 5-HT receptor agonists that were being investigated. The maximal responses of naratriptan, zolmitriptan, sumatriptan, N-methyl-3-[pyrrolidin-2(R)-ylmethyl]-1H-indol-5-ylmethyl sulphonamide (CP 122638), rizatriptan and dihydroergotamine were between 0.76 and 0.85 compared to 5-HT. The potency of these agonists showed a positive correlation (r2: 0.72, P=0.015) with their potency at the recombinant h 5-HT1B receptor. 1-naphthylpiperazine, (+/-)-cyanopindolol and (2'-methyl-4'-(5-methyl[1,2,4] oxadiazole-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935) elicited an even smaller response (Emax: 0.32 to 0.63). 4. The ligands 1'-methyl-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-carbonyl)-2,3,6,7tetrahydrospiro [furo[2,3-f]indole-3-spiro-4'-piperidine] (SB224289), methiothepin and ritanserin displayed inhibition of basal [35S]-GTPgammaS binding at concentrations relevant to their binding affinity for the gp 5-HT1B receptor. Methiothepin and SB224289 behaved as competitive antagonists at gp 5-HT1B receptors; pA2 values were 9.74 and 8.73, respectively when 5-HT was used as an agonist. These estimates accorded with the potencies measured in antagonism of zolmitriptan-mediated inhibition of forskolin-stimulated cyclic AMP formation. Ketanserin acted as a weak antagonist (pK(B): 5.87) at gp 5-HT1B receptors. 5. In conclusion, the recombinant gp 5-HT1B receptor shares important pharmacological similarities with the recombinant h 5-HT1B receptor. The finding that negative activity occurs at these receptors further suggests that SB224289, methiothepin and ritanserin are likely to be inverse agonists.

Amino Acid Sequence↗

PubMed1998

Modulation of the vagal bradycardia evoked by stimulation of upper airway receptors by central 5-HT1 receptors in anaesthetized rabbits.

1. The effects of central application of 5-HT1A and 5-HT1B/1D receptor ligands on the reflex bradycardia, apnoea, renal sympathoexcitation and pressor response evoked by stimulating upper airway receptors with smoke in atenolol-pretreated anaesthetized rabbits were studied. 2. Intracisternal administration of the 5-HT1A receptor antagonists WAY-100635 (100 microg kg(-1)) and (-)pindolol (100 microg kg(-1)) significantly reduced the smoke-induced bradycardia, attenuated the pressor response and in the case of (-)pindolol, sympathetic nerve activity. The same dose of WAY-100635 i.v. was without effect. 3. Buspirone (200 microg kg(-1), i.c.) potentiated the reflex bradycardia. This action was prevented if the animals were pretreated with WAY-100635 (100 Hg kg(-1), i.v.) 4. (+)8-OH-DPAT (25 microg kg(-1), i.c.) attenuated the evoked bradycardia, pressor response, apnoea and renal sympathoexcitation. The attenuation of the apnoea and renal sympathoexcitation, but not the bradycardia or pressor response was prevented in animals pretreated with WAY-100635 (100 microg kg(-1), i.v.). The attenuation of the reflex bradycardia and the reduction in the renal sympathoexcitation were reduced by pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (100 microg kg(-1), i.v.). 5. In WAY-100635 (100 microg kg(-1), i.v.) pretreated animals, sumatriptan (a 5-HT1B/1D receptor agonist) reduced the reflex bradycardia and the pressor response. The 5-HT1B/1D receptor antagonist GR127935 (20 microg kg(-1), i.c. or 100 microg kg(-1), i.v.) had no effect on the reflex responses. 6. In conclusion, the present data are consistent with the hypothesis that activation of central 5-HT1A receptors potentiate whilst activation of 5-HT1B/1D receptors attenuate the reflex activation of cardiac preganglionic vagal motoneurones evoked by stimulation of upper airway receptors with smoke in rabbits.

Anesthesia↗

PubMed2001

An endogenous 5-HT(7) receptor mediates pigment granule dispersion in Xenopus laevis melanophores.

Melatonin (5-methoxy N-acetyltryptamine) and serotonin (5-HT) exert rapid, but opposite effects on pigment granule distribution in Xenopus laevis melanophores. Low concentrations of melatonin (10(-11) - 10(-9) M) cause a dramatic perinuclear aggregation of the melanin-containing granules, while 5-HT (10(-8) - 10(-5) M) disperses pigment granules throughout the cell. The present study found that pharmacological doses of melatonin (> or =10(-6) M) induced a time- and concentration-dependent pigment granule dispersion, which was mediated by an endogenous melanophore 5-HT receptor. 5-HT produced a concentration-dependent elevation of melanophore cyclic AMP, and 5-HT-induced dispersion was blocked by H89 (10(-4) M), an inhibitor of protein kinase A (PKA), but not by a PKC inhibitor (Ro 31-8220, 10(-5) M), indicating a vital role for cyclic AMP in 5-HT-induced dispersion. 5-HT-mediated dispersion was not blocked by antagonists selective for G(s)-coupled 5-HT(4) (GR113808) or 5-HT(6) (Ro 04-6790, Ro 63-0563, olanzepine) receptors, nor by 5-HT(1 - 3) (pindolol, ketanserine, metoclopramide, MDL72222, tropisetron) receptor antagonists, but was inhibited by a selective 5-HT(7) receptor antagonist, DR4004, and other antagonists with a high affinity for 5-HT(7) receptors. The rank order of antagonist potency was: risperidone (mean pK(B) 7.82)>methiothepin (7.43)>DR4004 (6.92)>mesulergine (6.83)>methysergide (6.60)>[+/-]-sulpiride (5.81)>spiperone (5.52). The agonist potency order [mean pEC(50), 5-CT (8.68)>5-HT (7.13)>5-MT (6.94)>8-OH-DPAT (4.79)>sumatriptan (<4)] was also consistent with an action on 5-HT(7) receptors. RT - PCR confirmed that melanophores express 5-HT(7) receptor mRNA. The pigment dispersing effect of high melatonin concentrations in melanophores is most likely mediated by activation of 5-HT(7) receptors. Conceivably some of the effects attributed to pharmacological doses of melatonin in mammals may be mediated by activation of 5-HT(7) receptors.

Algorithms↗

PubMed2001

SB-272183, a selective 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor antagonist in native tissue.

A novel compound, SB-272183 (5-Chloro-2, 3-dihydro-6-[4-methylpiperazin-1-yl]-1[4-pyridin-4-yl]napth-1-ylaminocarbonyl]-1H-indole), has been shown to have high affinity for human 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with pK(i) values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors. [(35)S]-GTPgammaS binding studies showed that SB-272183 acts as a partial agonist at human recombinant 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with intrinsic activities of 0.4, 0.4 and 0.8 respectively, compared to 5-HT. SB-272183 inhibited 5-HT-induced stimulation of [(35)S]-GTPgammaS binding at human 5-HT(1A) and 5-HT(1B) receptors to give pA(2) values of 8.2 and 8.5 respectively. However, from [(35)S]-GTPgammaS autoradiographic studies in rat and human dorsal raphe nucleus, SB-272183 did not display intrinsic activity up to 10 microM but did block 5-HT-induced stimulation of [(35)S]-GTPgammaS binding. From electrophysiological studies in rat raphe slices in vitro, SB-272183 did not effect cell firing rate up to 1 microM but was able to attenuate (+)8-OH-DPAT-induced inhibition of cell firing to give an apparent pK(b) of 7.1. SB-272183 potentiated electrically-stimulated [(3)H]-5-HT release from rat and guinea-pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5-HT(1B) and 5-HT(1D) receptor antagonist, GR127935. Fast cyclic voltammetry studies in rat dorsal raphe nucleus showed that SB-272183 could block sumatriptan-induced inhibition of 5-HT efflux, with an apparent pK(b) of 7.2, but did not effect basal efflux up to 1 microM. These studies show that, in vitro, SB-272183 acts as an antagonist at native tissue 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors.

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

PubMed2001

Molecular cloning, pharmacological properties and tissue distribution of the porcine 5-HT(1B) receptor.

Using a combination of RT - PCR and inverse-PCR techniques, we amplified, cloned and sequenced a full-length porcine 5-HT(1B) receptor cDNA derived from porcine cerebral cortex. Sequence analysis revealed 1170 bp encoding an open reading frame of 390 amino acids showing a 95% similarity with the human 5-HT(1B) receptor. The recombinant porcine 5-HT(1B) cDNA was expressed in monkey Cos-7 cells and its pharmacological profile was determined by radioligand binding assay using [(3)H]-GR125743. The affinities of several agonists (L694247>ergotamine > or =5-carboxamidotryptamine=dihydroergotamine=5-HT>CP122638=zolmitriptan>sumatriptan) and putative antagonists (GR127935>methiothepin>SB224289>>ritanserin>ketanserin > or =BRL15572) correlated highly with those described for the recombinant human 5-HT(1B) receptor. In membranes obtained from cells co-expressing the porcine 5-HT(1B) receptor and a mutant G(alphao)Cys(351)Ile protein, 5-HT and zolmitriptan increased, while the 5-HT(1B) receptor antagonist SB224289 decreased basal [(35)S]-GTPgammaS binding, thus showing inverse agonism. The potency of zolmitriptan in the [(35)S]-GTPgammaS binding assay (pEC(50): 7.64+/-0.04) agreed with its affinity in displacing the antagonist [(3)H]-GR125743 (pK(i): 7.36+/-0.07). The 5-HT(1B) receptor mRNA was observed by RT-PCR in several blood vessels, cerebral cortex, cerebellum and trigeminal ganglion. In situ hybridization performed in frontal cerebral cortex sections revealed the expression of 5-HT(1B) receptor mRNA in pyramidal cells. In conclusion, we have cloned and established the amino acid sequence, ligand binding profile and location of the porcine 5-HT(1B) receptor. This information may be useful in exploring the role of 5-HT(1B) receptor in pathophysiological processes relevant for novel drug discovery in diseases such as migraine.

Amino Acid Sequence↗

PubMed2002

The atypical 5-HT2 receptor mediating tachycardia in pithed rats: pharmacological correlation with the 5-HT2A receptor subtype.

1. In pithed rats, 5-HT mediates tachycardia both directly (by 5-HT(2) receptors) and indirectly (by a tyramine-like effect). The receptor mediating tachycardia directly has been classified as an 'atypical' 5-HT(2) receptor since it was 'weakly' blocked by ketanserin. Moreover, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2) agonist, failed to mimic 5-HT-induced tachycardia. Since 5-HT(2) receptors consist of 5-HT(2A), 5-HT(2B) and 5-HT(2C) subtypes, this study investigated if these subtypes mediate the above response. 2. In pithed rats, intraperitoneally (i.p.) pre-treated with reserpine (5 mg kg(-1)), intravenous (i.v.) administration of 5-HT, 5-methoxytryptamine (5-MeO-T), 1-(3-chlorophenyl) piperazine (mCPP) and 5-carboxamidotryptamine (5-CT) (10, 30, 100 and 300 microg kg(-1) each), produced dose-dependent tachycardic responses. Interestingly, DOI (10 - 1000 microg kg(-1), i.v.) induced only slight, dose-unrelated, tachycardic responses, whilst the 5-HT(2C) agonist, Ro 60-0175 (10 - 1000 microg kg(-1), i.v.), produced a slight tachycardia only at 300 and 1000 microg kg(-1). In contrast, sumatriptan and 1-(m-trifluoromethylphenyl)- piperazine (TFMPP) were inactive. The rank order of potency was: 5-HT > or =5-MeO-T> mCPP > or =5-CT > or =DOI > Ro 60-0175. 3. The tachycardic responses to 5-HT, which remained unaffected after i.v. saline (0.3 and 1 ml kg(-1)) or propranolol (3 mg kg(-1)), were selectively blocked by the 5-HT(2A) antagonists ketanserin (30 and 100 microg kg(-1)) or spiperone (10 and 30 microg kg(-1)) as well as by the non-selective 5-HT(2) antagonists, ritanserin (10 and 30 microg kg(-1)) or mesulergine (100 microg kg(-1)). Remarkably, these responses were unaffected by the antagonists rauwolscine (5-HT(2B)), SB204741 (5-HT(2B/2C)) or Ro 04-6790 (5-ht(6)) (300 and 1000 microg kg(-1) each). 4. These results suggest that the 'atypical' 5-HT(2) receptors mediating tachycardia in reserpinized pithed rats are pharmacologically similar to the 5-HT(2A) receptor subtype.

Animals↗

PubMed2003

Pharmacological profile of the 5-HT-induced inhibition of cardioaccelerator sympathetic outflow in pithed rats: correlation with 5-HT1 and putative 5-ht5A/5B receptors.

Continuous infusions of 5-hydroxytryptamine (5-HT) inhibit the tachycardiac responses to preganglionic (C7-T1) sympathetic stimulation in pithed rats pretreated with desipramine. The present study identified the pharmacological profile of this inhibitory action of 5-HT. The inhibition induced by intravenous (i.v.) continuous infusions of 5-HT (5.6 microg x kg-1x min-1) on sympathetically induced tachycardiac responses remained unaltered after i.v. treatment with saline or the antagonists GR 127935 (5-HT1B/1D), the combination of WAY 100635 (5-HT1A) plus GR 127935, ritanserin (5-HT2), tropisetron (5-HT3/4), LY215840 (5-HT7) or a cocktail of antagonists/inhibitors consisting of yohimbine (alpha2), prazosin (alpha1), ritanserin, GR 127935, WAY 100635 and indomethacin (cyclooxygenase), but was abolished by methiothepin (5-HT1/2/6/7 and recombinant 5-ht5A/5B). These drugs, used in doses high enough to block their respective receptors/mechanisms, did not modify the sympathetically induced tachycardiac responses per se. I.v. continuous infusions of the agonists 5-carboxamidotryptamine (5-CT; 5-HT1/7 and recombinant 5-ht5A/5B), CP 93129 (r5-HT1B), sumatriptan (5-HT1B/1D), PNU-142633 (5-HT1D) and ergotamine (5-HT1B/1D and recombinant 5-ht5A/5B) mimicked the above sympatho-inhibition to 5-HT. In contrast, the agonists indorenate (5-HT1A) and LY344864 (5-ht1F) were inactive. Interestingly, 5-CT-induced cardiac sympatho-inhibition was abolished by methiothepin, the cocktail of antagonists/inhibitors, GR 127935 or the combination of SB224289 (5-HT1B) plus BRL15572 (5-HT1D), but remained unchanged when SB224289 or BRL15572 were given separately. Therefore, 5-HT-induced cardiac sympatho-inhibition, being unrelated to 5-HT2, 5-HT3, 5-HT4, 5-ht6, 5-HT7 receptors, alpha1/2-adrenoceptor or prostaglandin synthesis, seems to be primarily mediated by (i). 5-HT1 (probably 5-HT1B/1D) receptors and (ii). a novel mechanism antagonized by methiothepin that, most likely, involves putative 5-ht5A/5B receptors.

Animals↗

PubMed2006

Investigation of serotonin receptors in the isolated penile bulb of rats.

The aim of this study was to investigate serotonin (5-HT) receptors in the penile bulb, which have been suggested to play a role in penile erection. Serotonin (10(-7)-3 x 10(-4) M) contracted penile bulbs in a concentration-dependent manner. Ketanserin (5-HT(2A) antagonist, 10(-9)-10(-7) M) and prazosin (alpha(1)-adrenergic receptor blocker, 10(-9)-10(-7) M) suppressed the lower and upper parts of concentration-response curves to 5-HT, respectively. Guanethidine (adrenergic neuron blocker, 5 x 10(-5) M) reduced the responses to 5-HT at only 10(-4) and 3 x 10(-4) M concentrations. NAN-190 (5-HT(1A) antagonist, 10(-8), 10(-7) M) shifted the concentration-response curve to the right with a reduction in the maximum response to 5-HT. While ondansetron (5-HT(3) antagonist, 10(-6)-10(-5) M) and GR55562 (5-HT(1B/1D) antagonist, 10(-6)-10(-5) M) had no effect on the concentration-response curve to 5-HT. The 5-HT(1A) agonist 8-OH-DPAT (10(-7)-3 x 10(-4) M) contracted penile bulbs in a concentration-dependent manner with a lower pD(2) value than that of 5-HT. Sumatriptan (5-HT(1B/1D) agonist, 10(-8)-10(-4) M) did not produce any contractile response in the penile bulbs. Prucalopride, a selective 5-HT(4) agonist (R093877, 10(-7)-3 x 10(-4) M) produced concentration-dependent relaxation in penile bulbs contracted by phenylephrine (10(-5) M). 5-HT(4) agonists cisapride (10(-7)-10(-4) M) and metoclopramide (10(-7)-3 x 10(-4) M) also relaxed the tissue, concentration-dependently. Selective 5-HT(4) antagonists GR125487 (10(-6)-10(-5) M) and GR113808 (10(-6)-10(-5) M) slightly, but not significantly, decreased prucalopride- and cisapride-induced relaxation. Propranolol (beta-adrenergic receptor blocker, 10(-6)-10(-5) M) and L-NOARG (nitric oxide synthase inhibitor, 10(-4) M) had no effect on prucalopride-induced relaxation. These results suggest the existence of alpha(1)-adrenergic, 5-HT(1A) and 5-HT(2A) serotonergic receptors in the penile bulb of rats, which are responsible for 5-HT-induced contraction. Additionally, a serotonergic receptor resembling a 5-HT(4)-type plays a role in the relaxation. The latter receptor is activated by 5-HT(4) agonists, but is not antagonized by 5-HT(4) antagonists.

Animals↗

PubMed1992

Effects of 5-hydroxytryptamine and 5-hydroxytryptamine receptor agonists on ion transport across mammalian airway epithelia.

1. 5-Hydroxytryptamine has been suggested as a candidate for an endogenous inhibitor of airway sodium transport. Amiloride, an inhibitor of epithelial sodium channels, has therapeutic potential in disorders of airway ion transport such as cystic fibrosis, but its duration of action in vivo is short. 5-Hydroxytryptamine and related compounds have been studied to investigate whether any might be a useful alternative to amiloride for clinical use, and to further assess the possible physiological role of 5-hydroxytryptamine in the regulation of airway ion transport. 2. Sheep tracheal epithelium was mounted in Ussing chambers under short-circuit conditions. Mucosal application of 5-hydroxytryptamine resulted in an immediate, reversible, concentration-related decrease in the short-circuit current, maximal with 38% inhibition of the short-circuit current at 25 mmol/l. This response was completely inhibited by pretreatment of tissues with mucosal amiloride (100 mumol/l). These features are consistent with a direct effect of 5-hydroxytryptamine on amiloride-sensitive sodium channels. Similar results were obtained in a limited number of studies using human bronchial epithelium. 3. The effects of mucosal addition of a range of 5-hydroxytryptamine agonists were studied to determine if any was a more potent blocker of amiloride-sensitive sodium transport than 5-hydroxytryptamine. The 5-HT3 agonist 2-methyl-5-hydroxytryptamine had no effect on the short-circuit current at concentrations of up to 5 mmol/l. The 5-HT1D agonist sumatriptan had no effect at concentrations below 5 mmol/l and at 5 mmol/l had only a transient effect.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1999

The haemodynamic effect of the 5HT1 agonist BMS-180048: a class effect of triptans?

AIMS: To investigate the effects of an intravenous infusion of BMS-180048, a novel 5HT1-like agonist, on the systemic, pulmonary and coronary circulations in patients undergoing diagnostic cardiac catheterisation. METHODS: Ten patients (mean age 55 years (range 41-65)) were studied during diagnostic cardiac catheterisation. The haemodynamic response to an intravenous (i.v.) infusion for 30 min of BMS-180048 (0.56 mg kg(-1) h(-1) for 10 min and 0.39 mg kg(-1) h(-1) for 20 min) was assessed via a 7F Swan Ganz catheter and thermodilution cardiac output system. Quantitative coronary angiography was performed at 10 min intervals. RESULTS: BMS-180048 caused a significant increase in systemic arterial systolic blood pressure (rise of 32.5 mmHg, 95% CI 24,44.5) P=0.009), pulmonary artery systolic (12.2 mmHg, 95% CI 6.8,18.5; P=0.009) and diastolic pressures (8.5 mmHg, 95% CI 5.0,13.8; P=0.009), right atrial pressure (4 mmHg, 95% CI 1.5,5.2; P=0.013) and pulmonary capillary wedge pressure (9.5 mmHg 95% CI 5.2,14.0; P=0.09). There was no significant change in cardiac output (0.1 l min(-1), 95% CI -0.17,0.57, P>0.05). Mean coronary artery diameter in the proximal coronary segments decreased by 0.73 mm (95% CI -1.22,-0.15; P=0.03) at 35 min. The corresponding reduction in middle segments was 0.26 mm (95% CI -0.395,-0.08; P=0.02). There was a non-significant trend to constriction in the most distal segments of 0.28 mm (95% CI -0.68,0.015); P=0.06). One patient experienced chest pain with ECG changes suggestive of ischaemia. CONCLUSIONS: BMS-180048 displayed a cardiovascular profile similar to that previously reported for sumatriptan. These changes appear to reflect a class effect of these agents.

Adult↗

PubMed2001

Effect of MAO-A inhibition on the pharmacokinetics of almotriptan, an antimigraine agent in humans.

AIMS: To assess the effect of a reversible MAO-A inhibitor, moclobemide, on the single-dose pharmacokinetics of almotriptan and assess the clinical consequences of any interaction. METHODS: Twelve healthy volunteers received the following treatments in a randomized, open-label, two-way crossover design (with a 1 week washout between treatments): (A) one 150 mg moclobemide tablet every 12 h for 8 days and one 12.5 mg almotriptan tablet on the morning of day 8; and (B) one 12.5 mg almotriptan tablet on day 8. Plasma almotriptan was quantified by h.p.l.c.-MS-MS, while urinary concentrations were measured by h.p.l.c.-u.v. Vital signs, ECGs, and adverse events were evaluated after almotriptan administration. Treatment effects on pharmacokinetics and vital signs were assessed by analysis of variance. RESULTS: Mean almotriptan AUC was higher (483 +/- 99.9 vs 352 +/- 75.4 ng ml-1 h, P = 0.0001) and oral clearance was lower (26.6 +/- 4.00 vs 36.6 +/- 5.89 l h-1, P = 0.0001) when almotriptan was administered with moclobemide. Mean half-life was longer (4.22 +/- 0.78 vs 3.41 +/- 0.45 h, P = 0.0002) after coadministration with moclobemide. Renal clearance of almotriptan was unaffected by moclobemide. No serious adverse events occurred and no clinically significant vital sign changes were observed. CONCLUSIONS: Moclobemide increased plasma concentrations of almotriptan on average by 37%, but the combined administration of these two compounds was well tolerated. The degree of interaction was much less than that seen previously for sumatriptan or zolmitriptan given with moclobemide.

Adolescent↗

PubMedDate not supplied

Migraine: diagnosis and management.

Migraine is the most common form of disabling primary headache and affects approximately 12% of studied Caucasian populations. Non-pharmacological management of migraine largely consists of lifestyle advice to help sufferers avoid situations in which attacks will be triggered. Preventive treatments for migraine should usually be considered on the basis of attack frequency, particularly its trend to change with time, and tract-ability to acute care. Acute care treatments for migraine can be divided into non-specific treatments (general analgesics, such as aspirin or non-steroidal anti--inflammatory drugs) and treatments relatively specific to migraine (ergotamine and the triptans). The triptans--sumatriptan, naratriptan, rizatriptan, zolmitriptan, almotriptan, eletriptan and frovatriptan--are potent serotonin, 5-HT1B/1D, receptor agonists which represent a major advance in the treatment of acute migraine. Chronic daily headache in association with analgesic overuse is probably the major avoidable cause of headache disability in the developed world.

Chronic Disease↗

PubMed1992

Vasoreactivity of the intracranial internal carotid artery.

The vasoreactivity of the intracranial segment of the internal carotid artery to transmitters, present in the perivascular sympathetic, parasympathetic and sensory nerves, as well as to other vasoactive agents of relevance for headache, was tested in man and monkey. The total arterial segment from both species is equipped with contractile receptors for noradrenaline, serotonin, prostaglandin F2 alpha, ergotamine and sumatriptan. Further, the total arterial segment dilated upon exposure to calcitonin gene-related peptide in both species. Other vascoactive transmitters, acetylcholine, substance P and neurokinin A, caused only weak dilatation, restricted to the proximal extracavernous segment in the monkey. The findings are discussed in relation to the pathogenesis and treatment of cluster headache.

Adult↗

PubMed1994

Neuropeptides in migraine and cluster headache.

The cerebral circulation is invested by a rich network of neuropeptide Y (NPY) and noradrenaline containing sympathetic nerve fibers in arteries, arterioles and veins. However, the nerve supply of vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) containing fibers is sparse. While noradrenaline and NPY cause vasoconstriction, VIP, SP and CGRP are potent vasodilators. Stimulation of the trigeminal ganglion in cat and man elicits release of SP and CGRP. Subjects with spontaneous attacks of migraine show release of CGRP in parallel with headache. Cluster headache patients have release of CGRP and VIP during bouts. Treatment with sumatriptan aborts headache in migraine and cluster headache as well as the concomitant peptide release.

Animals↗

PubMed1995

Experimental headache in humans.

The need for valid human experimental models of headache is obvious. Several compounds have been proposed as headache-inducing agents, but only the nitroglycerin (NTG) model has been validated. In healthy subjects, intravenous infusions of the nitric oxide (NO) donor NTG induce a dose-dependent headache and dilatation of the temporal, radial and middle cerebral artery. NTG-induced headache, although less intense, resembles migraine in pain characteristics, but the accompanying symptoms are rarely present. Cephalic large arteries are dilated during migraine headache as well as during NTG headache. N-acetylcysteine enhances the formation of NO and potentiates NTG-induced headache, whereas mepyramine, a H1-antagonist capable of blocking histamine-induced headache, has no effect. Thus, the headache is dependent on NO or other steps in the NO cascade. The model is useful for pharmacological interventions and sumatriptan reduced the NTG-induced headache. The NTG model may be a valuable tool in the development of future migraine drugs.

Cerebrovascular Circulation↗

PubMed1996

Reactions of the middle meningeal artery of the cat to neural and humoral stimulation.

The physiology and pharmacology of the middle meningeal artery was investigated in cats in order to determine whether this artery was subject to normal neural and humoral control mechanisms. Carotid and middle meningeal arterial blood flows and resistances were measured in 16 cats anaesthetized with chloralose. The cervical sympathetic nerves were stimulated electrically. Stimulation of the cervical sympathetic nerves pre-ganglionically reduced blood flow in the middle meningeal artery by producing vasoconstriction in its resistance bed. The vasoconstriction was mediated via catecholamine-containing nerves, as it was abolished by prior intravenous administration of bretylium. Intravenous injections of noradrenaline or adrenaline also produced vasoconstriction in the middle meningeal arterial bed. 5-Hydroxytryptamine (5HT), on the other hand, produced a dilatation in the middle meningeal artery. We conclude that neurally or humorally released catecholamines can provide a plausible mechanism for vasoconstriction in the middle meningeal artery. The dilator effect of 5HT contrasts with the constrictor effect of the 5HT1-like receptor agonist sumatriptan and suggests a complex 5HT receptor pharmacology for the artery.

Adrenergic Fibers↗

PubMed1997

Regional cerebral blood flow and oxygen metabolism during migraine with and without aura.

Eleven cases of migraine with and without aura were investigated with positron emission tomography (PET). Regional cerebral blood flow (rCBF), oxygen metabolism (rCMRO2) and oxygen extraction (rOER) were measured during baseline (n = 11), aura (n = 6), headache (n = 10) and after treatment with sumatriptan (n = 4). Data were analysed using an ROI-based approach from 26 different anatomically defined regions, and also an exploratory approach whereby all subjects were normalized to a stereotactic brain atlas; t-maps were constructed by depicting significant changes between states. The exploratory approach revealed a region corresponding to the primary visual cortex with significant reductions in rCBF (23.1%) and rCMRO2 (22.5%), but no change in rOER during the headache phase compared to baseline. These data suggest that cerebral ischemia was not the primary cause of the attacks in these cases.

Adult↗