RESUMEN
The in vitro contractile response of the human uterine artery to sumatriptan was compared to that of human cerebral blood vessels. Artery rings were prepared for isometric contraction. Tachyphylaxis to the triptan-induced vascular contraction was observed in the uterine artery, but not in basilar and middle cerebral arteries. To evaluate 5-HT(1) receptor subtypes functionality, concentration-response curves to sumatriptan were performed at 0 and 24 h after uterine artery isolation. Both 10 µmol/l cyanopindolol and 63 nmol/l SB 224,289 (5-HT(1B) receptor antagonists) significantly antagonized the contractile response induced by sumatriptan at 0 h but not after 24 h of uterine artery isolation. The 5-HT(1B/1D) receptor antagonist BRL 15,572 at 10 µmol/l significantly antagonized the sumatriptan contractile response at both experimental conditions. We conclude that the tachyphylaxis to sumatriptan observed in the non-cerebral blood vessels, and not in the cerebral ones, may be due to loss of functionality of the 5-HT(1B) receptor subtype, increasing the safety of triptans.
Asunto(s)
Arteria Basilar/fisiología , Arteria Cerebral Media/fisiología , Receptor de Serotonina 5-HT1B/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Sumatriptán/farmacología , Taquifilaxis/fisiología , Arteria Uterina/fisiología , Adulto , Arteria Basilar/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Arteria Cerebral Media/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Pindolol/análogos & derivados , Pindolol/farmacología , Piperazinas/farmacología , Piperidonas/farmacología , Serotonina/farmacología , Serotonina/fisiología , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Compuestos de Espiro/farmacología , Sumatriptán/antagonistas & inhibidores , Factores de Tiempo , Arteria Uterina/efectos de los fármacosRESUMEN
Tegaserod, a 5-HT(4) receptor agonist, has been used to treat idiopathic constipation and constipation-predominant irritable bowel disease. It has recently been suggested that tegaserod has an affinity for 5-HT(1B) receptors, which mediate vasoconstriction. As some patients have experienced cardiac ischemia during treatment with tegaserod, we assessed contractions to tegaserod in healthy and diseased human isolated coronary arteries and compared the results with those obtained using sumatriptan, an established 5-HT(1B) receptor agonist. Proximal and distal human coronary arteries were divided into sets of healthy and diseased tissues based on functional endothelial responses. Concentration-response curves to tegaserod and sumatriptan were constructed to assess their contractile potential. Tegaserod's antagonist properties at 5-HT(1B) receptors were studied by constructing concentration-response curves to sumatriptan in the absence or presence of tegaserod (1 microM). Sumatriptan induced concentration-dependent contractions, which were greater in distal than in proximal coronary artery segments. In the proximal segments, tegaserod induced contractions only at concentrations of 10 microM or higher, while in distal segments contractions were generally absent. Tegaserod did not antagonize sumatriptan-induced contractions. There was no difference between the results obtained in healthy and diseased coronary arteries. In conclusion, tegaserod induced contractions in human proximal coronary arteries at concentrations 1000 times higher than C(max) (6 mg bid). Hence, tegaserod does not exhibit a relevant vasoconstrictor potential in the human coronary artery. Further, tegaserod did not behave as an antagonist at 5-HT(1B) receptors. Additional studies may be warranted to investigate the use of 5-HT(4) agonists in patients with cardiovascular risk factors.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Indoles/farmacología , Contracción Muscular/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Adolescente , Adulto , Benzamidas/farmacología , Vasos Coronarios/metabolismo , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Piridinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Serotonina 5-HT4/genética , Agonistas del Receptor de Serotonina 5-HT4 , Sumatriptán/antagonistas & inhibidores , Sumatriptán/farmacología , Vasoconstrictores/antagonistas & inhibidores , Vasoconstrictores/farmacología , Adulto JovenRESUMEN
1. It has previously been shown that the antimigraine drug sumatriptan constricts porcine carotid arteriovenous anastomoses via 5-HT1-like receptors, identical to 5-H1B/1D receptors. The recent availability of silent antagonists selective for the 5-HT1B (SB224289) and 5-HT1D (BRL15572) receptor led us to further analyse the nature of receptors involved. 2. In pentobarbitone-anaesthetized, bilaterally vagosympathectomized pigs, sumatriptan (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased carotid arteriovenous anastomotic conductance by up to 70+/-5%. 3. The dose-related decreases in carotid arteriovenous anastomotic conductance by sumatriptan (30, 100 and 300 microg kg(-1), i.v.) remained unchanged in animals treated (i.v.) with 1 mg kg(-1) of BRL15572 (maximum decrease: 72+/-3%), but were significantly attenuated by 1 mg kg(-1) (maximum decrease: 30+/-11%) and abolished by 3 mg kg(-1) (maximum decrease: 3+/-7%) of SB224289. The highest dose of SB224289 did not attenuate the hypertension, tachycardia or increases in carotid blood flow induced by bolus injections of noradrenaline (0.1-3 microg kg(-1), i.v.). 4. The results indicate that sumatriptan constricts porcine carotid arteriovenous anastomoses primarily via 5-HT1B, but not via 5-HT1D receptors.
Asunto(s)
Anastomosis Arteriovenosa/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Sumatriptán/farmacología , Vasoconstrictores/farmacología , Animales , Compuestos de Bifenilo/farmacología , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Piperazinas/farmacología , Piperidonas/farmacología , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Antagonistas de la Serotonina/farmacología , Compuestos de Espiro/farmacología , Sumatriptán/antagonistas & inhibidores , Porcinos , Simpatectomía , Vagotomía , Vasoconstrictores/antagonistas & inhibidoresRESUMEN
The antinociceptive effect of the antimigraine drug sumatriptan was assessed in mice (hot-plate and abdominal constriction tests). Antinociception induced by sumatriptan (10-30 mg kg-1 i.p.) was prevented by the muscarinic antagonist atropine (5 mg kg-1 i.p.), the ACh-depletor hemicolinium-3 (1 microgram per mouse i.c.v.) and the 5-HT1A antagonist NAN-190 (0.5 mg kg-1 i.p.). Naloxone, CGP-35348 and reserpine administered in doses suitable for blocking analgesia respectively induced by morphine, baclofen and clomipramine did not modify sumatriptan antinociception. On the basis of the above findings, we can deduce that sumatriptan was able to induce antinociception by increasing cholinergic neurotransmission through the stimulation of 5-HT1A receptors.
Asunto(s)
Analgésicos/farmacología , Umbral del Dolor/efectos de los fármacos , Receptores Colinérgicos/efectos de los fármacos , Sumatriptán/farmacología , Animales , Atropina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas del GABA/farmacología , Hemicolinio 3/farmacología , Masculino , Ratones , Compuestos Organofosforados/farmacología , Piperazinas/farmacología , Sumatriptán/antagonistas & inhibidoresRESUMEN
It has recently been shown that the external carotid vasoconstrictor response to 5-HT in the dog is primarily mediated by sumatriptan-sensitive 5-HT1-like receptors; however, the fact that these receptors are not blocked by metergoline, a 5-HT1D ligand, raises questions about their possible correlation with the 5-HT1D receptor subtype. Since a number of drugs display high affinity for the 5-HT1D (GR127935) and 5-HT1F (e.g. methysergide and oxymetazoline) receptor subtypes, in this study we have used these drugs to determine whether the above vasoconstrictor 5-HT1-like receptors correlate with the 5-HT1D and/or 5-HT1F receptor subtypes. One-minute intracarotid infusions of 5-HT (0.3-30 micrograms/min), sumatriptan (1-30 micrograms/min), oxymetazoline (0.03-3 micrograms/min) and noradrenaline (0.3-3 micrograms/min) resulted in dose-dependent decreases in external carotid blood flow without changes in arterial blood pressure or heart rate. These vasoconstrictor responses remained unaltered after i.v. administration of physiological saline (0.015, 0.05 and 0.15 ml/kg; n = 4) or ritanserin (1 mg/kg; n = 5). In contrast, GR127935 (1, 3 and 10 micrograms/kg, n = 6) potently blocked the responses to 5-HT (unmasking a dose-dependent vasodilator component) and sumatriptan without affecting those to oxymetazoline or noradrenaline. Interestingly, methysergide (10, 30 and 100 micrograms/kg, n = 5) also blocked the vasoconstrictor responses to 5-HT and sumatriptan, but unlike GR127935, did not revert the vasoconstrictor response to 5-HT; the responses to oxymetazoline remained unaffected, but those to noradrenaline were apparently attenuated by the highest dose. Taken together, the above findings suggest that the sumatriptan-sensitive 5-HT1-like receptors mediating canine external carotid vasoconstriction resemble 5-HT1D receptors, probably of the 5-HT1D beta subtype on the basis of the resistance to blockade by ritanserin. The pharmacological profile of these receptors could be similar (bovine and human cerebral arteries, porcine carotid arteriovenous anastomoses and human coronary arteries) to other putative 5-HT1D receptors mediating vascular responses.
Asunto(s)
Arteria Carótida Común/efectos de los fármacos , Oxadiazoles/farmacología , Piperazinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Sumatriptán/farmacología , Vasoconstricción/efectos de los fármacos , Análisis de Varianza , Animales , Presión Sanguínea/efectos de los fármacos , Arteria Carótida Común/fisiología , Perros , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Metisergida/farmacología , Receptores de Serotonina/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Ritanserina/farmacología , Sumatriptán/antagonistas & inhibidoresRESUMEN
1. It has previously been shown that the antimigraine drug, sumatriptan, a putative 5-HT1D receptor agonist, decreases porcine common carotid and arteriovenous anastomotic blood flows, but slightly increases the arteriolar (capillary) blood flow to the skin and ears. Interestingly, such responses, being mediated by 5-HT1-like receptors, are resistant to blockade by metergoline, which, in addition to displaying a very high affinity for (and occasionally intrinsic efficacy at) the 5-HT1D receptor subtypes, blocks (with lower potency than methiothepin) some 5-HT1D receptor-mediated vascular responses. These findings raise doubts whether sumatriptan-sensitive 5-HT1-like receptors mediating changes in the distribution of porcine carotid blood flow are identical to cloned 5-HT1D receptors. With the recent advent of the potent and selective 5-HT1D receptor antagonist, GR127935, we have examined in the present study whether the carotid vascular effects of sumatriptan in the pig are amenable to blockade by GR127935. 2. In animals pretreated with saline, sumatriptan (30, 100 and 300 micrograms kg-1, i.v.) reduced the total carotid and arteriovenous anastomotic blood flows in a dose dependent manner. In contrast, sumatriptan increased blood flow to the skin, ears and fat, although the total capillary fraction was not significantly affected. 3. While GR127935 pretreatment (0.25 and 0.5 mg kg-1) itself slightly reduced the total carotid and arteriovenous anastomotic blood flows, carotid vasoconstrictor responses to sumatriptan were either partly (0.25 mg kg-1) or completely (0.5 mg kg-1) blocked by the compound. In GR127935 pretreated animals, the sumatriptan-induced increases in blood flow to the skin, ears and fat were also attenuated. 4. Taken together, the results suggest that arteriovenous anastomotic constriction and, possibly, arteriolar dilatation in the skin, ears and fat by sumatriptan are mediated by 5-HT1D receptors. Therefore, vascular 5-HT1-like receptors in the porcine carotid bed appear to be identical to 5-HT1D receptors.
Asunto(s)
Arteria Carótida Común/efectos de los fármacos , Oxadiazoles/farmacología , Piperazinas/farmacología , Antagonistas de la Serotonina/farmacología , Sumatriptán/antagonistas & inhibidores , Animales , Anastomosis Arteriovenosa/efectos de los fármacos , Anastomosis Arteriovenosa/fisiología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Arteria Carótida Común/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Receptores de Serotonina/fisiología , PorcinosRESUMEN
1. The monosynaptic reflex (MSR), recorded in vitro from the neonatal rat spinal cord, was depressed by 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), methysergide and R(+)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and also by the selective 5-HT1D agonists, sumatriptan and N-methyl-3-(1-methyl-1-piperidinyl)-1H-indole-5-ethane sulphonamide (GR 85548). 2. Ketanserin (1 microM) and methiothepin (1 microM) reduced the duration of depressions elicited by 5-CT, but not those produced by 5-HT, sumatriptan, GR 85548, methysergide or 8-OH-DPAT. 3. The IC50 for MSR depression by 5-CT was 3.6, 2.1-6.2 nM (n = 4), by sumatriptan was 15.2, 12.9-18.0 nM (n = 32), by GR 85548 was 18.4, 11.7-29.1 nM (n = 12), by methysergide was 29.8, 10.2-87.1 nM (n = 4) and by 8-OH-DPAT was 0.21, 0.11-0.43 microM (n = 3) (geometric means and 95% confidence limits). 4. Ketanserin (0.1 or 1 microM) antagonized competitively responses to sumatriptan (apparent pA2 7.8 +/- 0.1, n = 5), GR 85548 (apparent pA2 7.6, unpaired data, n = 5), methysergide (apparent pA2 7.9 +/- 0.12, n = 4) and 8-OH-DPAT (apparent pA2 8.3 +/- 0.1, n = 3). Concentration-response curves to 5-CT showed a smaller, parallel shift to the right (apparent pA2 6.8 +/- 0.1, n = 4), but responses to 5-HT were unaffected by ketanserin (1 microM) (n = 4). 5. Methiothepin (1 microM) antagonized competitively responses to GR 85548 (apparent pA2 7.7, unpaired data, n = 5). 6. Mianserin (0.3 microM), a concentration sufficient to cause substantial block of 5-HT2C-mediated responses but have only a small effect on 5-HT1D-mediated actions, caused a small, non-parallel shift of the concentration-response curve to sumatriptan. 7. Depression of the MSR by sumatriptan was not blocked by (+/-)-cyanopindolol (0.1 microM), (+/-)-propranolol (0.5 or 1 microM) or spiroxatrine (0.1 microM), and depression of MSR by 8-OH-DPAT was not blocked by spiroxatrine (0.1 microM). (+/-)-Cyanopindolol (0.1 and 1 microM) itself induced a slow depression of the MSR. 8. The novel 5-HT1D antagonist, N-[4-methyl-1-piperazinyl) phenyl]2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide (GR 127935, 30 nM to 1 microM) caused a concentration-related depression of the reflex (up to 50%) usually slow in onset. Neither with these concentrations nor with concentrations in the range 1-3 nM was there any unequivocal blockade of responses to sumatriptan. 9. It is concluded that sumatriptan, GR 85548, methysergide and 8-OH-DPAT depress the MSR in the neonate rat spinal cord via ketanserin-sensitive receptors, which have some similarities to 5-HT1D alpha receptors but which are not blocked by GR 127935. 5-HT released by tryptaminergic pathways may act via the same receptors to depress the MSR. 5-HT applied to the cord probably acts via a different, possibly novel 5-HT receptor to depress the MSR.