ly-53857 and alpha-methylserotonin

In the presence of NMDA receptor open-channel blockers [Mg(2+); (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801); 1-amino-3,5-dimethyladamantane (memantine)] and TTX, high concentrations (30-100 microm) of either 5-hydroxytryptamine (5-HT) or alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) significantly potentiated NMDA-induced depolarizations of frog spinal cord motoneurones. Potentiation was blocked by LY-53,857 (10-30 microm), SB 206553 (10 microm), and SB 204741 (30 microm), but not by spiroxatrine (10 microm), WAY 100,635 (1-30 microm), ketanserin (10 microm), RS 102221 (10 microm), or RS 39604 (10-20 microm). Therefore, alpha-Me-5-HT's facilitatory effects appear to involve 5-HT(2B) receptors. These effects were G-protein dependent as they were prevented by prior treatment with guanylyl-5'-imidodiphosphate (GMP-PNP, 100 microm) and H-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp-Met-NH(2) (GP antagonist 2A, 3-6 microm), but not by pertussis toxin (PTX, 3-6 ng ml(-1), 48 h preincubation). This potentiation was not reduced by protein kinase C inhibition with staurosporine (2.0 microm), U73122 (10 microm) or N-(2-aminoethyl)-5-isoquinolinesulfonamide HCl (H9) (77 microm) or by intracellular Ca(2+) depletion with thapsigargin (0.1 microm) (which inhibits Ca(2+)/ATPase). Exposure of the spinal cord to the L-type Ca(2+) channel blockers nifedipine (10 microm), KN-62 (5 microm) or gallopamil (100 microm) eliminated alpha-Me-5-HT's effects. The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W7) (100 microm) diminished the potentiation. However, the calcium/calmodulin-dependent protein kinase II (CaM Kinase II) blocker KN-93 (10 microm) did not block the 5-HT enhancement of the NMDA responses. In summary, activation of 5-HT(2B) receptors by alpha-Me-5-HT facilitates NMDA-depolarizations of frog motoneurones via a G-protein, a rise in [Ca(2+)](i) from the entry of extracellular Ca(2+) through L-type Ca(2+) channels, the binding of Ca(2+) to calmodulin and a lessening of the Mg(2+) -produced open-channel block of the NMDA receptor.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Calcium; Calcium Channel Blockers; Calcium-Calmodulin-Dependent Protein Kinases; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Ergolines; Excitatory Amino Acid Antagonists; Gallopamil; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Indoles; Magnesium; Memantine; Membrane Potentials; Motor Neurons; N-Methylaspartate; Nifedipine; Protein Kinase C; Pyridines; Rana pipiens; Receptor, Serotonin, 5-HT2B; Receptors, N-Methyl-D-Aspartate; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Cord; Staurosporine; Sulfonamides; Tetrodotoxin

The present experiment was performed to investigate the haemodynamic effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT) in the anaesthetised normotensive rat. DOI (1-300 micrograms/kg i.v.) increased mean arterial pressure (MAP), total peripheral resistance (TPR) and decreased cardiac output (CO) and heart rate (HR). DOI increased all vascular resistances investigated (hindquarters, mesenteric and renal). Alpha-methyl-5-HT (10-300 micrograms/kg i.v.) dose-dependently increased MAP, TPR, all regional vascular resistances and decreased CO and HR. The bradycardia induced by alpha-methyl-5-HT was suppressed by bivagotomy. Both DOI and alpha-methyl-5-HT were more effective on renal vascular bed than hindquarters and mesenteric vascular beds. The effects of DOI and alpha-methyl-5-HT were antagonised by spiperone (10 or 100 micrograms/kg i.v.) and LY 53857 (10 micrograms/kg i.v.). Intracerebroventricular administration of DOI (100 micrograms/kg) increased MAP, TPR, regional vascular resistances and did not change HR and CO. Pretreatment with xylamidine (10 micrograms/kg i.v.), a selective peripheral 5-HT2 receptor antagonist, blocked i.v. and i.c.v. effects of DOI. These results suggest that: 1) the increase in MAP induced by DOI and alpha-methyl-5-HT is due to an increase in TPR. All regional vascular beds and in particular the renal vascular bed participate in the increase of TPR. 2) Peripheral--and may be--central 5-HT2 receptors seem to be implicated in the control of regional vascular resistances. 3) Cardiac effects of alpha-methyl-5-HT are baroreflexly-mediated whereas those of DOI are--at least in part--centrally mediated.

Topics: Amphetamines; Animals; Dose-Response Relationship, Drug; Ergolines; Hemodynamics; Injections, Intravenous; Injections, Intraventricular; Male; Rats; Rats, Wistar; Regional Blood Flow; Renal Circulation; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiperone; Splanchnic Circulation

Serotonin-induced contraction in porcine coronary artery was studied in ring segments of coronary artery without endothelium. 5-hydroxytryptamine (5-HT), 5-methoxytryptamine (5-MeOT) and alpha-methyl-5-HT (alpha Me-5-HT) concentration-dependently contracted vessels with similar maximal force. The agonist rank order potency was 5-HT > alpha Me-5-HT > 5-MeOT. Neither prazosin (1 microM) nor tetrodotoxin (0.3 microM) significantly altered 5-HT-induced contraction, ruling out activation of alpha-1 adrenoceptors and sodium channels in the contractile response, respectively. Using 5-MeOT as the prototype agonist, cyanopindolol blocked contraction with an antagonist dissociation constant lower than expected for 5-HT1-receptor blockade and ICS 205-930 (10 microM) did not affect 5-MeOT-induced contraction. Five structurally distinct 5-HT2-receptor antagonists (ketanserin, cisapride, spiperone, MDL11939, ICI169369) blocked 5-HT-induced contraction with antagonist dissociation constants similar to reported 5-HT2-receptor affinities. Two ergoline-based 5-HT2-receptor antagonists, LY53857 and sergolexole, blocked 5-HT-induced contraction with antagonist dissociation constants lower than expected for vascular 5-HT2-receptor blockade. Based on the agonist profile and the fact that ICS 205-930 and cyanopindolol were not potent antagonists, the 5-HT receptor-mediating contraction does not represent either the 5-HT1A/B/C/D, 5-HT3 or 5-HT4 receptor. Rather, based on the affinity of several established 5-HT2-receptor antagonists, a 5-HT2 receptor mediates contraction in porcine coronary artery. However, the low antagonist affinity of the ergolines (i.e., LY53857 and sergolexole) suggests that heterogeneity of 5-HT2 receptors may exist among species.

Topics: 5-Methoxytryptamine; Animals; Coronary Vessels; Endothelium, Vascular; Ergolines; In Vitro Techniques; Lysergic Acid; Muscle Contraction; Muscle, Smooth, Vascular; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Swine

Intravenously administered 5-HT and the 5-HT3 selective agonist, 2CH3-5-HT, and the 5-HT2 selective agonist, alpha-CH3-5-HT, transiently increased heart rate in conscious, instrumented dogs. 5-HT, alpha-CH3-5-HT and 2CH3-5-HT increased systolic blood pressure in conscious dogs. The increase in blood pressure produced by alpha-CH3-5-HT was blocked by the 5-HT2 selective antagonist, LY53857, supporting a role for vascular 5-HT2 receptors in the pressor response to these amines. In contrast, LY53857 did not antagonize tachycardia produced by 2CH3-5-HT. Furthermore, propranolol also did not block 2CH3-5-HT-induced tachycardia, indicating that an indirect neuronal effect to release norepinephrine cannot explain the increase in heart rate to 2CH3-5-HT. Tachycardia to 2CH3-5-HT (as well as to isoproterenol) was modestly inhibited, but never abolished by interruption of the autonomic nervous system with atropine or hexamethonium. 5-HT3 receptor antagonists, zacopride, ICS 205-930 and GR38032F, dose-dependently blocked the tachycardia and pressor response to 2CH3-5-HT. These data establish the presence of a 5-HT3 receptor mediating a direct positive chronotropic effect of 5-HT in conscious dogs, an effect that depends, only minimally, on the presence of an intact autonomic nervous system.

Topics: Animals; Benzamides; Blood Pressure; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Ergolines; Heart Rate; Hexamethonium; Hexamethonium Compounds; Imidazoles; Indoles; Male; Ondansetron; Receptors, Serotonin; Serotonin; Tropisetron

Administration of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI, 0.125-2.0 mg/kg i.v.) triggered dose-dependent increases in plasma glucose; plasma insulin levels remained unchanged. Pretreatment with the 5-HT1C/5-HT2 receptor antagonists LY 53857, ritanserin, or the mixed 5-HT2/alpha 1-adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT1C receptor agonists/5-HT2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-trifluoromethyl)phenyl)piperazine level (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The alpha 2-adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, Whilst the alpha 1-adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT1C/5-HT2 receptor agonist alpha-methyl-5-HT (0.5-1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished alpha-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT2 receptors, but not 5-HT1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT2 receptors may affect glycemia.

Topics: Amphetamines; Animals; Blood Glucose; Catecholamines; Ergolines; Hyperglycemia; Insulin; Male; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin

Serotonin is a biogenic amine that can exert multiple effects on smooth muscle, including smooth muscle of the genitourinary tract; effects that may be species dependent. The present study using isolated tissues documents potent contractile responses to serotonin in canine bladder smooth muscle. Contractile responses to serotonin in canine bladder could be mimicked by alpha-methyl serotonin, a selective 5HT2 receptor agonist. In fact, although alpha-methyl serotonin was slightly less potent as a contractile agonist relative to serotonin, the contractile response to alpha-methyl serotonin was more persistent as evidenced by a greater recovery time to resting force following washout. In contrast, the 5HT1A receptor agonist, 8-OH-DPAT and the 5HT3 selective agonist, 2-methyl serotonin, did not markedly contract canine bladder. These data establish that contractile responses to serotonin in the canine bladder are mediated by activation of 5HT2 receptors. We further demonstrated that the 5HT2 receptor antagonist, LY53857, potently inhibited the contractile response to both serotonin and alpha-methyl serotonin in the canine bladder consistent with agonist activation of 5HT2 receptors. In contrast to the potent response to serotonin observed in the canine bladder, rat bladder preparations did not markedly contract in response to serotonin, alpha-methyl serotonin, 8-OH-DPAT, or 2-methyl serotonin. Thus, these studies reinforce the marked species variability in responsiveness to serotonin and indicate that contraction to serotonin in the canine bladder is mediated by activation of the 5HT2 receptor.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Dogs; Dose-Response Relationship, Drug; Ergolines; Female; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Rats; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Species Specificity; Tetrahydronaphthalenes; Urinary Bladder

1. 5-Hydroxytryptamine (5-HT) was applied by microiontophoresis in the vicinity of identified sympathetic preganglionic neurones in the upper thoracic spinal cord of the rat, in vivo. 2. Sympathetic preganglionic neurones responded in one of three ways to 5-HT: by (a) excitation (76%), (b) inhibition (4%) or (c) in a biphasic manner (5%). 3. The excitatory responses evoked by 5-HT were mimicked by 5-carboxamidotryptamine (5-CT) and alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT). The inhibitory and biphasic responses evoked by 5-HT were mimicked by 2-methyl-5-hydroxytryptamine (2-Me-5-HT). The observed responses evoked by 5-HT and selective agonists may be different on the same cell. In several instances a single neurone excited by one agonist was inhibited by another agonist. 4. The 5-HT2-receptor antagonists, ketanserin and LY 53857, failed to abolish selectively the excitatory responses evoked by 5-HT and alpha-Me-5-HT, when applied by microiontophoresis. The antagonists non-selectively reduced the excitatory responses evoked by 5-HT, 5-CT, alpha-Me-5-HT, D,L-homocysteic acid (DLH) and noradrenaline (NA). A reduction in synaptically evoked activity was also observed. 5. The 5-HT3-receptor antagonist, ICS 205-930, failed to abolish the inhibitory responses evoked by 5-HT. 6. It was concluded that the excitatory responses evoked by 5-HT are mediated by a receptor that is neither 5-HT2 or 5-HT3, but shows similarities to the 5-HT1-like receptor profile. The inhibitory actions of 5-HT are mimicked by 2-Me-5-HT, but the receptor is not 5-HT3, or 5-HT1-like or 5-HT2.

Topics: Anesthesia; Animals; Electric Stimulation; Ergolines; Ganglia, Sympathetic; Homocysteine; Indoles; Iontophoresis; Ketanserin; Male; Neurons; Norepinephrine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tropisetron