bemesetron and 5-carboxamidotryptamine

The pharmacology of prejunctional serotonin (5-HT) heteroreceptors that regulate the release of norepinephrine (NE) was studied in isolated bovine and human iris-ciliary bodies. The effect of exogenous 5-HT and various 5-HT receptor agonists was examined on the release of [3H]-norepinephrine ([3H]NE). Both 5-HT and m-chlorophenyl-biguanide (m-CPBG) caused enhancement in the field-stimulated release of [3H]NE from bovine tissues whereas 5-carboxamidotryptamine (5-CT) had no such effect. On the other hand, 8hydroxy-dipropylaminotetralin (8-OH-DPAT), caused a significant dose-related inhibition of evoked [3H]NE release. In human iris-ciliary bodies, 5-HT caused an inhibitory response on electrically-evoked [3H]NE release at low concentrations but produced an excitatory action at concentrations greater than 3 microM. To further confirm the nature of the prejunctional 5-HT heteroreceptors regulating [3H]NE release, effects of 5-HT3, 5-HT6 and 5-HT7 receptor antagonists were examined on a standard response to 5-HT. All antagonists examined caused a concentration-dependent inhibition of the response elicited by the standard 5-HT-induced response with the following rank order of potency (as measured by IC30 values): MDL-72222 >> SB-258719 > RO-04-690. We conclude that the excitatory prejunctional 5-HT heteroreceptors present in bovine iris-ciliary bodies belong to the 5-HT3 receptor subtype.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Biguanides; Cattle; Ciliary Body; Dose-Response Relationship, Drug; Electric Stimulation; Humans; In Vitro Techniques; Iris; Norepinephrine; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides; Tritium; Tropanes

5-Hydroxytryptamine (5-HT) contracts and relaxes isolated stomach preparations. This study attempts to characterise receptors involved in the contractile response using electrically stimulated circular muscle strips from guinea pig stomach. Electrically induced contractions were abolished by atropine and tetrodotoxin. 5-HT enhanced contractions in corpus and fundus strips with pEC50% values (-log10 of the concentrations causing a 50% increase in twitch height) of 9.6 and 9.1, respectively. 5-Carboxamidotryptamine and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), 5-HT1A receptor agonists, and alpha-methyl-5-HT, an agonist at 5-HT2 receptors, reduced contractions. The 5-HT3 receptor agonist, 2-methyl-5-HT, increased contractions. The effect of 2-methyl-5-HT but not of 5-HT was antagonized by the 5-HT3 receptor antagonist, tropisetron (10(-7) M). The 5-HT3 receptor antagonists, tropisetron, MDL 72222 (1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate), grainsetron and ondansetron, did not modify twitch responses at concentrations below 10(-7) M. Renzapride and metoclopramide, agonists at 5-HT4 receptors, increased contractions and this effect was inhibited by the 5-HT4 receptor antagonist SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) with a pA2 of 7.4. The effect of 5-HT at a submaximal concentration of 10(-8) M was blocked by SDZ 205-557 (10(-6) M). It is concluded that electrically induced contractions in guinea pig stomach strips are enhanced by activation of 5-HT3- and 5-HT4 receptors and are diminished by 5-HT1 receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Aminobenzoic Acid; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Atropine; Benzamides; Binding Sites; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Electric Stimulation; Female; Guinea Pigs; In Vitro Techniques; Indoles; Ligands; Male; Metoclopramide; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; para-Aminobenzoates; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Stomach; Tetrodotoxin; Tropanes; Tropisetron

Peripherally administered serotonin (5-HT) induced a marked increase in the plasma glucagon level in mice. The hyperglucagonemic effects of 5-HT were completely antagonized by methysergide, ketanserin and ritanserin which have a high affinity for 5-HT2 receptors. However, the 5-HT3 receptor antagonist ICS 205-930 and MDL 72222 were without effect. These findings suggest that the activation of the peripheral 5-HT2 receptor induces the increase in plasma glucagon level and that these receptors may play a role in the release of glucagon.

Topics: Animals; Glucagon; Indoles; Injections, Intraperitoneal; Ketanserin; Male; Methysergide; Mice; Mice, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropanes; Tropisetron

1. The aim of the present work was to characterize the presynaptic 5-HT receptors that mediate either the facilitation of the responses to nerve stimulation in the nictitating membrane of the cat or the inhibition of the responses to nerve stimulation in the guinea-pig atria. 2. In the nictitating membrane of the cat, the shift to the left in the frequency-response curves produced by 5-HT (0.1 microM) was prevented by the 5-HT3 receptor antagonists, metoclopramide (1 microM) and MDL 72222 (0.01 microM). 3. The facilitatory effect of 5-HT is also prevented by the 5-HT2 receptor antagonist, 0.01 microM ketanserin. Nevertheless, this drug reduced by itself the responses to both nerve stimulation and exogenous NA in the nictitating membrane. 4. In the guinea-pig isolated atria, the inhibitory effect of 5-HT on the chronotropic responses to cardioaccelerans nerve stimulation was mimicked by the mixed 5-HT1A + 5-HT1B + 5-HT1D receptor agonist 5-carboxamidotryptamine (5-CT 0.1 and 1 microM). The 5-HT1A receptor agonist 8-OH-DPAT (0.1 and 1 microM) did not modify the responses of the atria to the nerve stimulation. 5. The 5-HT2 receptor antagonists, ketanserin (0.01 and 0.1 microM) and cyproheptadine (1 microM), did not prevent the inhibitory effect of 5-HT in the guinea-pig atria. 6. The present results suggest that the facilitatory effects of 5-HT in the nictitating membrane of the cat are linked to the activation of 5-HT3 receptors whereas the inhibitory effects observed in the guinea-pig atria are mediated by 5-HT1-like receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Cats; Cyproheptadine; Female; Guinea Pigs; Heart Rate; In Vitro Techniques; Ketanserin; Male; Membranes; Metoclopramide; Neurons; Norepinephrine; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Sympathetic Nervous System; Tetrahydronaphthalenes; Tropanes

5-HT induced a hyperpolarization of the rat superior cervical ganglion in vitro which was resistant to both MDL 72222 (10 microM), a 5-HT3 antagonist, and ketanserin (1 microM), a 5-HT2 antagonist. The 5-HT1-selective ligands 5-carboxamidotryptamine and 8-OH-DPAT also hyperpolarized the ganglion. The 5-HT-induced hyperpolarization was potently antagonised by spiperone. These results suggest that 5-HT hyperpolarizes the rat superior cervical ganglion via a 5-HT1-like receptor which resembles the central 5-HT1A binding site.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Ganglia, Sympathetic; In Vitro Techniques; Ketanserin; Membrane Potentials; Rats; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes; Tropanes

The actions of intravenously administered 5-hydroxytryptamine (5-HT) have been analysed in conscious DOCA-salt hypertensive rats using selective 5-HT receptor agonists and antagonists to determine the receptor mechanisms involved and to compare them with those in conscious normotensive rats. In both normotensive and hypertensive rats 5-HT, 3 and 10 micrograms i.v., produced a complex triphasic effect on blood pressure consisting of an initial short lasting depressor response, which was followed by a pressor response and then, finally, a hypotensive phase. Marked decreases in heart rate were observed immediately after dosing, which were followed by small increases in rate. The selective 5-HT3-receptor agonist, 2-methyl 5-HT, 3-30 micrograms i.v., produced immediate and marked dose-related decreases in blood pressure and heart rate in both normotensive and DOCA-salt hypertensive rats. The 5-HT3-receptor antagonist, MDL 72222, 0.03 and 0.1 mg/kg i.v., antagonised these effects in both normotensive and DOCA-salt hypertensive rats. Treatment with MDL 72222, 0.3 mg/kg i.v., abolished the initial depressor response and bradycardia produced by 5-HT. The 5-HT2 receptor agonist, alpha-methyl 5-HT, 3-30 micrograms i.v., produced dose-related increases in blood pressure which were significantly greater in magnitude in DOCA-salt hypertensive than normotensive rats. Bradycardia was observed consistently at 30 micrograms only. The 5-HT 2 receptor antagonist, ketanserin, 0.03-0.3 mg/kg i.v., caused a dose-dependent antagonism of the pressor responses produced by alpha-methyl 5-HT, but had no effect on the increases in blood pressure produced by angiotensin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Desoxycorticosterone; Heart Rate; Hemodynamics; Hypertension; Male; Rats; Serotonin; Serotonin Antagonists; Tropanes