thromboxane-a2 and 5-carboxamidotryptamine

1. 5-Hydroxytryptamine (5-HT) receptors mediating contraction and relaxation are present in Cynomolgus monkey isolated jugular vein denuded of endothelium. 2. In the absence of spasmogen, alpha-methyl-5-HT and sumatriptan contracted the tissues with potency values (pEC50) of 6.8 (n = 2) and 6.4 +/- 0.1 (mean +/- s.e. mean, n = 3), respectively. In contrast, 5-HT caused an initial contraction (10 nM - 1 microM), followed by relaxation (1 microM - 32 microM). The contractile effect of alpha-methyl-5-HT was antagonized by ketanserin with a pKB value of 8.1 (n = 2). 5-Carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and 8-OH-DPAT did not contract or relax the tissues in the absence of spasmogen. 3. In tissues precontracted with U46619 (10 nM) and in the presence of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3, and 5-HT4 receptor blockade, 5-CT and 5-MeOT caused endothelium-independent relaxation with potency values of 7.5 +/- 0.1 (n = 21) and 5.7 +/- 0.1 (n = 4), respectively. The potency of 5-HT was 7.2 (n = 2) while alpha-methyl-5-HT did not start to relax the tissues below a concentration of 10 microM. 4. Relaxations elicited by 5-CT were antagonized by the following compounds (with pKB values in parentheses): methiothepin (9.7), mesulergine (8.1), metergoline (8.0), clozapine (7.8), mianserin (7.7), spiperone (7.3), ritanserin (7.1), methysergide (7.0) and ketanserin (5.7). 5. It is concluded that the 5-HT receptor mediating endothelium-independent relaxation may be a functional correlate of the putative 5-ht7 receptor.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Female; In Vitro Techniques; Jugular Veins; Macaca fascicularis; Male; Prostaglandin Endoperoxides, Synthetic; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

1. A series of 5-hydroxytryptamine (5-HT) receptor agonists including 5-HT, 5-carboxamidotryptamine (5-CT) and sumatriptan produced little or no contraction of rabbit isolated mesenteric arteries under resting tone conditions, even at concentrations up to 10(-4) M. 2. When the same agonists were retested in mesenteric artery preparations pre-contracted with the thromboxane-mimetic, U46619, each demonstrated concentration-related vasoconstrictor activity. 5-CT and 5-HT were especially potent and effective in this model giving EC50 values of 4.3 x 10(-9) M and 1.6 x 10(-8) M respectively and maximum effects equivalent to those of KCl 80 mM. In preparations precontracted by U46619 (conditions retained throughout the rest of the study) the order of agonist potency was 5-CT > 5-HT > RU 24969 = sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) > cisapride. 3. The vasoconstrictor effects of 5-CT were competitively antagonized by methiothepin (pA2 8.20) but resistant to antagonism by a range of other 5-HT receptor antagonists, i.e. pindolol (5-HT1A/5-HT1B), propranolol (5-HT1B), spiperone (5-HT2A), ondansetron (5-HT3), ICS 205930 (5-HT3/5-HT4) and SDZ 205557 (5-HT4). 5-CT responses were slightly antagonized by a high concentration of ritanserin (5-HT2A/5-HT2C). Responses to 5-HT and sumatriptan were also antagonized by methiothepin with similar affinity (pA2/pKB values congruent to 8.0). 4. Metergoline and rauwolscine (10(-7)-10(-6) M) antagonized the effects of 5-CT in a non-competitive fashion giving pKBapp values of 7.13 (metergoline) and 6.86 (rauwolscine). 5. Vasoconstrictor responses to 5-HT were not modified in the presence of ritanserin (3 x 10-7 M) orspiperone (3 x 10-7 M) and only modestly antagonized by ketanserin (10-6 M) suggesting that 5-HT2Areceptors do not make a significant contribution in this model.6. Hence, precontraction of rabbit mesenteric arteries reveals potent vasoconstrictor effects of 5-HT and related agonists. Based on the agonist potency order and the antagonist studies performed, the receptor subtype responsible has the characteristics of a 5-HT1-like (probably 5-HTlD) receptor. This study therefore demonstrates a particularly striking example of vasoconstrictor synergy involving 5-HT1-like receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Rabbits; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sumatriptan; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents