Characterization of putative 5‐ht7 receptors mediating direct relaxation in Cynomolgus monkey isolated jugular vein

Abstract

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, a-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 pM), followed by relaxation (1 pMM-32 yM). The contractile effect of x-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-HTIA, 5-HTIB, 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 oa-methyl-5-HT did not start to relax the tissues below a concentration of 10 MM.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.

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

“…This explanation is, however, unlikely in our preparation as we have shown that fetal and 0 ± 24 h rabbit PRAs relax to acetylcholine . 5-HT receptors are known to mediate vasodilation in blood vessels either directly via 5-HT receptors located on the vascular smooth muscle (Cocks & Arnold, 1992;Leung et al, 1996) or indirectly via endothelial released NO (Bodelson et al, 1993;Glusa & Richter, 1993;Glusa & Roos, 1996). We show that, in 4-and 7-day-old rabbit small pulmonary arteries, 5-CT-evoked vasodilation is inhibited by the NO synthase inhibitor L-NAME.…”

“…In other vascular beds, 5-HT can induce endothelium-dependent vasodilation via the 5-HT 2C receptor (Bodelson et al, 1993), the 5-HT 2B receptor (Glusa & Roos, 1996;Ellis et al, 1995) and the 5-HT 1D/1B receptor (Gupta, 1992). There is also evidence that 5-HT can mediate vasodilation directly through 5-HT 4 and 5-HT 7 receptors located on vascular smooth muscle (Cocks & Arnold, 1992;Leung et al, 1996;Terron, 1996).…”

“…Spiperone, however, potently inhibited 5-CTinduced vasodilation in these vessels. Recently, the novel 5-HT 7 receptor has been described and has been found on the vascular smooth muscle of several preparations including the dog coronary artery (Terron, 1996) and Cynomolgus monkey jugular vein (Leung et al, 1996). This receptor is thought to mediate smooth muscle relaxation directly.…”

“…Spiperone displays a high binding a nity for the cloned 5-HT 7 receptor (Roth et al, 1994) and 5-HT 7 receptors located on vascular smooth muscle stimulate adenylate cyclase and mediate vascular relaxation directly (Hoyer et al, 1994;Leung et al, 1996). The pK B of spiperone against 5-CT mediated vasodilation was 7.6 which is comparable with its pK B of 7.1 ± 7.8 at 5-HT 7 receptors in the monkey jugular vein, rabbit femoral vein and dog coronary artery (Martin, 1994;Leung et al, 1996;Terron, 1996). Spiperone has a high a nity for 5-HT 2A receptors (Le & Martin, 1986) but the presence of ketanserin in these studies rules out 5-HT 2A receptors e ects.…”

Antisense Oligonucleotide‐Induced Reduction in 5‐Hydroxytryptamine7 Receptors in the Rat Hypothalamus Without Alteration in Exploratory Behaviour or Neuroendocrine Function

“…In the periphery, the 5-HT7 receptor is expressed in vascular smooth muscle (Ullmer et al, 1995), where activation probably causes relaxation in vitro (Sumner et a!., 1989;Cushing et a!., 1996;Leung et a!., 1996;Villalón et a!., 1997) and the prolonged hypotension following intravenous 5-HT in vivo (De Vries et a!., 1997). Within the CNS, 5-HT7 receptor-mediated effects are less well defined .…”