In segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by transmural electrical stimulation (2 Hz). Tritium overflow was inhibited by 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibitory potency of the drugs was significantly correlated with their affinity for 5-HTID receptors in human brain and for cloned human 5-HT1D alpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5-HT7 receptors. The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferential 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow. L-694,247, a potent 5-HT1D beta receptor agonist, did not inhibit tritium overflow, but counteracted the inhibitory effect of 5-HT. Ketanserin at a concentration which should block 5-HT1D alpha but not 5-HT1D beta receptors and methiothepin at a concentration which may be assumed to block both 5-HT1D alpha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT. Propranolol and ondansetron did not modify the 5-HT-induced inhibition of release. In conclusion, noradrenaline release in human right atrial appendages is inhibited via 5-HT receptors which are located on the noradrenergic axon terminals. These inhibitory presynaptic 5-HT receptors belong to the 5-HT1D subfamily. The ability of ketanserin to antagonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha.
Imidazoline receptors involved in modulation of noradrenaline release were characterized in the rabbit pulmonary artery preincubated with [3H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol. Tritium overflow was evoked by transmural electrical stimulation. The alpha 2-adrenoceptor blocking imidazolines tolazoline, BDF 6100 [2-(2-imidazoline-2-ylamino)-isoindoline] and BDF 7572 (4,7-dichloro-derivative of BDF 6100) increased the electrically evoked 3H overflow; the concentration-response curves were bell-shaped. In contrast, two other imidazolines, i.e. moxonidine and clonidine, two guanidine derivatives structurally related to BDF 6100, i.e. aganodine and BDF 7579 [4-chloro(2-isoindolinyl)-guanidine], as well as the catecholamine noradrenaline concentration-dependently inhibited the evoked 3H overflow. The concentration-response curves for moxonidine, clonidine, aganodine, BDF 7579 and noradrenaline were shifted to the right by rauwolscine. The apparent pA2 value of rauwolscine against moxonidine was 8.22, whereas those against clonidine, aganodine, BDF 7579 and noradrenaline were in the range of 6.37-6.77 and, hence, considerably lower than reported for alpha 2-adrenoceptors. In the presence of rauwolscine an inhibitory effect was also observed with the alpha 2-adrenoceptor blocking imidazolines tolazoline, BDF 6100, BDF 7572, and the imidazoline ST 587 [2-(2-chloro-5-trifluoromethylphenylimino)-imidazoline]; the rank order of potency of all guanidines and imidazolines investigated was: aganodine greater than BDF 7579 greater than BDF 7572 greater than BDF 6100 greater than clonidine greater than ST 587 greater than moxonidine greater than tolazoline.(ABSTRACT TRUNCATED AT 250 WORDS)
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