[3H]-serotonin release from bovine iris-ciliary body:: Pharmacology of prejunctional serotonin (5-HT7) autoreceptors

In the present study, we investigated the pharmacological characteristics of electrically stimulated [H-3]-serotonin release from mammalian iris-ciliary bodies. Isolated bovine and human iris-ciliary bodies were loaded with [H-3]-serotonin. superfused with Krebs buffer solution and then stimulated with trains of 300 direct current (d.c.) pulses to initiate the release of the transmitter. The modification of this [H-3]serotonin release process by various serotonergic agonists and antagonists was studied in order to define the pharmacology of serotonin receptor(s) present in the iris-ciliary body. In bovine iris-ciliary body. electrically-evoked [H-3]-serotonin release was calcium-dependent, tetrodotoxin-sensitive and was enhanced by serotonin (EC50 = 200 nM) and 5-carboxmidotryptamine (EC50 - 4 nM). The rank order of potency of agonists in enhancing field-stimulated [H-3]-serotonin release was: 5-carboamido-tryptamine > m-chlorophenylbiguanide > 2 -methyl-5-hydroxytryptamine = 5 -methoxy-dimethyltryptamine > serotonin > 5-methoxy-tryptamine >> L-694,247 = alpha -methyl-5-hydroxytryptamine >> CGS 12066A = 8-hydroxy-2-(di-n-propylamino)tetraline. Serotonin and m-chlorophenylbiguanide also enhanced electrically-evoked [3H]-serotonin release from human iris-ciliary bodies with EC(50)s of 3 muM and 30 nM, respectively. The pharmacological profile displayed by serotonin receptor agonists was supported by the potent antagonism of the serotonin-induced enhancement of [H-3]-serotonin release by 5HT(7) receptor antagonists SB-258718 (IC50 = 18.6 +/- 1.2 nM: n = 4) and mesulergine (IC50 = 0.26 +/- 0.05 nM: n = 4). However, antagonists at 5HT(6) and 5HT(3) receptors exhibited a relatively weak blockade of serotonin induced enhancement of field-stimulated [H-3]-serotonin release. These studies have shown the presence of functionally active prejunctional 5HT(7) autoreceptors regulating the release of [H-3]-serotonin from bovine iris-ciliary bodies. Excitatory prejunctional 5-HT autoreceptors also exist in human iris-ciliary bodies. It is possible that these serotonin autoreceptors may have relevance to the by 5HT(7) receptor antagonists SB-258718 (IC50 = 18.6 +/- 1.2 nM: n = 4) and mesulergine regulation of aqueous humor dynamics in the anterior uvea. (C) 2001 Academic Press.