Prejunctional 5-HT receptors enhance cholinergic neurosecretion in the rabbit and human iris-ciliary body.
OBJECTIVE
To characterize prejunctional 5-HT heteroreceptors which modulate 3Hacetylcholine (3H-ACh release) in isolated rabbit and human iris-ciliary bodies (ICB3).


METHODS
ICB tissue segments were incubated with 3H-choline, superfused and electrically stimulated four times (S1, S2, S3, S4) at 3-10 Hz for 1 min to elicit 3H-ACh. secretion. Test agents (5-HT agonists and antagonists) were added before S2, S3 and S4 and their effects determined by the stimulation ratio (Sx/S1) of evoked 3H-ACh. release. 3H-ACh in superfusate fractions was fractionated and quantified by ion exchange chromatography.


RESULTS
In rabbit ICBs, evoked 3H-ACh. release was enhanced in a concentration-dependent manner by 5-HT (10(-9)-10(-5) M, EC50 = 5.8 x 10(-8) M). The maximum effect of 5-HT (10(-6) M) corresponded to a 45.14 +/- 7.40%) (n = 6) increase in 3H-ACh release. Higher concentrations of 5-HT (> 10(-4) M) induced desensitization. The response to 5-HT (10(-6) M) in the presence of the 5-HT3/4 antagonist tropisetron (10(-9) M), 5-HT1 antagonist methiothepin ((10(-7) M), equated to 89.96% and 88.78% respectively of control value; in the presence of non-selective 5-HT antagonist mianserin, 5-HT4 antagonist SDZ-205557 (10(-7) M) was -15.20% and 32.84% of control. The 5-HT response was mimicked by the selective 5-HT4 agonist 5-methoxytryptamine (10(-9)-10(-4) M, EC50 = 7 x 10(-8) M), whereas the 5-HT3 agonist M-CPBG[(1-m-chlorophenyl)-biguanide] and phenylbiguanide, the 5-HT1 agonist 5-carboxamidotryptamine and the 5-HT2A agonist alpha-methyl-5-HT were ineffective. The selective 5-HT1A agonist (+)-8-OH-DPAT (10(-8)-10(-5) M) had no significant effect, but at concentration of 10(-4) M, inhibited evoked 3H-Ach. release. Similar results were obtained in the human ICB. The evoked 3H-Ach. release was enhanced in a concentration-dependent manner by 5-HT (10(-9)-10(-5) M, EC50 = 3.36 x 10(-8) M) or 5-MOT (10(-8)-10(-5) M, EC50 = 6.59 x 10(-7) M), The selective 5-HT4 antagonist, GR113808A (10(-8) M) inhibited the 5-HT-inducing increase of the cholinergic response, producing parallel right shits of the concentration-response curves to 5-HT. The selective 5-HT3 antagonist ondersetrone (5 x 10(-7) M) and tropisetron (10(-9) M) did not affect 5-HT inducing 3H-Ach release.


CONCLUSIONS
Our results indicate that cholinergic terminals in the rabbit and human ICB contain facilitatory 5-HT heteroreceptors that belong to the 5-HT4 subtype. Their role in modulation of intraocular pressure remains to be elucidated.
Yang
X
X
Department of Ophthalmology, Tangdu Hospital, Xian 710038, China.
Latt
J E
JE
D000109:Acetylcholine / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009489:Neurosecretion; D011817:Rabbits; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D000109:Acetylcholine