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V.F. Roche, C.A. Opere, G.G. L. Zhan, P. Sulaiman, D. Opere, S.E. Ohia; Inhibition of Cyclic AMP Production in Isolated Bovine Retinae by Bicyclic Hexahydroaporphines: Role of Dopamine Receptors . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2226.
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Evidence from our laboratories shows that bicyclic hexahydroaporphines (HHAs), including nor–HHA (1) and its N–methyl congener (2) can lower intraocular pressure in normotensive rabbits (Saha et al. J. Ocul. Pharmacol. Ther. 497, 1997). It is unclear which receptor(s) mediate(s) the ocular actions of HHAs. Purpose: In the present study, we compared the pharmacological actions of HHAs with those of known dopamine receptor ligands on forskolin–stimulated cyclic AMP production in isolated bovine retinae. Methods: Isolated bovine neural retinae were incubated in oxygenated Krebs buffer solution at 37oC containing forskolin alone or forskolin in the presence of HHAs, dopamine receptor agonists and antagonists. After incubation, the tissues were treated with cold 5% trichloroacetic acid, homogenized and centrifuged at 1,500 x g for 10 min. After extraction, cyclic AMP in the supernatant of samples was determined using an enzyme immuno–assay kit from Cayman Chemical Company, Ann Arbor, MI. Results: Forskolin (1–10 µM) caused a concentration–dependent increase in cyclic AMP production in the isolated bovine retina. Quinpirole (0.1–10 µM; dopamine D2–agonist) elicited a concentration–related inhibition of cyclic AMP levels induced by forskolin (1 µM). In the concentration range of 1 nM to 10 µM, both 1 and 2 caused a concentration–dependent inhibition of forskolin–stimulated cyclic AMP production. For instance, an equimolar concentration of compounds 1 and 2 (10 µM) inhibited forskolin–stimulated cyclic AMP levels by 91% and 99%, respectively. The dopamine D3–antagonist, U99194 (10 µM) blocked inhibition of cyclic AMP elicited by 1 and 2, whereas L741626 (10 µM; D2–antagonist) had no such effect. Conclusions: We conclude that HHAs act on dopamine D3–receptors to inhibit forskolin–stimulated cyclic AMP production in the isolated bovine retina. It remains to be determined if these receptors also mediate other pharmacological actions of HHAs in the eye.
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