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Naj Sharif, Ya Fatou Njie-Mbye, Sunny E Ohia, Madura Kulkarni-Chitnis; Contractile Effects of Serotonergic Receptor Agonists and Antagonists on Isolated Bovine Ciliary Arteries.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4596.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the serotonergic (5HT) receptor type mediating the contraction of isolated bovine ciliary arteries (BCA) in vitro.
Longitudnal isometric tension responses of BCA strips (4-5 mm) mounted in 25mL organ baths containing oxygenated Krebs solution at 37°C were recorded. Cumulative contractile concentration-response (C-R) curves were generated for various 5HT compounds to define their relative agonist potencies. Multiple agonist C-R curves generated in presence and absence of receptor-selective antagonists (3 concentrations) were used to perform Schild-analyses and thus obtain the respective antagonist potencies (-log concentration of antagonist required to shift the C-R to the right by 2-fold, pA2; Br J Pharmacol. Chemother. 14: 45-48, 1959). Tissues were challenged with carbachol (10 µM) at the beginning and end of each set of experiments in order to determine the viability and consistency of tissue responses. Data from such viable tissues were calculated and presented as mean +/- SEM of the agonist or antagonist potencies.
Concentration-dependent contractions of BCAs were recorded for numerous serotonergic agonists. The most potent agents were the 5HT2C-receptor-selective (MK-212; EC50 = 0.2 ± 0.1 nM, n = 8) and 5HT2B-receptor-selective (BW723C86; EC50 = 0.6 ± 0.1 nM, n = 8), while the 5HT2A-receptor-selective agonist R-DOI (EC50 = 290 ± 60 nM, n = 9) was much less potent. 5HT (EC50 = 710 ± 140 nM, n = 4), cabergoline (EC50 = 1370 ± 60 nM, n = 4), 8-hydroxy-tryptamine (5HT1A; inactive) and quipazine (5HT3; inactive), were also weaker agonists. The effects of receptor-selective agonists were most potently blocked by the antagonists RS-127445 (5HT2B-selective; pA2 = 7.8 ± 0.12; i.e. 15.1 nM) and RS-102221 (5HT2C-selective; pA2 = 6.2 ± 0.17; i.e. 575 nM).
Contraction of BCAs appears to be mediated primarily by a combination of 5HT2C / 5HT2B receptors. This is borne out by the high potency of 5HT2C and 5HT2B agonists, MK-212 (EC50 = 0.2 nM) and BW723C86 (EC50 = 0.6 nM), respectively. Other serotonergic receptors such as 5HT1A, 5HT2A and 5HT3 receptors appear not to be involved in the BCA contractile process. This tissue-bath contraction procedure illustrates the power of classical pharmacology to delineate the sub-type of serotonergic receptor involved in causing ocular arterial vasoconstriction.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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