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V.F. Roche, C.A. Opere, S.E. Ohia; Studies on the IOP-Lowering Activity of 10-Methoxy-3,11c-Ethano-1,2,3,3a,11b,11c-Hexahydroaporphine . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3440.
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Purpose: We have synthesized bicyclic hexahydroaporphines (HHAs) that lower intraocoular pressure (IOP). The mechanism of action of HHAs in lowering IOP is yet to be fully determined. In the present study, we investigated the role of second messengers in the IOP lowering action of HHAs in vitro and in vivo. Methods and Results: The most potent, long-lasting effect was provided by the secondary amine, norHHA. In 1.5% doses, norHHA decreased IOP by 41% over the course of 9 hours. The initial pressure drop was unaffected by COX inhibition (flurbiprofen) or chronic superior cervical ganglionectomy, although both interventions significantly shortened the secondary hypotensive effect. 1.5% NorHHA doubled outflow facility (0.17 vs. 0.36 µg/min/mmHg) but had no impact on aqueous flow. In doses of up to 100 µM, norHHA had no effect on adrenergic neurotransmission or on the contraction/relaxation of iris smooth muscle, but did inhibit carbachol-induced contractions by 70% at the highest dose tested. This inhibition was totally reversed by the NO scavenger C-PTIO, and by inhibitors of PLA2 (quinacrine) and COX (indomethacin), but unaffected by lipoxygenase inhibition (nordihydroxyguaiaretic acid). NO synthase inhibition (L-NAME) inhibited contractions at carcachol contractions at or below 300 µM. Direct stimulation of prostaglandin synthesis is not important to the action of norHHA, as basal levels of PGE2 and PGF2α are unaffected by up to 300 µM concentrations. Conclusions: To lower IOP, norHHA: 1) promotes outflow facility, 2) requires an intact sympathetic nervous system and 3) may depend on NO and the products of COX metabolism. Future studies on the mechanism of its IOP-lowering action will focus on the role of GABA and D3 receptor interaction.
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