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Baseline or post-drug outflow facility was measured by two-level constant pressure perfusion of the anterior chamber (AC). The AC of one eye of cynomolgus monkeys was exchanged with the myosin light chain kinase (MLCK) inhibitor ML-7, the protein kinase (PK) C inhibitor chelerythrine (CHEL), or the PKC activator phorbol myristate acetate (PMA), followed by continuous AC infusion of the drug. The opposite eye similarly received the corresponding vehicle solution. The facility-effectiveness of subthreshold doses of ML-7 or CHEL+a subthreshold dose of the serine-threonine kinase inhibitor H-7, and facility-effective doses of CHEL+a subthreshold or effective dose of PMA, were also determined. In 45-minute post-exchange perfusions, 100 and 500 μm ML-7 increased outflow facility by 32 and 76%, while 100 and 500 μm CHEL increased facility by 68 and 101%, respectively, adjusted for baseline and contralateral control eye resistance washout. In 90-minute post-exchange perfusions, 100 μm ML-7 or CHEL time-dependently increased outflow facility by 23, 49, and 69%, or by 44, 108, and 125% in the first, second and third 30-minute periods, respectively. At 50 μm, ML-7 was ineffective, but CHEL increased outflow facility by 36% in the third 30-minute period. Ten μm H-7 potentiated the outflow facility effect of 50 μm ML-7 or 20 μm CHEL by 36 and 28%, respectively, in the second 30-minute period, and that of 50 μm CHEL by 44% in the overall 60-minute post-exchange perfusion, compared to the H-7-only treated contralateral eye. Ten, 50 or 100 nm PMA dose-dependently increased outflow facility by 23 nm CHEL alone, while the effect of 50 nm PMA and 100 μm CHEL together was 63% more than that of 100 μm CHEL alone. In conclusion, ML-7/CHEL may increase outflow facility by a cytoskeletal mechanism. Separate or combined treatment with CHEL and PMA increases outflow facility, suggesting that PKC inhibition may not be involved in the facility-increase with either drug.
Dr. P.L. Kaufman, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, F4/328 CSC, 600 Highland Avenue, Madison, WI 53792-3220, USA. kaufmanp@mhub.ophth.wisc.edu
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)