Combined Effects of H-7 and Cytochalasin B on Outflow Facility in Monkeys

Abstract

The serine-threonine protein kinase inhibitor H-7 and the fungal metabolite cytochalasin B (CB) disrupt the actin microfilament network by different mechanisms, and increase outflow facility similarly in live monkeys. Their combined effect has therefore determined on total outflow facility in cynomolgus monkeys by 2-level constant pressure perfusion. (1) After unilateral anterior chamber (AC) bolus injection of H-7 [10 μm , 100 μm (subthreshold for increasing facility when given alone) or 500 μm (just-threshold)] followed by bilateral AC bolus injection of CB [2 μg (strong but submaximal for increasing facility when given alone)], no significant difference between eyes was observed. (2) After bilateral AC exchange with a subthreshold dose of H-7 (10 μm) followed by unilateral AC bolus injection of a subthreshold dose of CB (0.02, 0.05, 0.1 or 0.5 μg), 10 μm H-7 plus 0.1 or 0.5 μg CB increased facility by ∼40 or 80% compared to 10 μm H-7 alone. (3) After bilateral AC exchange with a maximal dose of H-7 (300 μm), followed by unilateral AC bolus injection of a subthreshold dose of CB (0.1 or 0.5 μg), 300 μm H-7 plus 0.5 μg CB increased outflow facility by 47% compared to 300 μm H-7 alone. (4) After unilateral AC exchange with a maximal dose of H-7 (300 μm) followed by bilateral AC bolus injection of a near-maximal dose of CB (2 μg), 300 μm H-7 plus 2 μg CB increased the facility by 67% compared to 2 μg CB alone. The significant effect of combined subthreshold doses of H-7 and CB on outflow facility, the potentiation of the facility-increasing effect of a maximal H-7 dose by both subthreshold and near-maximal CB doses, and the known cytoskeletal effects of both compounds, may suggest that both increase facility by disrupting actin filaments in the trabecular meshwork.