Combined effects of H-7 and cytochalasin B on outflow facility in monkeys.
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 micrometers, 100 micrometers (subthreshold for increasing facility when given alone) or 500 micrometers (just-threshold)] followed by bilateral AC bolus injection of CB [2 micrograms (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 micrometers) followed by unilateral AC bolus injection of a subthreshold dose of CB (0.02, 0.05, 0.1 or 0.5 microgram), 10 micrometers H-7 plus 0.1 or 0.5 microgram CB increased facility by approximately 40 or 80% compared to 10 micrometers H-7 alone. (3) After bilateral AC exchange with a maximal dose of H-7 (300 micrometers), followed by unilateral AC bolus injection of a subthreshold dose of CB (0.1 or 0.5 microgram), 300 micrometers H-7 plus 0.5 microgram CB increased outflow facility by 47% compared to 300 micrometers H-7 alone. (4) After unilateral AC exchange with a maximal dose of H-7 (300 micrometers) followed by bilateral AC bolus injection of a near-maximal dose of CB (2 micrograms), 300 micrometers H-7 plus 2 micrograms CB increased the facility by 67% compared to 2 micrograms 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.
Tian
B
B
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA.
Gabelt
B T
BT
Geiger
B
B
Kaufman
P L
PL
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology*; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects* / Q000502:physiology; D003571:Cytochalasin B / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008252:Macaca fascicularis; D047428:Protein Kinase Inhibitors
D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D003571:Cytochalasin B; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine