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Effects of the Marine Macrolides Swinholide A and Jasplakinolide on Outflow Facility in Monkeys

From the Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison Medical School.

PURPOSE. To determine effects of the marine macrolides swinholide A (Swin A) and jasplakinolide (Jas), alone or in conjunction with latrunculin B (Lat B) on outflow facility in monkeys.

METHODS. Total outflow facility was measured by two-level constant-pressure perfusion of the anterior chamber before and after exchange with Swin A, Jas, or vehicles followed by continuous anterior chamber infusion of drug or vehicle, in opposite eyes of cynomolgus monkeys. The effect of a facility-ineffective dose of Jas plus a threshold or submaximal facility-effective dose of the actin depolymerizer Lat B on outflow facility was also determined.

RESULTS. Ten or 100 nM Swin A or 20, 100, or 500 nM Jas had no significant effect on outflow facility. However, 500 nM Swin A and 2.5 µM Jas significantly increased facility by 80% ± 21% and 157% ± 57% (mean ± SEM) respectively, adjusted for corresponding baselines and resistance washout in contralateral control eyes. The facility increase in the eye treated with 500 nM Jas with 60 or 200 nM Lat B was similar to that in the eye treated with 60 or 200 nM Lat B only.

CONCLUSIONS. Swin A (which severs actin filaments and sequesters actin dimers) and Lat B (which sequesters actin monomers) similarly increase outflow facility. The potent inducer of actin polymerization Jas (500 nM) neither inhibits nor potentiates the facility increase induced by Lat B (60 or 200 nM). A higher dose of Jas increases rather than decreases outflow facility.

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