Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

Purpose: To characterize the effects of netarsudil on the aqueous humor outflow tract distal to the trabecular meshwork (TM). We hypothesized that netarsudil increases outflow facility in eyes with and without circumferential ab interno trabeculectomy (AIT) that removes the TM. Methods: 64 porcine anterior segment cultures were randomly assigned to groups with (n=32) and without circumferential AIT (n=32). Cultures were exposed to 0.1, 1, and 10 microM netarsudil (N= 8 eyes per concentration). For each concentration, IOP and vessel diameters were compared to their respective pretreatment baselines. Outflow tract vessel diameters were assessed by spectral-domain optical coherence tomography (SDOCT) and rendered in 4D (XYZ time-series). Results: Netarsudil at 1 microM reduced IOP in both eyes with TM (-0.60+/-0.24 mmHg, p = 0.01) and in eyes without TM (-1.79+/-0.42 mmHg, p<0.01). At this concentration, vessels of the distal outflow tract dilated by 72%. However, at 0.1 microM netarsudil elevated IOP in eyes with TM (1.59+/-0.36 mmHg, p<0.001) as well as in eyes without TM (0.23+/-0.32 mmHg, p<0.001). Vessels of the distal outflow tract constricted by 31%. Similarly, netarsudil at a concentration of 10 microM elevated IOP both in eyes with TM (1.91+/-0.193, p<0.001) and in eyes without TM (3.65+/-0.86 mmHg, p<0.001). At this concentration, outflow tract vessels constricted by 27%. Conclusion: In the porcine anterior segment culture, the dose-dependent IOP changes caused by netarsudil matched the diameter changes of distal outflow tract vessels. Hyper- and hypotensive properties of netarsudil persisted after TM removal. Keywords: Rho-kinase inhibitor; netarsudil; distal outflow tract; anterior chamber perfusion model; porcine eyes