Pharmacological regulation of outflow resistance distal to Schlemm's canal

The trabecular meshwork (TM) and Schlemm's canal generate the majority of outflow resistance; however, the distal regions of the conventional outflow pathway account for 25-50% of total resistance. Sections of distal vessels are surrounded by alpha-smooth muscle actin-containing cells, indicating that they may be vasoregulated. This study examined the effect of a potent vasodilator, nitric oxide (NO), and its physiological antagonist, endothelin-1 (ET-1), on the regulation of outflow resistance in the distal regions of the conventional outflow pathway. Using a physiological model of the conventional outflow pathway, human and porcine anterior segments were perfused in organ culture under constant flow conditions, while intrachamber pressure was continually monitored. For porcine anterior segments, a stable baseline outflow facility with TM intact was first achieved before anterior segments were removed and a trabeculotomy was performed. For human anterior segments, a trabeculotomy was immediately performed. In human anterior segments, 100 nM ET-1 significantly decreased distal outflow facility from 0.49 +/- 0.26 to 0.31 +/- 0.18 (mean +/- SD) mu 1.min(-1).mmHg, P < 0.01. Perfusion with 100 mu M diethylenetriamine-NO in the presence of 1 nM KT-1 immediately reversed FT-1 effects, significantly increasing distal outflow facility to 0.54 +/- 0.35 mu 1.-min(-1)center dot mmHg, P = 0.01. Similar results were obtained in porcine anterior segment experiments. Therefore, data show a dynamic range of resistance generation by distal vessels in both the human and the porcine conventional outflow pathways. Interestingly, maximal contraction of vessels in the distal outflow tract of trabeculotomized eyes generated resistance very near physiological levels for both species having an intact TM.