Intraocular pressure response to intravitreal injection of endothelin-1 and the mediatory role of ETA receptor, ETB receptor, and cyclooxygenase products in rabbits

Endothelin-1 (ET-1) affects intraocular pressure (IOP) in rabbits. First, we studied IOP responses to the intravitreal injection of various doses of ET-1 ranging from 5 ng to 5 μg in unanesthetized rabbits, and observed a transient rise in IOP, from 0.5 to 2 h in duration, invariably followed by a prolonged IOP reduction, lasting for more than 72 h in rabbits treated with 0.5 μg and 5 μg of ET-1. ET-1 (0.05 μg and 0.15 μg) resulted in a prolonged IOP reduction without an early IOP rise. Both IOP rise and reduction were significantly related to the dose of ET-1. A masked, randomized, study revealed that the intraperitoneal administration of indomethacin (50 mg/kg) prior to ET-1 injection significantly reduced the ocular hypertensive response, but not the ocular hypotensive response, to ET-1. The ETA receptor selective antagonist, 97-139 (155 μg) had no effect on IOP when used alone. However, when used in combination with 0.5 μg of ET-1, 97-139 significantly inhibited both the IOP rise (0.5-2 h) and reduction (8-96 h) caused by ET-1. The ETB receptor selective agonist, sarafotoxin S6c (0.5 μg), caused a sustained IOP reduction of 2 to 96 h in duration without the initial IOP rise. We also determined the concentration of prostaglandin (PG) E2 in the aqueous humor using radioimmunoassay techniques on samples obtained at 1 and 24 h after ET-1 injection, and examined the effects of pretreatment with indomethacin or 97-139 on PGE2 concentration. Either the intravitreal injection of 97-139 prior to the ET-1 injection or intraperitoneal administration of indomethacin significantly suppressed the increase in PGE2 concentration found in the aqueous humor after ET-1 injection. These results suggest that the initial ET-1-induced IOP increase is mediated by cyclooxygenase products primarily through the stimulation of ETA receptor. In contrast, the prolonged decrease in IOP is mediated by ETB receptors and, at least in part, by ETA receptors without the involvement of cyclooxygenase products.