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

Abstract

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 ET_A 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 ET_B 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 ET_A receptor. In contrast, the prolonged decrease in IOP is mediated by ET_B receptors and, at least in part, by ET_A receptors without the involvement of cyclooxygenase products.

Key Words:

• endothelin-1
• ET_A receptor antagonist
• ET_B receptor agonist
• indomethacin
• intraocular pressure (IOP)
• rabbit