An in vivo model of chronic optic nerve ischemia: The dose-dependent effects of endothelin-1 on the optic nerve microvasculature

The purpose of this study was to evaluate the effects induced by chronic microapplication of endothelin-1 on the anterior optic nerve microvasculature and to determine the dose-response characteristics of endothelin-1 on this vascular bed. Daily dosages between 4.69X10(-4) and 9.0X10(-1) mu g/day of endothelin-1 were delivered continually over 3 days, and at a constant flow rate, to the perineural region of the anterior optic nerve of 15 albino rabbits via osmotically-driven minipumps. The vasomotor effect of local endothelin-1 on the microvasculature of the optic nerve was examined using intraluminal microvascular corrosion casting technique. The vasomotor effects were quantified by measuring the relative amount of vasoconstriction of the arterioles supplying the anterior optic nerve (primary and secondary branches of the short posterior ciliary arteries). The average constriction was calculated for the endothelin-treated eyes and the untreated, contralateral eyes. The mean vasoconstriction in the endothelin treated eyes ranged from 14.7% to 30.0% and was highly correlated with the logarithmic value of the daily dose of endothelin-1 (R(2) = 0.59, p = 0.00083). The interocular difference (between treated and untreated eyes) of the optic nerve vasoconstriction ranged from 0-19% (mean +/- SD: 7.23 +/- 5.7%). This interocular difference also correlated highly with the log of the daily endothelin-1 dosage (R(2) = 0.80; p < 0.0001), By additionally accounting for the weight and sex in a multiple linear regression function, the correlation was markedly improved (R(2) = 0.92; p < 0.0001). In conclusion, the microvasculature supplying the anterior optic nerve of the rabbit demonstrates a dose dependent vasoconstriction with chronic local application of endothelin-1. This in vivo, experimental model offers a titratable method with which the effects of chronic vasoconstriction and vascular insufficiency on the optic nerve can be examined.