Age-associated alterations in retinal arteriole reactivity to endothelin-1 differ between the sexes

Endothelin-1 (ET-1) is a vasoconstrictor implicated in age-related retinal pathologies. This study determined whether responses to ET-1 differed in retinal arterioles isolated from adult (2-3 months) and aged (>20 months) Fischer 344 rats of both sexes. Risk factors for retinal disease (retinal perfusion pressure, intraocular pressure, blood glucose) were not affected by age. However, sensitivity to ET-1 declined with age, especially in females. Vasoconstrictor responses to 50mM KCl and Ca(2+) release by caffeine (10mM) were similar in all groups. Retinal ET(A) and ET(B) receptor expression also was similar in young and aged rats, regardless of sex. Contractions elicited by 10nM ET-1 were inhibited by the ET(A) antagonist BQ-123 (1 μM) in all groups. In contrast, the ET(B) antagonist BQ-788 (1 μM) restored ET-1-induced contractions in aged female vessels, but had no effect in any other group. Removal of the endothelium also restored contractions in vessels from aged females but not males. Thus, responsiveness to ET-1 declines with age in retinal microvasculature. In males, this is likely mediated by age-related changes in the ET(A) receptor signaling pathway. By contrast, effects of ET-1 on endothelial ET(B) receptors attenuate vasoconstrictor responses in aged females.