To characterize the functional role of specific ET receptor subtypes, we examined the vascular response to ET-1, a nonselective ET
A and ET
B agonist, and to sarafotoxin, a selective ET
B agonist. Both agonists caused concentration-dependent constriction; however, the maximal response to ET-1 was approximately fivefold greater. ET-1–induced vasoconstriction appeared to be mediated primarily by the ET
A receptor subtype because selective ET
A blocker BQ123 abolished the vasoconstriction except at the highest concentration of ET-1. Given that the ET
B antagonist BQ788 completely inhibited sarafotoxin-induced vasoconstriction and only slightly attenuated constriction in response to the higher concentrations of ET-1 (1 and 10 nM), it appears that high concentrations of ET-1 also activate ET
B receptors for vasoconstriction. The vasoconstriction in response to ET-1 in the range of 1 pM to 1 nM observed in the present study is considered pathophysiologically relevant because the level of ET-1 in the vitreous and in the vascular wall can reach picomolar
30 and nanomolar
41 ranges, respectively. The EC
50 (0.14 nM) of ET-1 was comparable to that reported for isolated, pressurized resistance arteries in other tissues, such as coronary (0.57 nM)
50 and intracerebral (4.8 pM)
51 arterioles. Our results are also consistent with the estimated EC
50 (0.50 nM) of ET-1 in the retinal circulation in vivo.
15 Interestingly, a recent clinical study in healthy subjects has shown that intravenous administration of ET-1 did not alter the diameters of large retinal arteries but significantly reduced retinal blood flow,
18 suggesting that ET-1 exerts its vasoconstrictor action primarily on downstream small retinal arterioles. Consistent with BQ123 administration blunting the ET-1–induced reduction in human retinal blood flow,
18 our findings support the predominant role of ET
A receptors in mediating ET-1–induced constriction of small retinal arterioles.