Inhibitors of 20-Hydroxyeicosatetraenoic Acid Reduce Renal Vasoconstrictor Responsiveness

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Abstract
20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450-derived constrictor eicosanoid produced by the preglomerular vasculature where it contributes to regulation of tone. Removal of the tonic inhibitory influence of nitric oxide (NO) has been reported to increase renal 20-HETE release. Because inhibition of NO synthesis enhances responses to vasoconstrictor agents, we examined a contribution for increased 20-HETE generation. In the rat kidney perfused with Krebs' buffer, responses to U46619 (9,11-dideoxy-9α,11α-methanoepoxy PGF2α), a thromboxane A2 mimetic, were compared before and after 50 μM l-nitroarginine (l-NA) to inhibit NO synthase. l-NA raised perfusion pressure (PP) from 79 ± 3 to 190 ± 7 mm Hg and enhanced constrictor responsiveness to U46619. U46619 (10, 30, 100, and 300 ng) increased PP by 7 ± 1, 17 ± 2, 50 ± 7, and 67 ± 7 mm Hg, respectively, before l-NA and 15 ± 1, 37 ± 7, 68 ± 10, and 85 ± 11 mm Hg, respectively, after l-NA, which did not increase 20-HETE efflux from the kidney. Nonetheless, an inhibitor of ω-hydroxylase, dibromododecencyl methylsulfonimide (DDMS), which reduced 20-HETE release, normalized the enhanced responsiveness to U46619. When PP was elevated with phenylephrine, vasoconstrictor responses to U46619 were similarly enhanced, an effect that was also prevented by DDMS. DDMS and an antagonist of 20-HETE, 20-HEDE [20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid], also reduced vasoconstrictor responses to U46619 in the absence of elevation of PP. Because 20-HETE inhibits K+ channels, we examined the effects of K+ channel inhibitors on vasoconstrictor responses and showed that both tetraethylammonium (TEA) and charybdotoxin enhanced renal vasoconstrictor responses to U46619. However, the inhibitory effects of 20-HEDE on vasoconstrictor responses remained after treatment with TEA. These results support a role for 20-HETE vasoconstrictor responses but suggest an action independent of K+ channels.