Received for publication March 25, 2003.
Revised April 17, 2003.
Accepted for publication June 26, 2003.

Inhibitors of 20-HETE reduce renal vasoconstrictor responsiveness

Abstract

20-HETE is a CYP-derived constrictor eicosanoid produced by the preglomerular vasculature where it contributes to regulation of tone. Removal of the tonic inhibitory influence of NO has been reported to increase renal 20- HETE release. As 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, a TxA₂ mimetic, were compared before and after 50µM L-nitroarginine (L-NA) to inhibit NOS. L-NA raised perfusion pressure (PP) from 79±3 mmHg to 190±7 mmHg and enhanced constrictor responsiveness to U46619. 10, 30, 100 and 300 ng U46619 increased PP by 7±1, 17±2, 50±7 and 67±7 mmHg, respectively, before L-NA and 15 ±1, 37±7, 68±10 and 85±11 mmHg, respectively, after L-NA which did not increase 20- HETE efflux from the kidney. Nonetheless, an inhibitor of -hydroxylase, 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, also reduced vasoconstrictor responses to U46619 in the absence of elevation of PP. As 20-HETE inhibits K⁺ channels, we examined the effects of K⁺ channel inhibitors on vasoconstrictor responses and showed that both 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.

Key words: 20-HETE, DDMS, K channel inhibitors, kidney, nitric oxide, vasoconstriction

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