INHIBITION OF RENAL OUTER MEDULLARY 20-HETE PRODUCTION PRODUCES HYPERTENSION IN LEWIS RATS

Recent studies have indicated that a deficiency in the production of 2 0-hydroxyeicosatetraenoic acid (20-HETE) in the outer medulla of the k idney may contribute to the abnormalities in the renal handling of sod ium and the development of hypertension in Dahl salt-sensitive rats. T o determine whether a reduction in 20-HETE production in the outer med ulla is sufficient to induce hypertension, an inhibitor of the renal m etabolism of arachidonic acid by P450 enzymes, 17-octadecenoic acid (1 7-ODYA), was chronically infused directly into the outer medulla of th e left kidney of uninephrectomized Lewis rats fed a high salt diet. Re nal medullary interstitial infusion of 17-ODYA (400 pmol/min) reduced the formation of 20-HETE in the outer medulla of the infused kidney by 70% compared with values seen in the right kidney collected when the rat was uninephrectomized, but it had no effect on the production of 2 0-HETE in the renal cortex. After 5 days, mean arterial pressure rose from 115 +/- 2 to 142 +/- 2 mm Hg (n = 6) in the rats infused with 17- ODYA, while mean arterial pressure was not significantly altered in th e rats infused with vehicle alone (116 +/- 1 versus 117 +/- 2 mm Hg, n = 6). These results suggest that inhibition of the renal metabolism o f arachidonic acid by P450 enzymes in the outer medulla of the kidney is sufficient to induce the development of hypertension in Lewis rats fed a high salt diet and support the view that P450 metabolites of ara chidonic acid play an important role in the regulation of renal functi on and the long-term control of arterial pressure.