Role of 20-hydroxyeicosatetraenoic acid in mediating hypertension in response to chronic renal medullary endothelin type B receptor blockade.
BACKGROUND
The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production.


RESULTS
The effect of increasing sodium intake from low (NS = .8%) to high (HS = 8%) on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS) to 120.7±9.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS) to 164.2±7.1 (HS). Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS), an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS). Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor.


CONCLUSIONS
These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal medulla.
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Joshua S
JS
Speed
Eric M
EM
George
Marietta
M
Arany
Kathy
K
Cockrell
Joey P
JP
Granger
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065131:Endothelin B Receptor Antagonists; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013997:Time Factors
D065131:Endothelin B Receptor Antagonists; D006893:Hydroxyeicosatetraenoic Acids; D017673:Sodium Chloride, Dietary; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid