Journal Article

Role of 20-Hydroxyeicosatetraenoic Acid in Mediating Hypertension in Response to Chronic Renal Medullary Endothelin Type B Receptor Blockade

Cockrell, Kathy, Granger, Joey P., Speed, Joshua S., Arany, Marietta, George, Eric M.

2011

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids / Activation / Animals / Arachidonic acid / Biology / Biophysics / Blood / Blood pressure / Blood Pressure - drug effects / Cytochrome / Diet / Electrolytes / Endothelin / Endothelin 1 / Endothelin B Receptor Antagonists / Excretion / Hydroxyeicosatetraenoic Acids - biosynthesis / Hydroxyeicosatetraenoic Acids - metabolism / Hypertension / Hypertension - chemically induced / Hypertension - metabolism / Hypertension - physiopathology / Kidney Medulla - drug effects / Kidney Medulla - metabolism / Kidney Medulla - physiopathology / Kidneys / Male / Medicine / Metabolites / Physiology / Rats / Rats, Sprague-Dawley / Receptor mechanisms / Receptors / Rodents / Salts / Sodium / Sodium Chloride, Dietary - pharmacology / Studies / Time Factors / Unsaturated fatty acids