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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSION: 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

Renal medullary tissue levels of 20-HETE in response to blockade of medullary ET-B receptors.

<p>In response to increasing salt intake in male SD rats, renal medullary 20-HETE levels are significantly elevated (5.6±0.75 vs. 14.3±3.7, n = 4 and n = 7 respectively). With chronic intramedullary blockade of ET-B receptors, this response is completely abolished (4.9±0.79 vs. 4.5±0.55, n = 5 and n = 6 respectively). * denotes p<.05 vs. NS + VEH.</p

Mean arterial pressure in rats with intramedullary blockade of ET-B receptors in the presence and absence of a 20-HETE inhibitor.

<p><b>A</b>) This figure illustrates the changes in blood pressure in response to chronic intramedullary infusion of the ET-B antagonist, A-192621, the 20-HETE inhibitor, HET0016, and rats pretreated with HET0016, and then administered A-192621. <b>B</b>) Illustrates that the increase in blood pressure in response to intramedullary blockade of ET-B receptors is blunted when the rats are pretreated with a 20-HETE inhibitor. *indicates that p<0.05 vs. A-192621 treated group.</p

Mean arterial pressure in response to chronic intramedullary blockade of ET-B receptors.

<p>Chronic intramedullary blockade of ET-B receptors causes a slight increase in MAP in rats on a normal salt diet (112.8±2.4 in vehicle vs. 120.7±9.3). However, rats placed on high salt diet had a much greater elevation in MAP in response to IM ET-B blockade (123.7±3.2 vs. 164.2±7.1). * denotes p<.05 vs. all other groups.</p