Abstract
BackgroundThe 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 FindingsThe 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.ConclusionThese 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.
Highlights
Endothelin (ET-1) was first isolated and characterized in 1988 as a very potent vasoconstrictor produced by vascular endothelial cells [1]
These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to endothelin type B receptors (ET-B) receptor activation within the renal medulla
In order to determine if chronic intramedullary blockade of ETB receptors causes a reduction in pressure natriuresis and salt sensitive hypertension, we examined the sodium excretion and blood pressure relationship in rats treated with an ET-B receptor antagonist, delivered to the renal medulla
Summary
Endothelin (ET-1) was first isolated and characterized in 1988 as a very potent vasoconstrictor produced by vascular endothelial cells [1]. ET-A receptors are responsible for the vasoconstrictor properties of ET-1, and chronic activation results in hypertension [2] Their role in blood pressure regulation has been extensively researched. A reduction in renal production of ET-1 may be important in the pathogenesis of essential salt sensitive hypertension [10,11], the mechanisms by which renal medullary ET-1 enhances pressure natriuresis have yet to be fully elucidated. 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
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