Role of 20-Hydroxyeicosatetraenoic Acid in Mediating Hypertension in Response to Chronic Renal Medullary Endothelin Type B Receptor Blockade
ABSTRACT 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.
Full-textDOI: · Available from: Kathy Cockrell, Jun 25, 2015
- Hypertension 05/2013; 61(6):1142-1145. DOI:10.1161/HYPERTENSIONAHA.113.00595 · 7.63 Impact Factor
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ABSTRACT: Acute stress in both rodents and humans causes a transient rise in blood pressure associated with an increase in plasma endothelin-1 (ET-1). High salt (HS) intake also increases ET-1 production, and interestingly, blunts the pressor response to acute air jet stress in rats. We previously reported that female rats lacking functional ETB receptors everywhere except sympathetic nerves (ETB def) had a greater degree of hypertension in response to a HS diet compared to their male counterparts when measured by the tail cuff method. However, we now report that salt-induced hypertension is not different between sexes when measured by telemetry. Therefore, additional experiments were designed to test the hypothesis that female ETB def rats are more sensitive to acute stress when on a HS diet. The pressor response, measured by telemetry, to acute air jet stress was similar between male transgenic control (Tg control) and ETB def rats following chronic HS intake. In contrast, female ETB def rats had a significantly greater pressor response (about twofold higher) than female or male Tg control or male ETB def rats maintained on HS, a finding that cannot be explained by increased vascular reactivity to ET-1 in female rats as we observed that male ETB def rats had a greater pressor response to i.v. infusion of ET-1 compared to females. Furthermore, HS feeding exacerbated the pressor response to ET-1 in both male and female ETB def rats. Given our previous studies demonstrating that the ETA receptor functions to reduce the pressor response to acute stress, these findings further support a role for the ET receptor system in the pressor response to acute stress and that female rats have reduced ETA receptor activity when on a HS diet compared to males. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.03/2015; 3(3). DOI:10.14814/phy2.12326
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ABSTRACT: With rising rates of obesity, research continues to explore the contributions of homeostatic and hedonic mechanisms related to eating behaviour. In this Review, we synthesize the existing information on select biological mechanisms associated with reward-related food intake, dealing primarily with consumption of highly palatable foods. In addition to their established functions in normal feeding, three primary peripheral hormones (leptin, ghrelin and insulin) play important parts in food reward. Studies in laboratory animals and humans also show relationships between hyperphagia or obesity and neural pathways involved in reward. These findings have prompted questions regarding the possibility of addictive-like aspects in food consumption. Further exploration of this topic may help to explain aberrant eating patterns, such as binge eating, and provide insight into the current rates of overweight and obesity.Nature Reviews Endocrinology 06/2014; 10(9). DOI:10.1038/nrendo.2014.91 · 12.96 Impact Factor