Endothelin B receptor regulation of nitric oxide synthase in the renal inner medulla

Abstract

Hypertension affects one in five Americans and inappropriate handling of sodium has been implicated in the pathogenesis of the disease. The kidney plays an important role in controlling blood pressure through regulation of sodium and water reabsorption and the renal inner medulla (IM) functions to fine-tune sodium reabsorption. The IM synthesizes ten-times more immwioreactive endothelin (ET) compared to any other nephron site, is enriched with a high density of endothelin B (ET s) receptors, and has the highest amount of nitric oxide synthase (NOS) activity in the kidney. Thus, the goal of these studies was to determine if ET stimulation of ET B receptors in the renal inner medulla leads to an increase in NOS activity and an inhibition of sodium transport. In order to help answer these questions, animals deficient in functional ET 8 receptors were utilized. Homozygous ET B receptor deficient animals (sllsl) have been shown to have elevated plasma ET levels and exhibit salt-sensitive hypertension. First,. experimel}ts were performed to determine if elevated plasma ET levels in sllsl rats led to a downregulation of renal ET A receptors. Results indicated that sllsl rats do have decreased renal cortical and outer medullary ET A receptor density, and that sllsl rats also express a novel inner medullary ET binding site. Next, experiments were performed examining the effect this down-regulation of renal cortical and outer medullary ETA receptors, the novel ET binding site, and ETs receptor deficiency might have when animals were given a sodium challenge. In addition, female rats were also used since gender has been shown to influence both the NOS and ET systems. Results showed that on a normal salt diet, male I • sllsl rats had higher blood pressures due to a combination of gender, ET s deficiency, and reduced NOS activity. However, on a high salt diet, gender differences disappear and the lack of functional ET 8 receptors led to an increased severity of the hypertension due to a further decrease in NOS activity. Lastly, discernment of cellular mechanisms of sodium .transport studies utilizing electrical transepithelial resistance measurements were addressed using primary IM collecting duct cells. Results indicate sodium transport was inhibited when cells were stimulated with ET and this can be blocked with NOS inhibitors and an ETa receptor antagonist. Taken together, the renal inner medulla appears to rely on the ability of a functional ET a receptor to activate NOS in order promote natriuresis and a lowering of blood pressure.