High salt intake increases endothelin B receptor function in the renal medulla of rats

Abstract

Aims Endothelin (ET)-1 promotes natriuresis via the endothelin B receptor (ETB) within the renal medulla. In male rats, direct interstitial infusion of ET-1 into the renal medulla has no effect on renal sodium and water excretion but is associated with endothelin A receptor (ETA)-dependent reductions in medullary blood flow. Loss of ETB function leads to salt-sensitive hypertension. We hypothesized that HS intake would increase the natriuretic and diuretic response to renal medullary infusion of ET peptides. Main methods Male Sprague Dawley (SD) rats were fed a normal (NS) or high (HS) salt diet for 7 days. Rats were anesthetized and a catheter implanted in the renal medulla for interstitial infusion along with a ureteral catheter for urine collection. Medullary infusion of a low dose of ETB receptor agonist, sarafotoxin 6c (S6c; 0.15 μg/kg/h), or ET-1 (0.45 μg/kg/h) was used to determine changes in sodium excretion (UNaV). Key findings In HS fed rats, intramedullary infusion of a low dose of S6c induced a significant increase in UNaV, roughly 2-fold over baseline, compared to no response to this low dose in NS fed rats. In HS fed rats, intramedullary infusion of ET-1 induced a significantly greater increase in UNaV compared to NS fed rats, although this increase was not different from the HS time control studies. Significance We conclude that high salt intake enhances the diuretic and natriuretic effects of ETB receptor activation in vivo consistent with a role for the ETB receptor in maintaining fluid-electrolyte homeostasis.

High dietary sodium causes dyssynchrony of the renal molecular clock in rats

“…The present findings indicate a diurnal rhythm in the renal production of ET-1 as measured in the urine that is associated with diurnal rhythms in Na ϩ excretion. Furthermore, our laboratory has shown that HS intake increases ET-1 receptor binding and shifts ET-1 binding in the inner medulla from 60/40% ET B /ET A to 100% ET B (9,13). Finally, Richards et al (26) reported higher levels of ET B receptor expression at midnight, or the middle of the active phase, in the inner medulla of mice with a concurrent decrease in ET A receptor 2).…”

“…The fact that clock genes within a single organ become desynchronized in terms of the molecular clock is contrary to the dogma that peripheral clock genes function as one synchronous unit. At least part of the mechanism leading to this discrepancy is most likely due to the fact that expression of ET-1 and ET B receptors is~10-fold higher in the inner medullary collecting duct compared with the renal cortex (13,29,31). Given that disruption of the molecular clock leads to elevated CVD risk, we speculate that risk associated with HS intake may be partially due to dyssynchrony between peripheral clocks of the kidney (17).…”

Recent advances in understanding the circadian clock in renal physiology

“…The expression of these genes is not altered in Per1 heterozygote mice, however, endothelin-1 levels during the active period are higher in inner medullary collecting duct cells isolated from Per1 heterozygote mice compared to wild type mice on the 129/sv background strain [31]. HS stimulates renal ET-1 production and activation of the ETb receptor [33]. Additionally, HS can alter the circadian rhythm of blood pressure.…”

Induction of renal tumor necrosis factor-α and other autacoids and the beneficial effects of hypertonic saline in acute decompensated heart failure

“…Endothelin is a vasoconstrictor involved in regulating renal blood flow and sodium transport (59,60). Rats fed a high salt diet exhibit an increase in endothelin expression, which leads to an increase in glomerular filtration rate (GFR) and increases in diuresis and natriuresis (60)(61)(62). Endothelin mediates inhibition of TAL sodium reabsorption during high salt intake and prevents increases in blood pressure (43).…”