Effects of endothelin-1 on renal function in humans: Implications for physiology and Pathophysiology

Abstract

Elevated levels of the vasocontrictor peptide endothelin-1 have been demonstrated in various pathological conditions that are characterized by sodium retention and/or renal vasoconstriction, such as heart failure, hepatorenal syndrome, renal failure and during administration of cyclosporin and radiocontrast. In the present study we studied in seven healthy subjects the renal and endocrine effects of systemic administration of endothelin-1 (0.5, 1.0 and 2.5 ng/kg/min). During endothelin-1 infusion plasma levels rose from 3.2 +/- 0.5 to respectively 5.0 +/- 0.8, 6.2 +/- 0.5 and 8.5 +/- 1.1 pmol/liter, values that can also be observed in physiological and pathological conditions. Infusion of low dosages of endothelin-1, that result in a twofold increase in plasma levels, decreased sodium excretion by 36%, without a significant effect on systemic and renal hemodynamics. Infusion of 2.5 ng/kg/min of endothelin-1 further enhanced sodium retention and, in addition, increased renal vascular resistance by 37%. Blood pressure did not change significantly. Pretreatment with the calcium channel blocker nifedipine caused renal vasodilation, which compensated for the renal vasocontriction by endothelin-1 and prevented sodium retention. Apparently, endothelin-1 participates in volume homeostasis in human, whereas pathophysiological concentrations can contribute to renal vasoconstriction and sodium retention. Calcium channel blockers may protect against these effects of endothelin-1.

In vivo effect of endothelin-1 on plasma calcium and parathyroid hormone concentrations

“…There have been several papers reporting the effect of infusion of ET-1 to either animals (Miller et al 1989) or human volunteers (Vierhapper et al 1990, Sorensen et al 1994, Rabelink et al 1994. However, the most frequently observed parameters were either systemic or organ-specific, such as changes in blood pressure, cardiac output, renal blood flow, glomerular filtration rate and various endocrine hormones.…”

Renal endothelin in heart failure and its relation to sodium excretion

“…8 The sodium retentive activity of circulating ET-1 in human beings was demonstrated by low-dose infusion of exogenous ET-1 (1 ng/kg per minute), which caused sodium retention without any changes in renal plasma flow. 24 ET-1 locally produced in the kidney also seems to participate in sodium and water handling, favoring sodium retention and increasing free water clearance. 9 In experimental severe HF, the administration of ETA antagonists reduced sodium retention, whereas ETB antagonists had no effect.…”

Comments on the manuscript "Hepatorenal syndrome: an update"

“…When I published a small study in 1996 with favorable results from the use of relatively small doses of BQ123 in severely affected patients, I tried unsuccessfully to attract commercial interest to pursue the investigation. The physiological effects of ET-1 in healthy volunteers in Rabelink's study 2 seemed to affect them similarly to features seen in early hepatorenal syndrome (HRS) at comparable plasma levels, irrespective of the important question of intrarenal generation. Such effects in healthy subjects were completely abolished by selective ET-A blockade 3 .…”