Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

Abstract

Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ET(B) antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental doses of big ET-1 (0.3, 1. 0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113+/-7 mm Hg to a maximum of 148+/-6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5+/-1 to 110+/-14 microL/min, and fractional excretion of sodium increased from 0.38+/-0.13% to 7.51+/-1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg. kg(-1). h(-1)) significantly abolished the diuretic (17+/-5 microL/min to a maximum of 19+/-3 microL/min) and natriuretic (0. 29+/-0.1% to a maximum of 1.93+/-0.37%) responses induced by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg. kg(-1). h(-1)) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg. kg(-1). h(-1)) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1-induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ET(B) receptor subtype activation.

Adverse effects of pneumoperitoneum on renal function: involvement of the endothelin and nitric oxide systems

“…This observation is further supported by our laboratory's previous findings that ET B receptor is preferably expressed in the outer and inner medulla, mainly in the vasa recta, thick ascending limb of Henles' loop, and collecting duct (11). Moreover, our finding that ET B blockade worsened the oliguria characterizing pneumoperitoneum supports the role of tubular ET B receptors in mediating the diuretic effect of ET-1 under physiological conditions (11,18,25).…”

“…In this regard, several studies have demonstrated that medullary NO plays a pivotal role in the regulation of renal medullary hemodynamics and excretory function (27,28,30). Previously, our laboratory (14,18) and others (48) have shown that the renal vasodilatory actions of ET B , as well as its stimulatory effects on water and sodium excretion, are mediated through generation of NO. Similarly, Mattson et al (32) have demonstrated that chronic intravenous administration of the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) selectively decreases renal medullary blood flow, causes sodium and water retention, and leads to hypertension.…”

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

“…Inner medullary ET-1 is well characterized natriuretic peptide that stimulates compounds such as nitric oxide and cGMP (55,61). Similarly, ET-1 potently inhibits sodium transport through the epithelial sodium channel in collecting duct cells (34,36). Consequently, aldosterone induction of edn1 may represent an important negative feedback loop on aldosterone-stimulated sodium reabsorption in the collecting duct.…”

“…These same processes are also influenced by aldosterone. However, renal ET-1 is a well documented natriuretic peptide that directly blocks sodium transport in the tubule collecting duct (28,(33)(34)(35)(36)(37). The physiological importance of collecting duct ET-1 is emphasized by the fact that collecting duct cell-specific edn1 knock-out mice exhibit saltsensitive hypertension (31).…”

Renal Parenchymal Hypoxia, Hypoxia Adaptation, and the Pathogenesis of Radiocontrast Nephropathy

“…This response, which resembles the effect of mannitol, is mediated at least in part by an increase in plasma volume and the release of natriuretic peptides (14 -16). Natriuresis and diuresis may also be related to dye-induced endothelin release (14), mediated through ET B endothelin receptors (17). All of these factors, in addition to the substantial osmotic load provided by hyperosmolar radiocontrast agents, enhance solute delivery to the distal nephron and lead to increased oxygen consumption caused by enhanced tubular sodium reabsorption.…”