Renal vasodilating and diuretic actions of a selective endothelin ETB receptor agonist, IRL1620

Yukimura, Tokihito; Yamashita, Yutaka; Miura, Katsuyuki; Kim, Shokei; Itoh, Hiroshi; Takai, Makoto; Okada, Toshikazu

doi:10.1016/0014-2999(94)00501-x

Cited by 31 publications

(17 citation statements)

References 20 publications

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“…In agreement are also studies utilizing in vivo administration of endothelin receptor-specific agonists and antagonists. For instance, ET-1 administered in the presence of specific ET A but not ET B receptor inhibition uncovers a natriuertic effect and specific ET B receptor agonists increase urinary Na ϩ excretion (6,7,10,55). The current findings are also consistent with a pathogenic role for the loss of normal ENaC regulation by ET-1 in the elevated blood pressure associated with collecting duct-specific knockout of ET-1 and ET B receptors in mice and the spontaneous null mutation of ET B in rescued sl/sl rats (2,18,20,33,34,42).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the epithelial Na⁺channel by endothelin-1 in rat collecting duct

Bugaj

Pochynyuk

Mironova

et al. 2008

American Journal of Physiology-Renal Physiology

100

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We used patch-clamp electrophysiology to investigate regulation of the epithelial Na ϩ channel (ENaC) by endothelin-1 (ET-1) in isolated, split-open rat collecting ducts. ET-1 significantly decreases ENaC open probability by about threefold within 5 min. ET-1 decreases ENaC activity through basolateral membrane ETB but not ETA receptors. In rat collecting duct, we find no role for phospholipase C or protein kinase C in the rapid response of ENaC to ET-1. ET-1, although, does activate src family tyrosine kinases and their downstream MAPK1/2 effector cascade in renal principal cells. Both src kinases and MAPK1/2 signaling are necessary for ET-1-dependent decreases in ENaC open probability in the split-open collecting duct. We conclude that ET-1 in a physiologically relevant manner rapidly suppresses ENaC activity in native, mammalian principal cells. These findings may provide a potential mechanism for the natriuresis observed in vivo in response to ET-1, as well as a potential cause for the salt-sensitive hypertension found in animals with impaired endothelin signaling.salt-sensitive hypertension; systemic blood pressure ENDOTHELIN-1 (ET-1) is a powerful vasoconstricting peptide hormone that is an important regulator of systemic blood pressure (53). Independent of its vascular effects, ET-1 also affects renal Na ϩ and water handling favoring natriuresis and diuresis. While circulating ET-1 arises from endothelial cells, local ET-1 systems also exist. For instance in the kidney, the collecting duct produces significant amounts of 25,38,51). ET-1 targets cells through two distinct receptor subtypes, ET A and ET B (32, 41). Renal collecting duct cells have both types of receptors and are able to bind 49,50). Thus, collecting duct-derived ET-1, acting in a paracrine/ autocrine manner, is an important regulator of renal Na ϩ handling (2,20,26,42).Regulated Na ϩ reabsorption in the renal collecting duct, in part, controls blood pressure. Here, activity of the aldosteronesensitive epithelial Na ϩ channel (ENaC) is limiting for Na ϩ transport (reviewed in Refs. 19,30,31). Dysfunction and inappropriate regulation of ENaC consequently result in improper renal Na ϩ handling and thus, blood pressure disorders. For instance, gain of ENaC function in rodents and humans is causative for hypertension associated with the hallmarks of low plasma renin activity and aldosterone levels (1,22,23,45,46). Amiloride, an ENaC blocker, ameliorates this hypertension.Spotting lethal (sl) rats have a naturally occurring null mutation of ET B (17). These rats, when rescued from lethal intestinal aganglionosis by directed ET B transgene expression in the enteric nervous system, are particularly sensitive to DOCA and salt-induced hypertension (18,33,34). Similarly, mice with collecting duct-specific knockout of the ET B receptor have elevated blood pressure that further increases with high salt feeding (20). Collecting duct-specific ET-1 knockout, moreover, leads to hypertension exacerbated by high salt (2, 42). Plasma renin activity and aldoste...

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Section: Discussionmentioning

confidence: 99%

Regulation of the epithelial Na⁺channel by endothelin-1 in rat collecting duct

Bugaj

Pochynyuk

Mironova

et al. 2008

American Journal of Physiology-Renal Physiology

100

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“…When ET-1 is given in the setting of ETA, but not ETB, receptor blockade, a natriuretic effect is uncovered (5,11). Specific ETB receptor agonists also increase urinary Na excretion (6,52). An issue with these pharmacological studies is that ET agonists or antagonists invariably affect renal hemodynamics, making identification of a direct nephron effect problematic.…”

Section: Discussionmentioning

confidence: 99%

Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention

Ge¹,

Bagnall²,

Stricklett³

et al. 2006

American Journal of Physiology-Renal Physiology

190

152

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. Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention. Am J Physiol Renal Physiol 291: F1274 -F1280, 2006. First published July 25, 2006 doi:10.1152/ajprenal.00190.2006.-Collecting duct (CD)-derived endothelin-1 (ET-1) inhibits renal Na reabsorption and its deficiency increases blood pressure (BP). The role of CD endothelin B (ETB) receptors in mediating these effects is unknown. CD-specific knockout of the ETB receptor was achieved using an aquaporin-2 promoter-Cre recombinase transgene and the loxP-flanked ETB receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB receptor, ETA receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal-and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal-and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide. blood pressure; urinary sodium excretion; cell-specific gene targeting NUMEROUS LINES OF EVIDENCE indicate that collecting duct (CD)-derived endothelin-1 (ET-1) is an important regulator of renal Na reabsorption and systemic blood pressure (BP). First, the CD is the major renal site of ET-1 production (8,25,41,48,49), synthesizing more of the peptide than any other cell type (24). Second, the distribution of ET receptors in the kidney closely corresponds to the sites of ET production. Binding and RT-PCR studies using microdissected nephron segments indicate that endothelin receptors are primarily expressed by the inner medullary CD, moderately expressed by outer medullary CD and cortical CD, with much lower expression by other nephron segments (43,45). Third, cultured inner medullary CD cells secrete ET-1 from, and bind ET-1 to, the same (basolateral) side (27). Fourth, in vitro studies indicate that ET-1 inhibits CD Na transport. ET-1 decreases Na reabsorption by the isolated CD, an effect that may be mediated by inhibition of amiloride-sensitive sodium channel activity (14,31,32,46) and/or Na-K-ATPase activity (53). Perhaps the most compelling evidence implicating CD-derived ET-1 in the regulation of renal Na excretion and BP comes from gene targeting studies. Mice with CD-specific knockout of the ET-1 gene (CD ET-1 KO) are hypertensive on a normal-Na diet and this is exacerbated by high Na intake, with systolic BP increasing by almost 40...

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“…12,44,47 In the present study, we used a highly selective ET B antagonist, A-192621.1, to characterize the contribution of this receptor subtype to the diuretic and natriuretic responses induced by big ET-1. In agreement with our findings, Yukimura et al 47 reported that the intrarenal infusion of IRL 1620 in anesthetized dogs increased UV and RBF without an affect on GFR. Pretreatment of the dogs with either L-nitroarginine (an NO synthase inhibitor) or ibuprofen (a cyclooxygenase inhibitor) decreased the IRL 1620 -induced elevation in RBF, particularly in animals receiving the NO synthase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the present study was carried out to test the involvement of the ET B receptor/NO axis in the renal and systemic actions of big ET-1. Furthermore, because the actions of ET-1 are known to be mediated in part by an increase in cytosolic calcium, 45 as well as by the stimulation of PG synthesis, 46,47 we explored the effects of verapamil and indomethacin on the excretory actions of big ET-1.…”

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confidence: 99%

Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

et al. 2000

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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.

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Renal vasodilating and diuretic actions of a selective endothelin ETB receptor agonist, IRL1620

Cited by 31 publications

References 20 publications

Regulation of the epithelial Na⁺channel by endothelin-1 in rat collecting duct

Regulation of the epithelial Na⁺channel by endothelin-1 in rat collecting duct

Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention

Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

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Renal vasodilating and diuretic actions of a selective endothelin ETB receptor agonist, IRL1620

Cited by 31 publications

References 20 publications

Regulation of the epithelial Na+channel by endothelin-1 in rat collecting duct

Regulation of the epithelial Na+channel by endothelin-1 in rat collecting duct

Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention

Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis

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Regulation of the epithelial Na⁺channel by endothelin-1 in rat collecting duct

Regulation of the epithelial Na⁺channel by endothelin-1 in rat collecting duct