Endothelin inhibits thick ascending limb chloride flux via ET<sub>B</sub>receptor-mediated NO release

Plato, Craig F.; Pollock, David M.; Garvin, Jeffrey L.

doi:10.1152/ajprenal.2000.279.2.f326

Cited by 124 publications

(115 citation statements)

References 46 publications

(49 reference statements)

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…9,32,33 Despite these effects, this and previous studies demonstrate that rats genetically deficient in ET B or undergoing chronic ET B blockade exhibit saltsensitive hypertension responsive to ET A blockade, suggesting that Na retention and hypertension under these conditions results not from a lack of ET B -mediated natriuresis or diuresis in the kidney but from an increase in ET A signaling. 11,15 This study goes further to demonstrate that although intrarenal ET B plays a significant role in determining BP in these animals on DNa diet, it plays a relatively minor role in determining BP in these animals on HNa diet.…”

Section: Perspectivesmentioning

confidence: 51%

Extrarenal ET _B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

et al. 2005

View full text Add to dashboard Cite

Abstract-Endothelin-B receptor (ET B )-deficient rats have low-renin, salt-sensitive hypertension. We hypothesized this was caused by an absence of renal ET B signaling and performed a series of experiments to examine the effect of dietary sodium (Na) on endothelin-1 (ET1) expression and renal function in wild-type (WT) and ET B -deficient rats. We found that ET B deficiency, but not dietary Na, increases circulating and tissue (kidney and aorta) ET1 levels. Quantitative reverse-transcription polymerase chain reaction reveals that aortic and renal ET1 and endothelin-A receptor (ET A ) mRNA, however, are similarly increased by dietary Na in ET B -WT and ET B -deficient rats. We then determined the effect of chronic ET A blockade on blood pressure (direct conscious measurements), urinary protein excretion, and creatinine clearance (Crcl). On a Na-deficient diet, ET B -deficient rats have mild proteinuria and impaired Crcl. On a high-Na diet, severe hypertension and renal dysfunction develop in ET B -deficient rats. Chronic ET A blockade prevents hypertension and renal injury. To determine the role of the renal versus the extrarenal endothelin system, we performed renal cross-transplantation. We found that ET B deficiency in the body is associated with renal injury and an impaired ability to excrete an Na load. We also found that ET B deficiency in the body affects blood pressure response to dietary Na. Expression of ET1 and ET A are regulated by dietary Na. ET B receptors outside of the kidney, likely by functioning as a clearance receptor for ET1, limit salt-sensitivity in rats. Key Words: endothelin Ⅲ natriuresis Ⅲ proteinuria Ⅲ sympathetic nervous system Ⅲ transplantation T he endothelin-B (ET B ) receptor-deficient rat is a model of salt-sensitive hypertension resulting from a naturally occurring mutation in a single locus. These rats were created through the transgenic rescue of the spotting lethal (sl) rat. Spotting lethal is a 301-bp deletion in the ET B gene that abrogates functional receptor expression. 1 ET B sl/sl rats are rescued from their lethal intestinal phenotype via a dopamine-␤-hydroxylase (D␤H)-ET B transgene. D␤H-ET B ;ET B sl/sl rats express ET B in adrenergic tissues but fail to express ET B in other sites where they are normally expressed. [2][3][4] Although adult transgenic ET B wild-type (WT) (D␤H-ET B ;ET B ϩ/ϩ ) rats are not responsive to dietary sodium (Na), ET B -deficient (D␤H-ET B ;ET B sl/sl ) rats exhibit low-renin, amilorideresponsive, salt-sensitive hypertension. 4 The functional role of ET B in vascular homeostasis is controversial because it has both pressor and depressor effects. ET B activation on vascular smooth muscle mediates endothelin-1 (ET1)-induced vasoconstriction, whereas ET B activation on vascular endothelium produces a depressor response by evoking the production of the endotheliumderived vasodilators nitric oxide and/or prostacyclin. 5 ET B on the vascular endothelium also plays an important role in clearing circulating ET1, thereby reducing ET A -mediated press...

show abstract

Section: Perspectivesmentioning

confidence: 51%

Extrarenal ET _B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The extent to which the antinatriuresis associated with medullary NOS inhibition was a direct consequence of reduction of MBF (16,102) or was related to changes of intrarenal paracrine/autocrine systems (95,100) or was a direct consequence of tubular epithelial transport actions of NO (80,136) awaited a better understanding of the intrarenal sites of NO production. Initial efforts to determine regional NO biosynthesis by determining tissue nitrite/nitrate and cGMP levels in slices of dissected renal zones, isolated glomeruli, and various cell cultures systems.…”

Section: Localization Of No Production Within Vascular and Tubular Stmentioning

confidence: 99%

Role of renal NO production in the regulation of medullary blood flow

Cowley

Mori

Mattson

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

175

202

View full text Add to dashboard Cite

. Role of renal NO production in the regulation of medullary blood flow. Am J Physiol Regul Integr Comp Physiol 284: R1355-R1369, 2003 10.1152/ajpregu.00701.2002The unique role of nitric oxide (NO) in the regulation of renal medullary function is supported by the evidence summarized in this review. The impact of reduced production of NO within the renal medulla on the delivery of blood to the medulla and on the long-term regulation of sodium excretion and blood pressure is described. It is evident that medullary NO production serves as an important counterregulatory factor to buffer vasoconstrictor hormoneinduced reduction of medullary blood flow and tissue oxygen levels. When NO synthase (NOS) activity is reduced within the renal medulla, either pharmacologically or genetically [Dahl salt-sensitive (S) rats], a super sensitivity to vasoconstrictors develops with ensuing hypertension. Reduced NO production may also result from reduced cellular uptake of L-arginine in the medullary tissue, resulting in hypertension. It is concluded that NO production in the renal medulla plays a very important role in sodium and water homeostasis and the long-term control of arterial pressure. renal medulla; Dahl salt-sensitive rats; hypertension; L-arginine THE RENAL MEDULLARY CIRCULATION is now recognized to be of importance for reasons that extend far beyond providing the economy of countercurrent exchange to concentrate large volumes of filtrate to produce small volumes of concentrated urine. It is now recognized that medullary blood flow (MBF) can play an important role in determining long-term levels of arterial pressure and that 15-30% reductions of blood flow to the renal medulla in the face of imperceptibly small changes of total renal blood flow can lead to the development of hypertension (16,21). Evidence is reviewed showing that nitric oxide (NO) plays a unique role in the acute and chronic regulation of renal MBF, sodium homeostasis, and arterial pressure. More specifically, the role of NO in the regulation of MBF, in linking tubular metabolic needs with delivery of nutrients and as a counterregulatory system to protect the medulla from the consequences of underperfusion, are the focus of this review. The influence of NO on the renal cortex and such issues that relate to pressure-natriuresis, autoregulation of total renal blood flow, tubuloglomerular feedback, and glomerular filtration rate (GFR) regulation are important subjects of renal function that either have been reviewed by others (2,29,43,55,96) or are beyond the scope of this relatively brief review.

show abstract

“…Taylor et al 65 found that in ET B receptor-deficient rats, medullary NOS activity and renal endothelin production are decreased, indicating that renal endothelin regulates NOS 3 activity as reported for the thick ascending limb. 66 Mori et al 67 found that vasopressin stimulated a rapid increase in intracellular NO via increased intracellular calcium levels in the inner medullary collecting duct. Although they did not assess which NOS isoform was activated, NOS 3 is likely responsible because of its high expression in the collecting duct.…”

Section: Hormonal Regulation Of Nosmentioning

confidence: 99%

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Herrera

Garvin

2005

Hypertension

Self Cite

View full text Add to dashboard Cite

Abstract-Nitric oxide (NO) plays important roles in the regulation of renal function and the long-term control of blood pressure. New roles of NO have been proposed recently in diabetes, nephrotoxicity, and pregnancy. NO derived from all 3 NOS isoforms contributes to the overall regulation of kidney function, and recent advances in our understanding of their regulation have been made lately. In this regard, substrate and cofactor availability play important roles in regulating nitric oxide synthase (NOS) activity not only by limiting enzyme activity but also by influencing the coupling of NOS with its cofactors, tetrahydrobiopterin and NADPH. Protein-protein interactions are now recognized to be important negative and positive regulators of NOS. Phosphorylation is another component of the mechanism whereby NOS is activated or deactivated. Increased NOS expression can also influence enzyme activity; however, the degree of expression does not always correlate with enzyme activity because increased NO levels can result in inhibition of NOS. Finally, other potential regulators of NOS such as endogenous L-arginine analogs may also be important. In this article, we summarize recent advances in the regulation of activity and expression of the NOS isoforms within the kidney. renal function and long-term regulation of blood pressure. [1][2][3][4] This is best evidenced by the fact that inhibiting intrarenal NO production increased blood pressure. 5 In addition, reduced NO has been identified as a common denominator of many hypertensive models. 6 -9 The effects of NO on blood pressure via actions in the kidney occur through multiple mechanisms. These include increasing renal blood flow caused by vasodilatation, 10 increasing glomerular filtration, 11 inhibiting sodium transport along the nephron, 12-14 and regulating release of renin. 15 NO produced by each of the 3 nitric oxide synthases (NOS), NOS 1, NOS 2, and NOS 3, reportedly contributes to the regulation of renal function. Inhibition of NOS activity within the kidney is known to lead to sodium retention and hypertension. This review addresses recent advances in our understanding of the role played by renal NO in various physiological and pathophysiological conditions, as well as how NO production is regulated. Roles for Renal NOHistorically, NO produced by the kidney has been thought of primarily as a factor that regulates urinary volume and sodium excretion. The physiological effects of NO can be mediated via changes in renal hemodynamics and/or salt and water absorption by the nephron. NO reduces renal vascular tone in part by dilating the afferent arteriole. 16 It also increases glomerular filtration rate. 11 NO modulates renin secretion by the juxtaglomerular apparatus 15 and tubuloglomerular feedback. 3 Finally, NO regulates transport in various nephron segments as reviewed recently by Ortiz and Garvin. 12 More recently it has been recognized that in a number of pathophysiological conditions, the actions of NO on renal hemodynamics and/or nephron transport are ...

show abstract

Endothelin inhibits thick ascending limb chloride flux via ET_Breceptor-mediated NO release

Cited by 124 publications

References 46 publications

Extrarenal ET _B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

Extrarenal ET _B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

Role of renal NO production in the regulation of medullary blood flow

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Contact Info

Product

Resources

About

Endothelin inhibits thick ascending limb chloride flux via ETBreceptor-mediated NO release

Cited by 124 publications

References 46 publications

Extrarenal ET B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

Extrarenal ET B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

Role of renal NO production in the regulation of medullary blood flow

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Contact Info

Product

Resources

About

Endothelin inhibits thick ascending limb chloride flux via ET_Breceptor-mediated NO release

Extrarenal ET _B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats

Extrarenal ET _B Plays a Significant Role in Controlling Cardiovascular Responses to High Dietary Sodium in Rats