Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat.

in the medullary thick ascending limb of Henle (MTALH) contributes to NaCl balance and is also responsible for the creation of medullary interstitial hypertonicity. Despite the presence of angiotensin II subtype 1 (AT1) receptors in both the luminal and the basolateral plasma membranes of MTALH cells, no information is available on the effect of angiotensin II on NaCl reabsorption in MTALH and, furthermore, on angiotensin II-dependent medullary interstitial osmolality. MTALHs from male Sprague-Dawley rats were isolated and microperfused in vitro; transepithelial net chloride absorption (JCl) as well as transepithelial voltage (V te) were measured. Luminal or peritubular 10 Ϫ11 and 10 Ϫ10 M angiotensin II had no effect on JCl or V te. However, 10 Ϫ8 M luminal or peritubular angiotensin II reversibly decreased both J Cl and Vte. The effect of both luminal and peritubular angiotensin II was prevented by the presence of losartan (10 Ϫ6 M). By contrast, PD-23319, an AT 2-receptor antagonist, did not alter the inhibitory effect of 10 Ϫ8 M angiotensin II. Finally, no additive effect of luminal and peritubular angiotensin II was observed. We conclude that both luminal and peritubular angiotensin II inhibit NaCl absorption in the MTALH via AT1 receptors. Because of intrarenal angiotensin II synthesis, angiotensin II concentration in medullary tubular and interstitial fluids may be similar in vivo to the concentration that displays an inhibitory effect on NaCl reabsorption under the present experimental conditions. in vitro microperfusion; renal tubule; NaCl transport; angiotensin II subtype 1; losartan ANGIOTENSIN II IS A POTENT regulator of extracellular fluid volume, mainly through its direct effects on renal tubular sodium reabsorption, as well as on aldosterone synthesis. Acute systemic infusion of low-dose angiotensin II stimulates overall tubular sodium reabsorption and decreases urine sodium excretion, independently of changes in renal or systemic hemodynamics (5, 15). In rat experiments using in vivo superficial tubule microperfusion, systemic angiotensin II infusion at 20 ng⅐kg Ϫ1 ⅐min Ϫ1 , which achieves a subpressor, physiological plasma concentration (picomolar range), stimulates proximal water and NaCl reabsorption (24). Conversely, saralazin infusion, which suppresses endogenous angiotensin II activity, inhibits proximal tubule absorption (24). In addition, endogenously produced angiotensin II is responsible for a nanomolar intratubular angiotensin II concentration that stimulates proximal sodium reabsorption (33). In the more distal part of the nephron, angiotensin II also directly stimulates sodium reabsorption by activating Na ϩ /H ϩ exchange and the amiloridesensitive Na ϩ channel (2, 23, 37). Finally, angiotensin II stimulates aldosterone synthesis and thereby indirectly enhances sodium reabsorption via the epithelial sodium channel in the cortical collecting duct (26) and likely via the thiazidesensitive sodium-chloride cotransporter in the distal convoluted tubule (21).In the loop of Henle, available...

Section: Discussionmentioning

confidence: 99%

Angiotensin II inhibits NaCl absorption in the rat medullary thick ascending limb

Lerolle¹,

Leviel²,

Lebrun³

et al. 2004

“…While there is ample data to support that furosemide leads to increases in circulating levels of renin, data documenting how furosemide (and other diuretics) affects components of the intrarenal RAS is absent. This is particularly relevant with respect to intratubular and intrarenal levels of ANG II, which shows very substantial compartmentalization and have been reported to be up to 1,000 and 100 times plasma levels of ANG II, respectively (19,143). Conversely, data about the natriuresis in response to furosemide in the absence and presence of inhibitors of the RAS is limited and not consistent.…”

Section: Questions Pertaining To the Natriuretic Response To Furosemidementioning

confidence: 97%

Everything we always wanted to know about furosemide but were afraid to ask

Huang

Mees

Vos

et al. 2016

Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol 310: F958 -F971, 2016. First published February 24, 2016 doi:10.1152/ajprenal.00476.2015.-Furosemide is a widely used, potent natriuretic drug, which inhibits the Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion. extracellular fluid volume; natriuresis; renal function; chronic kidney disease; heart failure DIURETICS BLOCKING THE Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC) have an important place in the treatment of fluid overload, specifically in the context of kidney disease and heart failure (64). Of the drugs that inhibit the NKCC2 in the loop of Henle (furosemide, bumetanide, torsemide, ethacrynic acid), furosemide is most commonly applied (66) and Ͼ40 million prescriptions are dispensed every year in the USA (66a). However, many uncertainties remain about intrarenal and systemic actions of furosemide, including its two main targets NKCC1 and NKCC2.Clinically, there are a number of undesirable consequences of the use of furosemide, of which the pathophysiological mechanisms have not been sufficiently investigated. Furosemide has been associated with worsening of kidney function in patients treated for volume overload admitted for acute heart failure (104) and even glomerular filtration rate (GFR) ...

“…The renal outer medulla is inaccessible to micropuncture, so that direct sampling of outer medullary DVR plasma directly downstream of juxtamedullary glomeruli cannot be performed. Seikaly and colleagues (142) found that ANG II concentrations in star vessel plasma sampled downstream of superficial glomeruli exceed circulating levels by as much as 1,000-fold. On this basis, it seems possible that DVR could be exposed to nanomolar ANG II in vivo.…”

Section: Role Of Dvr Endothelia In the Regulation Of Vasoactivitymentioning

confidence: 99%

Physiology of the renal medullary microcirculation

Pallone

Zhang

Rhinehart

2003

186

193

Pallone, Thomas L., Zhong Zhang, and Kristie Rhinehart. Physiology of the renal medullary microcirculation. Am J Physiol Renal Physiol 284: F253-F266, 2003; 10.1152/ajprenal.00304.2002.-Perfusion of the renal medulla plays an important role in salt and water balance. Pericytes are smooth muscle-like cells that impart contractile function to descending vasa recta (DVR), the arteriolar segments that supply the medulla with blood flow. DVR contraction by ANG II is mediated by depolarization resulting from an increase in plasma membrane Cl Ϫ conductance that secondarily gates voltage-activated Ca 2ϩ entry. In this respect, DVR may differ from other parts of the efferent microcirculation of the kidney. Elevation of extracellular K ϩ constricts DVR to a lesser degree than ANG II or endothelin-1, implying that other events, in addition to membrane depolarization, are needed to maximize vasoconstriction. DVR endothelial cytoplasmic Ca 2ϩ is increased by bradykinin, a response that is inhibited by ANG II. ANG II inhibition of endothelial Ca 2ϩ signaling might serve to regulate the site of origin of vasodilatory paracrine agents generated in the vicinity of outer medullary vascular bundles. In the hydropenic kidney, DVR plasma equilibrates with the interstitium both by diffusion and through water efflux across aquaporin-1. That process is predicted to optimize urinary concentration by lowering blood flow to the inner medulla. To optimize urea trapping, DVR endothelia express the UT-B facilitated urea transporter. These and other features show that vasa recta have physiological mechanisms specific to their role in the renal medulla. vasa recta; perfusion; hypertension; oxygenation; urinary concentration; patch clamp; calcium; fura 2 THE MICROCIRCULATION OF THE kidney is regionally specialized. In the cortex, afferent and efferent arterioles govern the driving forces that promote glomerular filtration. A dense peritubular capillary plexus arising from efferent arterioles surrounds the proximal and distal convoluted tubules to accommodate enormous reabsorption of glomerular filtrate. In contrast, vasa recta serve needs specific to the medulla. Through the counterflow arrangement of descending (DVR) and ascending vasa recta (AVR), countercurrent exchange traps NaCl and urea deposited to the interstitium by collecting ducts and the loops of Henle. This is vital to maintain corticomedullary osmotic gradients but conflicts with the need to supply nutrient blood flow to medullary tissue. Metabolic substrates that enter the medulla in DVR blood diffuse to the AVR to be shunted back to the cortex. To deal with the threat of medullary hypoxia resulting from this process, the kidney has evolved a capacity to exert subtle control over regional perfusion of the outer and inner medulla. The details are far from clear, but much experimental evidence points to the complex interactions of many autocoids and paracrine agents to modulate vasomotor tone at various sites along the microvascular circuit. The goal of this review is to summarize ...