scholarly journals Modulation of NCC activity by low and high K+ intake: insights into the signaling pathways involved

2014 ◽  
Vol 306 (12) ◽  
pp. F1507-F1519 ◽  
Author(s):  
María Castañeda-Bueno ◽  
Luz Graciela Cervantes-Perez ◽  
Lorena Rojas-Vega ◽  
Isidora Arroyo-Garza ◽  
Norma Vázquez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Alkalosis ◽  
Plasma Aldosterone ◽  
Ang Ii ◽  
High K ◽  
The Face ◽  
Low K ◽  
Positive Effect ◽  
Genetic Mouse Models

Modulation of Na+-Cl− cotransporter (NCC) activity is essential to adjust K+ excretion in the face of changes in dietary K+ intake. We used previously characterized genetic mouse models to assess the role of Ste20-related proline-alanine-rich kinase (SPAK) and with-no-lysine kinase (WNK)4 in the modulation of NCC by K+ diets. SPAK knockin and WNK4 knockout mice were placed on normal-, low-, or high-K+-citrate diets for 4 days. The low-K+ diet decreased and high-K+ diet increased plasma aldosterone levels, but both diets were associated with increased phosphorylation of NCC (phospho-NCC, Thr44/Thr48/Thr53) and phosphorylation of SPAK/oxidative stress responsive kinase 1 (phospho-SPAK/OSR1, Ser383/Ser325). The effect of the low-K+ diet on SPAK phosphorylation persisted in WNK4 knockout and SPAK knockin mice, whereas the effects of ANG II on NCC and SPAK were lost in both mouse colonies. This suggests that for NCC activation by ANG II, integrity of the WNK4/SPAK pathway is required, whereas for the low-K+ diet, SPAK phosphorylation occurred despite the absence of WNK4, suggesting the involvement of another WNK (WNK1 or WNK3). Additionally, because NCC activation also occurred in SPAK knockin mice, it is possible that loss of SPAK was compensated by OSR1. The positive effect of the high-K+ diet was observed when the accompanying anion was citrate, whereas the high-KCl diet reduced NCC phosphorylation. However, the effect of the high-K+-citrate diet was aldosterone dependent, and neither metabolic alkalosis induced by bicarbonate, nor citrate administration in the absence of K+ increased NCC phosphorylation, suggesting that it was not due to citrate-induced metabolic alkalosis. Thus, the accompanying anion might modulate the NCC response to the high-K+ diet.

Dissociation in plasma renin and adrenal ANG II and aldosterone responses to sodium restriction in rats

1991 ◽  
Vol 261 (4) ◽  
pp. E487-E494 ◽  
Author(s):  
A. Menachery ◽  
L. M. Braley ◽  
I. Kifor ◽  
R. Gleason ◽  
G. H. Williams
Keyword(s):  
Plasma Renin ◽  
Fold Increase ◽  
Plasma Aldosterone ◽  
Delayed Response ◽  
Ang Ii ◽  
Sodium Restriction ◽  
Sodium Depletion ◽  
Pathway Activity

In rats, plasma renin activity (PRA) increases sharply, reaching a plateau within hours of sodium restriction. Plasma aldosterone increases gradually, not reaching a plateau for 1-2 days. To determine whether this dissociation is secondary to the time needed to modify adrenal sensitivity to angiotensin II (ANG II) and to assess the role of locally produced ANG II in this process, rats were salt restricted for 0-120 h. Plasma hormone levels were assessed, adrenal ANG II was measured, and basal and ANG II (1 x 10(-8) M)-stimulated steroidogenesis were determined in vitro. Although PRA attained an elevated plateau within 8 h, plasma aldosterone did not peak until after 48 h of sodium depletion. The in vitro aldosterone sensitivity to exogenous ANG II was not apparent until rats had been salt restricted for 16 h. A plateau (4-fold increase above the ANG II response on high salt) was achieved between 24 and 48 h. Adrenal ANG II also exhibited a similar delayed response that correlates significantly with changes in aldosterone biosynthesis and late pathway activity. Thus the dissociation between PRA and plasma aldosterone may be secondary to a lag in the zona glomerulosa's (ZG) steroidogenic response to ANG II as well as a parallel lag in tissue ANG II production, suggesting that changes in tissue ANG II may mediate ZG sensitivity to ANG II during sodium deprivation.

scholarly journals Aldosterone-dependent and -independent regulation of Na+ and K+ excretion and ENaC in mouse kidneys

2020 ◽  
Vol 319 (2) ◽  
pp. F323-F334
Author(s):  
Lei Yang ◽  
Gustavo Frindt ◽  
Yuanyuan Xu ◽  
Shinichi Uchida ◽  
Lawrence G. Palmer
Keyword(s):  
Glomerular Filtration Rate ◽  
Western Blot ◽  
Filtration Rate ◽  
Ex Vivo ◽  
Western Blots ◽  
High K ◽  
Collecting Ducts ◽  
Low K ◽  
Clearance Methods

We investigated the regulation of Na+ and K+ excretion and the epithelial Na+ channel (ENaC) in mice lacking the gene for aldosterone synthase (AS) using clearance methods to assess excretion and electrophysiology and Western blot analysis to test for ENaC activity and processing. After 1 day of dietary Na+ restriction, AS−/− mice lost more Na+ in the urine than AS+/+ mice did. After 1 wk on this diet, both genotypes strongly reduced urinary Na+ excretion, but creatinine clearance decreased only in AS−/− mice. Only AS+/+ animals exhibited increased ENaC function, assessed as amiloride-sensitive whole cell currents in collecting ducts or cleavage of αENaC and γENaC in Western blots. To assess the role of aldosterone in the excretion of a K+ load, animals were fasted overnight and refed with high-K+ or low-K+ diets for 5 h. Both AS+/+ and AS−/− mice excreted a large amount of K+ during this period. In both phenotypes the excretion was benzamil sensitive, indicating increased K+ secretion coupled to ENaC-dependent Na+ reabsorption. However, the increase in plasma K+ under these conditions was much larger in AS−/− animals than in AS+/+ animals. In both groups, cleavage of αENaC and γENaC increased. However, Na+ current measured ex vivo in connecting tubules was enhanced only in AS+/+ mice. We conclude that in the absence of aldosterone, mice can conserve Na+ without ENaC activation but at the expense of diminished glomerular filtration rate. Excretion of a K+ load can be accomplished through aldosterone-independent upregulation of ENaC, but aldosterone is required to excrete the excess K+ without hyperkalemia.

Role of EGFR/ErbB2 and PI3K/AKT/e-NOS in Lycium barbarum polysaccharides Ameliorating Endothelial Dysfunction Induced by Oxidative Stress

2019 ◽  
Vol 47 (07) ◽  
pp. 1523-1539 ◽  
Author(s):  
Wenjuan Zhang ◽  
Huifang Yang ◽  
Lingqin Zhu ◽  
Yan Luo ◽  
Lihong Nie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Cell Viability ◽  
Therapeutic Option ◽  
Critical Role ◽  
Ang Ii ◽  
Lycium Barbarum ◽  
Underlying Mechanisms ◽  
Lycium Barbarum Polysaccharides

Lycium barbarum polysaccharides (LBP) are the major ingredients of wolfberry. In this study, we investigated the role of LBP in endothelial dysfunction induced by oxidative stress and the underlying mechanisms using thoracic aortic endothelial cells of rat (RAECs) as a model. We found that Ang II inhibits cell viability of RAECs with 10[Formula: see text][Formula: see text]mol/L of Ang II treatment for 24[Formula: see text]h most potential ([Formula: see text]), the level of reactive oxygen species (ROS) is increased by Ang II treatment ([Formula: see text]), and the expression of Occludin and Zonula occludens-1 (ZO-1) is decreased by Ang II treatment ([Formula: see text]). However, preincubation of cells with LBP could inhibit the changes caused by Ang II, LBP increased cell viability ([Formula: see text]), decreased the level of ROS ([Formula: see text]), and up-regulated the expression of Occludin ([Formula: see text]) and ZO-1. In addition, Ang II treatment increased the expression of EGFR and p-EGFR (Try1172) and which can be inhibited by LBP. On the contrary, expression of ErbB2, p-ErbB2 (Try1248), PI3K, p-e-NOS (Ser1177) ([Formula: see text]), and p-AKT (Ser473) ([Formula: see text]) was inhibited by Ang II treatment and which can be increased by LBP. Treatment of the cells with inhibitors showed that the regulation of p-e-NOS and p-AKT expression by Ang II and LBP can be blocked by PI3K inhibitor wortmannin but not EGFR and ErbB2 inhibitor AC480. Taken together, our results suggested that LBP plays a critical role in maintaining the integrality of blood vessel endothelium through reduced production of ROS via regulating the activity of EGFR, ErbB2, PI3K/AKT/e-NOS, and which may offer a novel therapeutic option in the management of endothelial dysfunction.

scholarly journals MicroRNA-194 (miR-194) regulates ROMK channel activity by targeting intersectin 1

2014 ◽  
Vol 306 (1) ◽  
pp. F53-F60 ◽  
Author(s):  
Dao-Hong Lin ◽  
Peng Yue ◽  
Chengbiao Zhang ◽  
Wen-Hui Wang
Keyword(s):  
Collecting Duct ◽  
Luciferase Reporter ◽  
Pcr Analysis ◽  
Seed Sequence ◽  
Cortical Collecting Duct ◽  
Channel Activity ◽  
Luciferase Reporter Gene ◽  
High K ◽  
Low K

The aim of the study is to explore the role of miR-194 in mediating the effect of high-K (HK) intake on ROMK channel. Northern blot analysis showed that miR-194 was expressed in kidney and that HK intake increased while low-K intake decreased the expression of miR-194. Real-time PCR analysis further demonstrated that HK intake increased the miR-194 expression in the cortical collecting duct. HK intake decreased the expression of intersectin 1 (ITSN1) which enhanced With-No-Lysine Kinase (WNK)-induced endocytosis of ROMK. Expression of miR-194 mimic decreased luciferase reporter gene activity in HEK293 T cells transfected with ITSN-1–3′UTR containing the complementary seed sequence for miR-194. In contrast, transfection of miR-194 inhibitor increased the luciferase activity. This effect was absent in the cells transfected with mutated 3′UTR of ITSN1 in which the complimentary seed sequence was deleted. Moreover, the inhibition of miR-194 expression increased the protein level of endogenous ITSN1 in HEK293T cells. Expression of miR-194 mimic also decreased the translation of exogenous ITSN1 in the cells transfected with the ITSN1 containing 3′UTR but not with 3′UTR-free ITSN1. Expression of pre-miR-194 increased K currents and ROMK expression in the plasma membrane in ROMK-transfected cells. Coexpression of ITSN1 reversed the stimulatory effect of miR-194 on ROMK channels. This effect was reversed by coexpression of ITSN1. We conclude that miR-194 regulates ROMK channel activity by modulating ITSN1 expression thereby enhancing ITSN1/WNK-dependent endocytosis. It is possible that miR-194 is involved in mediating the effect of a HK intake on ROMK channel activity.

scholarly journals Dependence of mammalian putrescine and spermidine transport on plasma-membrane potential: identification of an amiloride binding site on the putrescine carrier

1998 ◽  
Vol 330 (3) ◽  
pp. 1283-1291 ◽  
Author(s):  
Richard POULIN ◽  
Chenqi ZHAO ◽  
Savita VERMA ◽  
René CHAREST-GAUDREAULT ◽  
Marie AUDETTE
Keyword(s):  
Plasma Membrane ◽  
Membrane Potential ◽  
Binding Site ◽  
Biochemical Properties ◽  
Mitochondrial Potential ◽  
Plasma Membrane Potential ◽  
High K ◽  
Polyamine Transport ◽  
Low K

The mechanism of mammalian polyamine transport is poorly understood. We have investigated the role of plasma-membrane potential (ΔΨpm) in putrescine and spermidine uptake in ZR-75-1 human breast cancer cells. The rate of [3H]putrescine and [3H]spermidine uptake was inversely correlated to extracellular [K+] ([K+]o) and to ΔΨpm, as determined by the accumulation of [3H]tetraphenylphosphonium bromide (TPP). Inward transport was unaffected by a selective decrease in mitochondrial potential (ΔΨmit) induced by valinomycin at low [K+]o, but was reduced by ≈ 60% by the rheogenic protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP), which rapidly (≤ 15 min) collapsed both ΔΨpm and ΔΨmit. Plasma-membrane depolarization by high [K+]o or CCCP did not enhance putrescine efflux in cells pre-loaded with [3H]putrescine, suggesting that decreased uptake caused by these agents did not result from a higher excretion rate. On the other hand, the electroneutral K+/H+ exchanger nigericin (10 μM) co-operatively depressed [3H]TPP, [3H]putrescine and [3H]spermidine uptake in the presence of ouabain. Suppression of putrescine uptake by nigericin+ouabain was Na+-dependent, suggesting that plasma-membrane repolarization by the electrogenic Na+ pump was required upon acidification induced by nigericin, due to the activation of the Na+/H+ antiporter. The sole addition of 5-N,N-hexamethylene amiloride, a potent inhibitor of the Na+/H+ antiporter, strongly inhibited putrescine uptake in a competitive fashion [Ki 4.0±0.9 (S.D.) μM], while being a weaker antagonist of spermidine uptake. The potency of a series of amiloride analogues to inhibit putrescine uptake was clearly different from that of the Na+/H+ antiporter, and resembled that noted for Na+ co-transport proteins. These data demonstrate that putrescine and spermidine influx is mainly unidirectional and strictly depends on ΔΨpm, but not ΔΨmit. This report also provides first evidence for a high-affinity amiloride-binding site on the putrescine carrier, which provides new insight into the biochemical properties of this transporter.

Role of oxidative stress in angiotensin II-induced enhanced expression of Giα proteins and adenylyl cyclase signaling in A10 vascular smooth muscle cells

2007 ◽  
Vol 292 (4) ◽  
pp. H1922-H1930 ◽  
Author(s):  
Yuan Li ◽  
Georgios Lappas ◽  
Madhu B. Anand-Srivastava
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Adenylyl Cyclase ◽  
Vascular Smooth Muscle Cells ◽  
Ang Ii ◽  
Enhanced Expression

We have previously reported that angiotensin II (ANG II) treatment of A10 vascular smooth muscle cells (VSMCs) increased inhibitory G proteins (Gi protein) expression and associated adenylyl cyclase signaling which was attributed to the enhanced MAP kinase activity. Since ANG II has been shown to increase oxidative stress, we investigated the role of oxidative stress in ANG II-induced enhanced expression of Giα proteins and examined the effects of antioxidants on ANG II-induced enhanced expression of Giα proteins and associated adenylyl cyclase signaling in A10 VSMCs. ANG II treatment of A10 VSMCs enhanced the production of O2− and the expression of Nox4 and P47phox, different subunits of NADPH oxidase, which were attenuated toward control levels by diphenyleneiodonium (DPI). In addition, ANG II augmented the expression of Giα-2 and Giα-3 proteins in a concentration- and time-dependent manner; the maximal increase in the expression of Giα was observed at 1 to 2 h and at 0.1–1.0 μM. The enhanced expression of Giα-2 and Giα-3 proteins was restored to control levels by antioxidants such as N-acetyl-l-cysteine, α-tocopherol, DPI, and apocynin. In addition, ANG II also enhanced the ERK1/2 phosphorylation that was restored to control levels by DPI. Furthermore, the inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of 5′- O-(3-triotriphosphate) (receptor-independent Gi functions) and ANG II-, des(Glu18,Ser19,Glu20,Leu21,Gly22)atrial natriuretic peptide4-23-NH2 (natriuretic peptide receptor-C agonist), and oxotremorine-mediated inhibitions of adenylyl cyclase (receptor-dependent functions) that were augmented in ANG II-treated VSMCs was also restored to control levels by antioxidant treatments. In addition, Gsα-mediated diminished stimulation of adenylyl cyclase by stimulatory hormones in ANG II-treated cells was also restored to control levels by DPI. These results suggest that ANG II-induced enhanced levels of Giα proteins and associated functions in VSMCs may be attributed to the ANG II-induced enhanced oxidative stress, which exerts its effects through mitogen-activated protein kinase signaling pathway.

Abstract 434: Sirt4 Accelerates Ang II-induced Pathological Cardiac Hypertrophy by Inhibiting Mnsod Activity

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Depei Liu ◽  
Yu-Xuan Luo ◽  
Xiaoqiang Tang ◽  
Xi-Zhou An ◽  
Xue-Min Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Manganese Superoxide Dismutase ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy

Aims: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress. Methods and results: Male C57BL/6 Sirt4 knockout mice, transgenic mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analyzed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-transgenic mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with MnTBAP, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice. Conclusions: Sirt4 promotes hypertrophic growth and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.

Cardiac hypertrophy is associated with altered thioredoxin and ASK-1 signaling in a mouse model of menopause

2008 ◽  
Vol 295 (4) ◽  
pp. H1481-H1488 ◽  
Author(s):  
Talin Ebrahimian ◽  
M. Ram Sairam ◽  
Ernesto L. Schiffrin ◽  
Rhian M. Touyz
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Receptor Expression ◽  
Ang Ii ◽  
Antioxidant Function ◽  
Endogenous Antioxidant

Oxidative stress is implicated in menopause-associated hypertension and cardiovascular disease. The role of antioxidants in this process is unclear. We questioned whether the downregulation of thioredoxin (TRX) is associated with oxidative stress and the development of hypertension and target-organ damage (cardiac hypertrophy) in a menopause model. TRX is an endogenous antioxidant that also interacts with signaling molecules, such as apoptosis signal-regulated kinase 1 (ASK-1), independently of its antioxidant function. Aged female wild-type (WT) and follitropin receptor knockout (FORKO) mice (20–24 wk), with hormonal imbalances, were studied. Mice were infused with ANG II (400 ng·kg−1·min−1; 14 days). Systolic blood pressure was increased by ANG II in WT (166 ± 8 vs. 121 ± 5 mmHg) and FORKO (176 ± 7 vs. 115 ± 5 mmHg; P < 0.0001; n = 9/group) mice. In ANG II-infused FORKO mice, cardiac mass was increased by 42% ( P < 0.001). This was associated with increased collagen content and augmented ERK1/2 phosphorylation (2-fold). Cardiac TRX expression and activity were decreased by ANG II in FORKO but not in WT ( P < 0.01) mice. ASK-1 expression, cleaved caspase III content, and Bax/Bcl-2 content were increased in ANG II-infused FORKO ( P < 0.05). ANG II had no effect on cardiac NAD(P)H oxidase activity or on O2•− levels in WT or FORKO. Cardiac ANG II type 1 receptor expression was similar in FORKO and WT. These findings indicate that in female FORKO, ANG II-induced cardiac hypertrophy and fibrosis are associated with the TRX downregulation and upregulation of ASK-1/caspase signaling. Our data suggest that in a model of menopause, protective actions of TRX may be blunted, which could contribute to cardiac remodeling independently of oxidative stress and hypertension.

K+-induced natriuresis is preserved during Na+ depletion and accompanied by inhibition of the Na+-Cl− cotransporter

2013 ◽  
Vol 305 (8) ◽  
pp. F1177-F1188 ◽  
Author(s):  
Nils van der Lubbe ◽  
Arthur D. Moes ◽  
Lena L. Rosenbaek ◽  
Sharon Schoep ◽  
Marcel E. Meima ◽  
...  
Keyword(s):  
Control Diet ◽  
Plasma Aldosterone ◽  
Distal Convoluted Tubule ◽  
Similar Degree ◽  
Ang Ii ◽  
High K ◽  
Tubule Cells ◽  
Na Depletion

During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na+ retention and K+ secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na+ diet, high-K+ diet, or combined diet. The low-Na+ and combined diets increased plasma and kidney ANG II. The low-Na+ and high-K+ diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na+ intake and higher aldosterone, the high-K+ and combined diets caused a greater natriuresis than the control and low-Na+ diets, respectively ( P < 0.001 for both). This K+-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na+-Cl− cotransporter (NCC). In contrast, the epithelial Na+ channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high-K+ and combined diets also increased WNK4 but decreased Nedd4-2 in the kidney. Total and phosphorylated Ste-20-related kinase were also increased but were retained in the cytoplasm of distal convoluted tubule cells. In summary, high dietary K+ overrides the effects of ANG II and aldosterone on NCC to deliver sufficient Na+ to ENaC for K+ secretion. K+ may inhibit NCC through WNK4 and help activate ENaC through Nedd4-2.

Control of capillary hydraulic conductivity via membrane potential-dependent changes in Ca2+ influx

1992 ◽  
Vol 262 (1) ◽  
pp. H144-H148 ◽  
Author(s):  
R. S. Zhang ◽  
V. H. Huxley
Keyword(s):  
Membrane Potential ◽  
Repeated Measures ◽  
Chloride Concentration ◽  
Barrier Properties ◽  
Extracellular Potassium ◽  
High K ◽  
Important Regulator ◽  
Low K

Capillary permeability has been shown to be sensitive to the levels of intracellular calcium. We examined the role of membrane potential in the regulation of capillary water permeability by a Ca2+ leak mechanism. Repeated measures of Lp were taken in situ on individually perfused mesenteric capillaries of cerebrally pithed frogs (Rana pipiens). A rise in extracellular potassium ([K+]o) to 24 mM induced a 45% decrease in Lp (n = 20), whereas lowering [K+]o to 0.24 mM elevated Lp by twofold (n = 9). To investigate whether these changes in Lp were due specifically to changes in membrane potential and consequent changes in the driving force for Ca2+ influx, we performed the following experiments: 1) [K+]o was elevated while the product of [K+]o and extracellular chloride concentration [Cl-]o was kept constant, 2) [K+]o was elevated under nominally Ca(2+)-free conditions, 3) K+ leak was induced by addition of 10 microM valinomycin, and 4) Na(+)-K+ pump was blocked by 10 microM ouabain. A constant [K+]o [Cl-]o product did not prevent high K+ from lowering Lp. Nominally Ca(2+)-free conditions abolished the effect of high K+. Valinomycin mimicked the response to low K+, and ouabain failed to change Lp. The data from this study conform to the hypothesis that membrane potential is an important regulator of capillary barrier properties via changes in Ca2+ influx through leak channels.

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