Hypokalemia and Prostaglandin Overproduction in Bartter’s Syndrome

Senba, Shigetoshi; Konishi, Konosuke; Saruta, Takao; Ozawa, Yukio; Kato, Eiichi; Amagasaki, Y; Nakata, Isao

doi:10.1159/000183260

Cited by 13 publications

(4 citation statements)

References 21 publications

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“…It has long been observed that epithelial transport function and urinary concentrating ability in the mTAL were compromised severely during hypokalemia (Rutecki et al 1982; Senba et al 1984; Unwin et al 1994). Our present finding that the sensitivity of the apical K channel to the extracellular Ca 2 + concentration is significantly enhanced in the mTAL from rats on a KD diet may be useful to explain why some pathophysiological observations occurred during hypokalemia.…”

Section: Discussionmentioning

confidence: 99%

K Depletion Enhances the Extracellular Ca2+-Induced Inhibition of the Apical K Channels in the Mtal of Rat Kidney

Wei

Jiang

et al. 2001

The Journal of General Physiology

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We have shown previously that raising extracellular Ca2+ inhibited the apical 70-pS K channel in the thick ascending limb (TAL; Wang, W.H., M. Lu, and S.C. Hebert. 1996. Am. J. Physiol. 270:C103–C111). We now used the patch-clamp technique to study the effect of increasing the extracellular Ca2+ on the 70-pS K channel in the mTAL from rats on a different K diet. Increasing the extracellular Ca2+ from 10 μM to 0.5, 1, and to 1.5 mM in the mTAL from rats on a K-deficient (KD) diet inhibited the channel activity by 30, 65, and 90%, respectively. In contrast, raising the extracellular Ca2+ to 1.5 mM had no significant effect on channel activity in the mTAL from animals on a high K (HK) diet and further increasing the extracellular Ca2+ to 2.5, 3.5, and 5.5 mM decreased the channel activity by 29, 55, and 90%, respectively. Inhibition of the cytochrome P450 monooxygenase completely abolished the effect of the extracellular Ca2+ on channel activity in the mTAL from rats on a different K diet. In contrast, blocking cyclooxygenase did not significantly alter the responsiveness of the 70-pS K channel to the extracellular Ca2+. Moreover, addition of sodium nitropruside, a nitric oxide (NO) donor, not only increased the channel activity, but also blunted the inhibitory effect of the extracellular Ca2+ on the 70-pS K channel and decreased 20-hydroxyeicosatetraenoic acid (20-HETE) concentration in the mTAL from rats on a KD diet. In contrast, inhibiting NOS with L-NAME enhanced the inhibitory effect of the extracellular Ca2+ on the channel activity and increased 20-HETE concentration in the mTAL from rats on a high K diet. Western blot has further shown that the expression of inducible NO synthase (iNOS) is significantly higher in the renal medulla from rats on an HK diet than that on a KD diet. Also, addition of S-nitroso-N-acetylpenicillamine abolished the inhibitory effect of arachidonic acid on channel activity in the mTAL, whereas it did not block the inhibitory effect of 20-HETE. We conclude that a low dietary K intake increases the sensitivity of the 70-pS K channel to the extracellular Ca2+, and that a decrease in NOS activity is involved in enhancing the inhibitory effect of the extracellular Ca2+ on channel activity in the mTAL during K depletion.

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Section: Discussionmentioning

confidence: 99%

K Depletion Enhances the Extracellular Ca2+-Induced Inhibition of the Apical K Channels in the Mtal of Rat Kidney

Wei

Jiang

et al. 2001

The Journal of General Physiology

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“…Moreover, the fact that high concentrations of PGE 2 inhibit the apical K ϩ channels by a PKC-dependent mechanism may also be important to understand the beneficial effect of inhibiting prostaglandin synthesis in treatment of Bartter's syndrome. One of the characteristics of Bartter's syndrome is an increase in plasma PGE 2 level (29). Inhibition of cyclooxygenase (COX) improves the manifestation of the disease (27).…”

Section: Discussionmentioning

confidence: 99%

Vasopressin and PGE₂ regulate activity of apical 70 pS K⁺ channel in thick ascending limb of rat kidney

Liu

Wei

Fererri

et al. 2000

American Journal of Physiology-Cell Physiology

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Vasopressin and prostaglandin E(2) (PGE(2)) are involved in regulating NaCl reabsorption in the thick ascending limb (TAL) of the rat kidney. In the present study, we used the patch-clamp technique to study the effects of vasopressin and PGE(2) on the apical 70 pS K(+) channel in the rat TAL. Addition of vasopressin increased the channel activity, defined as NP(o), from 1.11 to 1.52 (200 pM) and 1.80 (500 pM), respectively. The effect of vasopressin can be mimicked by either forskolin (1-5 microM) or 8-bromo-cAMP/dibutyryl-cAMP (8-Br-cAMP/DBcAMP) (200-500 microM). Moreover, the effects of cAMP and vasopressin were not additive and application of 10 microM H-89 abolished the effect of vasopressin. This suggests that the effect of vasopressin is mediated by a cAMP-dependent pathway. Applying 10 nM PGE(2) alone had no significant effect on the channel activity. However, PGE(2) (10 nM) abolished the stimulatory effect of vasopressin. The PGE(2)-induced inhibition of the vasopressin effect was the result of decreasing cAMP production because addition of 200 microM 8-Br-cAMP/DBcAMP reversed the PGE(2)-induced inhibition. In addition to antagonizing the vasopressin effect, high concentrations of PGE(2) reduced channel activity in the absence of vasopressin by 33% (500 nM) and 51% (1 microM), respectively. The inhibitory effect of high concentrations of PGE(2) was not the result of decreasing cAMP production because adding the membrane-permeant cAMP analog failed to restore the channel activity. In contrast, inhibiting protein kinase C (PKC) with calphostin C (100 nM) abolished the effect of 1 microM PGE(2). We conclude that PGE(2) inhibits apical K(+) channels by two mechanisms: 1) low concentrations of PGE(2) attenuate the vasopressin-induced stimulation mainly by reducing cAMP generation, and 2) high concentrations of PGE(2) inhibit the channel activity by a PKC-dependent pathway.

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“…The hypothesis that excessive biosynthesis of prostaglandins is the central defect in Bartter syndrome has been especially attractive given the spectacular improvement that usually follows treatment with cyclooxygenase inhibitors. However, it is now evident that the altered eicosanoid metabolism is only an epiphenomenon of chronic hypokalemia and angiotensin excess [72,73].…”

Section: Pathophysiologymentioning

confidence: 99%

Bartter and related syndromes: the puzzle is almost solved

Rodríguez‐Soriano

1998

Pediatric Nephrology

163

147

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It is now evident that the term Bartter syndrome does not represent a unique entity but encompasses a variety of disorders of renal electrolyte transport. Application of molecular biology techniques has permitted a better understanding of these "Bartter-like syndromes," which at present can be divided into three different genetic and clinical entities. Neonatal Bartter syndrome is observed in newborn infants and characterized by polyhydramnios, premature delivery, life-threatening episodes of fever and dehydration during the early weeks of life, growth retardation, hypercalciuria, and early-onset nephrocalcinosis. Two molecular defects have been identified: either at the gene encoding the renal bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) or the gene encoding an ATP-sensitive inwardly rectifying K channel (ROMK). "Classic" Bartter syndrome is mostly observed during infancy and childhood and is characterized clinically by polyuria and growth retardation. Nephrocalcinosis is not present. Very recently, either deletions or mutations at the gene encoding a renal chloride channel (ClC-Kb) have been identified. Gitelman syndrome is observed in older children and adults presenting with intermittent episodes of muscle weakness and tetany, hypokalemia, and hypomagnesemia. Mutations at the gene encoding the thiazide-sensitive Na-Cl cotransporter have been identified in the majority of patients studied. Obviously the validity of this classification must be confirmed in the near future when all mutations have been described and genotypic-phenotypic correlations are better defined.

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Hypokalemia and Prostaglandin Overproduction in Bartter’s Syndrome

Cited by 13 publications

References 21 publications

K Depletion Enhances the Extracellular Ca2+-Induced Inhibition of the Apical K Channels in the Mtal of Rat Kidney

K Depletion Enhances the Extracellular Ca2+-Induced Inhibition of the Apical K Channels in the Mtal of Rat Kidney

Vasopressin and PGE₂ regulate activity of apical 70 pS K⁺ channel in thick ascending limb of rat kidney

Bartter and related syndromes: the puzzle is almost solved

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Hypokalemia and Prostaglandin Overproduction in Bartter’s Syndrome

Cited by 13 publications

References 21 publications

K Depletion Enhances the Extracellular Ca2+-Induced Inhibition of the Apical K Channels in the Mtal of Rat Kidney

K Depletion Enhances the Extracellular Ca2+-Induced Inhibition of the Apical K Channels in the Mtal of Rat Kidney

Vasopressin and PGE2 regulate activity of apical 70 pS K+ channel in thick ascending limb of rat kidney

Bartter and related syndromes: the puzzle is almost solved

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Vasopressin and PGE₂ regulate activity of apical 70 pS K⁺ channel in thick ascending limb of rat kidney