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  • Cystic fibrosis  (8)
  • Rat  (7)
  • 1
    Electronic Resource
    Electronic Resource
    Regulation of epithelial ion channels by the cystic fibrosis transmembrane conductance regulator (1996)
    Springer
    Journal of molecular medicine 74 (1996), S. 527-534 
    Details
    ISSN: 1432-1440
    Keywords: Cystic fibrosis ; Cl- channel ; K+ channel ; Na+ channel ; Respiratory tract ; Colon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In most epithelia ion transport is tightly regulated. One major primary target of such regulation is the modulation of ion channels. The present brief review focuses on one specific example of ion channel regulation by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a cAMP-regulated Cl- channel. Its defect leads to the variable clinical pictures of cystic fibrosis (CF), which today is understood as a primary defect of epithelial Cl- channels in a variety of tissues such as the respiratory tract, intestine, pancreas, skin, epididymis, fallopian tube, and others. Most recent findings suggest that CFTR also acts as a channel regulator. Three examples are discussed by which CFTR regulates other Cl- channels, K+ channels, and epithelial Na+ channels. From this perspective it is evident that CFTR may play a major role in the integration of cellular function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00204979
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  • 2
    Electronic Resource
    Electronic Resource
    Characterization of human sweat duct chloride conductance by chloride channel blockers (1987)
    Springer
    Pflügers Archiv 408 (1987), S. 511-514 
    Details
    ISSN: 1432-2013
    Keywords: Human sweat duct ; Cl− conductance ; Cl− channel blockers ; Cystic fibrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To characterize the chloride conductance of human sweat duct the effect of various analogues of diphenylamine-2-carboxylate was investigated on the transepithelial potential difference (PDT) and resistance (R T ) of isolated microperfused sweat ducts. Although the most powerful analogues which block Cl− channels in various secretory and absorptive epithelia were ineffective, a number of analogues (in particular Cl substituted ones) were found which at high concentrations significantly and reversibly increased PDT andR T . The data suggest that the main chloride conductance pathway of sweat duct epithelium resides in the cell membranes rather than in the tight junctions. In addition the different blocking spectra of the chloride conductances of sweat duct and tracheal epithelium (Welsh MJ, Science 232:1648, 1986) suggest that the combined impairment of both conductances in cystic fibrosis does not result from a molecular defect in the Cl− channels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00585077
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  • 3
    Electronic Resource
    Electronic Resource
    Handling of allantoin by the rat kidney (1975)
    Springer
    Pflügers Archiv 357 (1975), S. 201-207 
    Details
    ISSN: 1432-2013
    Keywords: Allantoin ; Uricase ; Kidney ; Clearance ; Micropuncture ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Renal excretion of allantoin was measured by tracer techniques. After injection of 2-C14 urate and H3 inulin, clearances of allantoin and inulin were measured and both proximal and distal tubules were micropunctured. In confirmation of earlier results 2-C14 urate injected into an intact animal is very rapidly converted to C14 allantoin: after 15 min more than 90% of urinary tracer is present as allantoin. It was further observed that 1) allantoin clearance is essentially identical with inulin clearance over a wide range of urine flows; 2) no net transport of allantoin occurs in either proximal or distal tubules. Clearly allantoin is handled by the rat kidney like inulin. The total excretion of filtered allantoin unlike that of filtered urate provides an easy and effective mechanism for animals possessing the enzyme uricase to dispose of their purine loads.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00585975
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  • 4
    Electronic Resource
    Electronic Resource
    In vivo studies on uricase activity in the rat (1974)
    Springer
    Pflügers Archiv 351 (1974), S. 323-330 
    Details
    ISSN: 1432-2013
    Keywords: Uricase ; Urate ; Allantoin ; Liver ; Kidney ; Microperfusion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. In vivo uricase activity was tested in rats by injection of 2-C14 urate and measurement of the total C14 activity and the fractional activities of allantoin, allantoic acid and urea in samples of blood and urine. In control animals, 5 min after the injection, 70% of the plasma tracer was already present in the form of allantoin. No allantoic acid and urea were produced. Intestinectomy had no measurable influence on uricase activity. On the other hand, hepatectomy or ligation of the hepatic artery combined with subtotal viscerectomy did abolish uricase activity almost completely. 2. Following microinjections into proximal tubules of Ringer solution containing 2-C14 urate, urine samples during early recovery mainly contained labelled urate, whereas in later samples the fraction of labelled allantoin increased. About 12 min after the microinjection the urine of both kidneys contained equal amounts of tracer mainly in the form of allantoin. 3. When segments of proximal tubules were perfused with an equilibrium solution containing tracer amounts of C 14 urate, no urate was metabolized during its passage through the proximal tubule. 4. C 14 urate was offered from the peritubular capillaries and samples of tubular fluid were analyzed, Again, all the tracer in the tubular fluid was in the form of urate, indicating that urate is not oxidized when it is transported across the tubular cell. It is concluded from these results that: 1. The rat kidney has no significant uricase activity. 2. Urate transport in the kidney is not influenced by this enzyme. 3. The degradation of urate to allantoin takes place at extrarenal sites, mainly in the liver.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00593318
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  • 5
    Electronic Resource
    Electronic Resource
    N-Acetyl-L-cysteine and its derivatives activate a Cl− conductance in epithelial cells (1996)
    Springer
    Pflügers Archiv 431 (1996), S. 549-555 
    Details
    ISSN: 1432-2013
    Keywords: Key wordsN-Acetyl-L-cysteine ; S-Carboxymethyl-L-cysteine ; Respiratory epithelial cells ; Cystic fibrosis ; CFTR ; Cl ; conductance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract N-Acetyl-L-cysteine (NAC) is a widely used mucolytic drug in patients with a variety of respiratory disorders including cystic fibrosis (CF). The beneficial effects of NAC are empirical and the exact mechanism of action in the airways remains obscure. In the present study we examined the effects on whole-cell (wc) conductance (G m) and voltage (V m) of NAC and the congeners S-carboxymethyl-L-cysteine (CMC) and S-carbamyl-L-cysteine (CAC) and L-cysteine in normal and CF airway epithelial cells. L-Cysteine (1 mmol/l) had no detectable effect. The increase in G m (ΔG m) by the other compounds was concentration dependent and was (all substances at 1 mmol/l) 3.8 ± 1.4 nS (NAC; n = 11), 4.2 ± 1.0 nS (CMC; n = 16) and 3.8 ± 1.6 nS (CAC; n = 18), respectively. The changes in G m were paralleled by an increased depolarization (ΔV m) when extracellular Cl− concentration was reduced to 34 mmol/l: under control conditions = −4.1 ± 2.1 versus 10.2 ± 2.1 mV in the presence of NAC, CMC, CAC (n = 36). In the presence of NAC, CMC and CAC, the reduction in Cl− concentration was paralleled by a reduction of G m by 2.1 ± 0.4 nS (n = 35), indicating that all substances acted by increasing the Cl− conductance. Analysis of intracellular pH did not reveal any changes by any of the compounds (1 mmol/l). A Cl− conductance was also activated in HT29 colonic carcinoma and CF tracheal epithelial (CFDE) cells but not in CFPAC-1 cells, which do not express detectable levels of ΔF508-CFTR, suggesting that the presence of CFTR may be a prerequisite for the induction of Cl− currents. Next we examined the ion currents in Xenopus oocytes microinjected with CFTR-cRNA. Water-injected oocytes did not respond to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) (ΔG m = 0.08 ± 0.04 μS; n = 10) and no current was activated when these oocytes were exposed to NAC or CMC. In contrast, in CFTR-cRNA-injected oocytes G m was enhanced when intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) was increased by forskolin and IBMX (G m = 4.5 ± 1.3 μS; n = 8). G m was significantly increased by 0.74 ± 0.2 μS (n = 11) and 0.46 ± 0.1 μS (n = 10) when oocytes were exposed to NAC and CMC, respectively (both 1 mmol/l). In conclusion, NAC and its congeners activate Cl− conductances in normal and CF airway epithelial cells and hence induce electrolyte secretion which may be beneficial in CF patients. CFTR appears to be required for this response in an as yet unknown fashion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240050034
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  • 6
    Electronic Resource
    Electronic Resource
    Small and intermediate conductance chloride channels in HT29 cells (1993)
    Springer
    Pflügers Archiv 424 (1993), S. 456-464 
    Details
    ISSN: 1432-2013
    Keywords: Cl− channels ; Cl− secretion ; HT29 ; Ca2+ ; cAMP ; Protein kinase A ; Cytosolic inhibitor ; Cystic fibrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recently, it has been shown that intermediate conductance outwardly rectifying chloride channels (ICOR) are blocked by cytosolic inhibitor (C. I.) found in the cytosol of human placenta and epithelial cells. C. I. also reduced the baseline current in excised membrane patches of HT29 cells. In the present study, this effect of C. I. was characterized further. Heat treated human placental cytosol was extracted in organic solvents and dissolved in different electrolyte solutions. It is shown that the reduction of baseline conductance (g o) is caused by inhibition of small non-resolvable channels, which are impermeable to Na+ and SO4 2−, but permeable to Cl−. The regulation of these small Cl−-conducting channels (g o) and of ICOR was examined further. First, no activating effects of protein kinase A (PKA) on the open probability (P o) of the ICOR or on the go) were observed. The Po of the ICOR was reduced by 22% in a Ca2+-free solution. g o was insensitive to changes in the Ca2+ activity. The effects of C. I. from a cystic fibrosis (CF) placenta and the CF pancreatic duct cell line CFPAC-1 were compared with the effects of corresponding control cytosols, and no significant differences between CF and control cytosols were found. We conclude that the excised patches of HT29 cells contain ICOR and small non-resolvable Cl−-conducting channels which are similarly inhibited by C. I. Apart from a weak effect of Ca2+ on the ICOR, g o and the ICOR do not seem to be directly controlled by Ca2+ or PKA. C. I. of normal and CF epithelia have a similar inhibitory potency on Cl− channels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00374908
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  • 7
    Electronic Resource
    Electronic Resource
    cAMP stimulation of CFTR-expressing Xenopus oocytes activates a chromanol-inhibitable K+ conductance (1996)
    Springer
    Pflügers Archiv 432 (1996), S. 516-522 
    Details
    ISSN: 1432-2013
    Keywords: Key words Cl ; channel ; K+ channel ; Cellular homeostasis ; Cystic fibrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a Cl–channel in a large variety of cells expressing this protein. Recently evidence has accumulated that it also regulates other ion channels. A coordinated increase in Cl–and K+ conductances is necessary in many Cl–-secreting epithelia. This has, for example, recently been demonstrated for the colonic crypt, for which a new type of K+ channel and a specific inhibitor of this channel, the chromanol 293B, have been described. In the present study we have examined whether the cAMP-evoked activation of CFTR, overexpressed in Xenopus oocytes, in addition to its known activation of a Cl–conductance, also upregulates endogenous K+ channels. It is shown that CFTR-cRNA-injected but not water-injected oocytes possess a cAMP-activated Cl–conductance. Of the cAMP-induced whole-cell current increase, 15–25% was due to a 293B-, Ba2+and TEA+-inhibitable K+ conductance. The cRNA of the mutated CFTR (ΔF508 CFTR) had no such effect. We conclude that cAMP activated CFTR and an endogenous IsK-type and 293B-sensitive K+ conductance. Similar events, occurring, for example, in the colonic crypt possessing CFTR and 293B-sensitive K+ channels, might explain the coordinated cAMP-mediated increase in Cl–and K+ conductances.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240050164
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  • 8
    Electronic Resource
    Electronic Resource
    Na+ and Cl− conductances in airway epithelial cells: increased Na+ conductance in cystic fibrosis (1995)
    Springer
    Pflügers Archiv 431 (1995), S. 1-9 
    Details
    ISSN: 1432-2013
    Keywords: Na+ channel ; Respiratory epithelial cells ; Human Na+ channel ; Micropuncture ; Patch clamp ; Cystic fibrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Na+ and Cl− conductances in the apical membrane of respiratory epithelial cells are essential for electrolyte and water transport in the airways. Apart from the well described defect in adenosine 3′∶5′ cyclic monophosphate-(cAMP-) dependent activation of Cl− conductances in cystic fibrosis (CF), an increased Na+ conductance has also been reported from transepithelial measurements. In the present experiments we tried to identify these conductances in nasal epithelial cells using patch-clamp and microelectrode techniques. With these methods we found identical and relatively low membrane voltages of about −36 mV in both freshly isolated and primary cultured normal and CF nasal epithelial cells. A Cl− conductance could be activated by cAMP in normal (ΔG=3.1±0.8 nS, n=10) but not in CF (ΔG=0.3±0.1 nS, n=11) cells, whereas Ca2+-dependent Cl− currents activated by adenosine 5′-triphosphate (ATP) and bradykinin were present in both types of cells. Cell-attached membrane patches from stimulated cells did not reveal discernible singlechannel events when activated with any of the agonists. A Na+ conductance was also detected in freshly isolated ciliated respiratory cells in impalement studies, as evidenced by the hyperpolarization induced by 10 μmol/l amiloride (ΔV= −5.2±0.6 mV, n=56) and when Na+ was replaced in the bath by N-methyld-glucamine (NMDG) (ΔV = −5.7±0.9 mV, n=14). In whole-cell patch-clamp experiments, the amilorideinduced hyperpolarization was significantly larger in CF (ΔV = −9.7±2.4 mV, n=22) when compared to normal (ΔV = −3.3±0.9 mV, n=27) cells in short-term culture. Reverse transcriptase polymerase chain reaction analysis of normal respiratory cells identified messenger RNA of both the cystic fibrosis transmembrane conductance regulator (CFTR) as well as the human epithelial Na+ channel (hNaCh). The present experiments confirm the absence of a cAMP-dependent Cl− conductance in CF respiratory epithelial cells and support previous findings obtained in transepithelial and microelectrode studies which indicate an increased Na+ conductance in respiratory epithelial cells from CF patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00374371
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  • 9
    Electronic Resource
    Electronic Resource
    N-Acetyl-l-cysteine and its derivatives activate a Cl− conductance in epithelial cells (1996)
    Springer
    Pflügers Archiv 431 (1996), S. 549-555 
    Details
    ISSN: 1432-2013
    Keywords: N-Acetyl-l-cysteine-S-Carboxymethyl-l-cysteine ; Respiratory epithelial cells ; Cystic fibrosis ; CFTR ; Cl− conductance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract N-Acetyl-l-cysteine (NAC) is a widely used mucolytic drug in patients with a variety of respiratory disorders including cystic fibrosis (CF). The beneficial effects of NAC are empirical and the exact mechanism of action in the airways remains obscure. In the present study we examined the effects on whole-cell (we) conductance (G m) and voltage (V m) of NAC and the congeners S-carboxymethyl-l-cysteine (CMC) andS-carbamyl-L-cysteine (CAC) andL-cysteine in normal and CF airway epithelial cells.L-Cysteine (1 mmol/1) had no detectable effect. The increase inG m (ΔGm) by the other compounds was concentration dependent and was (all substances at 1 mmol/1) 3.8 ± 1.4 nS (NAC; n = 11), 4.2 ± 1.0 nS (CMC;n = 16) and 3.8 ± 1.6 nS (CAC;n = 18), respectively. The changes in Gm were paralleled by an increased depolarization (ΔVm) when extracellular Cl− concentration was reduced to 34 mmol/1: under control conditions = -4.1 ± 2.1 versus 10.2 ± 2.1 mV in the presence of NAC, CMC, CAC (n = 36). In the presence of NAC, CMC and CAC, the reduction in Cl− concentration was paralleled by a reduction ofG m by 2.1 ± 0.4 nS (n = 35), indicating that all substances acted by increasing the Cl− conductance. Analysis of intracellular pH did not reveal any changes by any of the compounds (1 mmol/1). A Cl− conductance was also activated in HT29 colonic carcinoma and CF tracheal epithelial (CFDE) cells but not in CFPA1 cells, which do not express detectable levels of ΔF508-CFTR, suggesting that the presence of CFTR may be a prerequisite for the induction of Cl− currents. Next we examined the ion currents in Xenopus oocytes microinjected with CFTR-cRNA. Water-injected oocytes did not respond to activation by forskolin and 3-isobutyl-l-methylxanthine (IBMX) (ΔGm = 0.08 ±0.04 μS;n = 10) and no current was activated when these oocytes were exposed to NAC or CMC. In contrast, in CFTR-cRNA-injected cocytesG m was enhanced when intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) was increased by forskolin and IBMX (G m = 4.5 ± 1.3 μS;n = 8).G m was significantly increased by 0.74 ± 0.2 μS (n = 11) and 0.46 ± 0.1 μS (n = 10) when oocytes were exposed to NAC and CMC, respectively (both I mmol/1). In conclusion, NAC and its congeners activate Cl− conductances in normal and CF airway epithelial cells and hence induce electrolyte secretion which may be beneficial in CF patients. CFTR appears to be required for this response in an as yet unknown fashion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02191902
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  • 10
    Electronic Resource
    Electronic Resource
    Luminal ATP induces K+ secretion via a P2Y2 receptor in rat distal colonic mucosa (1998)
    Springer
    Pflügers Archiv 436 (1998), S. 712-716 
    Details
    ISSN: 1432-2013
    Keywords: Key words ATP ; Distal colon ; Exocrine secretion ; K+ secretion ; Luminal receptors ; P2Y2 receptor ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We have previously investigated, in studies of rat distal colonic mucosa, the effect of ATP added to the basolateral side on ion transport and [Ca2+]i. It was demonstrated that ATP acts via a P2Y1 receptor to increase [Ca2+]i and NaCl secretion. In the present study we investigated the effect of luminally added nucleotides (ATP, UTP) on transepithelial voltage (V te) and resistance (R te) in Ussing chamber experiments on rat distal colonic mucosa. Both nucleotides induced a rapid and transient (within 30 s) change of V te to lumen-positive values (resting V te: –2±1 mV; peak V te after 100 µmol/l ATP: +2.4±1.1 mV) and a decrease of R te from 89.9±10.3 to 83.8±9.1 Ωcm2 (n=10). Similar values were obtained with luminal UTP (n=15). The estimated EC50 values for both nucleotides were approximately 6 µmol/l. The ATP-induced V te effect was nearly completely sensitive to Ba2+. Addition of the K+ channel blocker Ba2+ (1 mmol/l) to the luminal solution reversibly inhibited 77±4% (n=5) of the ATP-induced V te effect. Experiments to identify the respective P2 receptor subtype revealed the following rank order of potency at 500 µmol/l agonist: UTP≥ATP〉〉2-methylthio-ATP=ADP〉〉adenosine〉 AMP〉β,γ-methylene-ATP (n=5). This closely resembles the published rank order for the P2Y2 receptor. Using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique P2Y2 receptor-specific mRNA was detected in total RNA extracted from isolated crypts. In summary these data indicate that luminal ATP and UTP act via a P2Y2 receptor in the luminal membrane of colonic mucosa to elicit a transient K+ secretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240050693
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