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  • 1
    Electronic Resource
    Electronic Resource
    Hypo-osmotic challenge stimulates transepithelial k+ secretion and activates apical i sK channel in vestibular dark cells (1995)
    Springer
    The journal of membrane biology 147 (1995), S. 263-273 
    Details
    ISSN: 1432-1424
    Keywords: Regulatory volume decrease ; Slowly activating K+ channel ; Vestibular Labyrinth ; Vibrating probe ; Micro-Ussing chamber ; Patch clamp
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Volume regulation of vestibular dark cells from the gerbilline inner ear in response to a hypoosmotic challenge depends on the presence of cytosolic K+ and Cl−. The present study addresses the questions: (i) whether and by what mechanism K+ is released during volume regulation, (ii) whether the osmolarity of the basolateral medium has an effect on the steady-state rate of transepithelial K+ transport and (iii) whether there is cross-talk between the basolateral membrane responsible for K+ uptake and the apical membrane responsible for K+ release. K+ secretion $$(J_{{\text{K}}^{\text{ + }} ,{\text{probe}}} )$$ and current density (I sc,probe) were measured with vibrating probes in the vicinity of the apical membrane and the transepithelial potential (V t) and resistance (R t) were measured in a micro-Ussing chamber. The equivalent short-circuit current (I sc) was calculated. The current (I IsK), conductance (g IsK) and inactivation time constant (τIsK) of the I sK channel and the apparent reversal potential of the apical membrane (V r) were obtained with the cell-attached macropatch technique. V rwas corrected (V rc) for the membrane voltage (V m) measured separately with microelectrodes. A hypo-osmotic challenge (294 to 154 mosm by removal of 150 mm mannitol) on the basolateral side of the epithelium increased $$J_{K^{\text{ + }} ,{\text{probe}}} $$ and I sc,probe by a factor of 2.7 and 1.6. When this hypo-osmotic challenge was applied to both sides of the epithelium V tand I sc increased from 5 to 14 mV and from 189 to 824 μA/cm2 whereas R tdecreased from 27 to 19 Ω-cm2. With 3.6 mm K+ in the pipette I IsK was outwardly directed, τIsK was 267 msec and the hypo-osmotic challenge caused I IsK and g IsK to increase from 14 to 37 pA and from 292 to 732 pS. V rc hyperpolarized from −44 to −76 mV. With 150 mm K+ in the pipette I IsK was inwardly directed, τIsK was 208 msec and the hypo-osmotic challenge caused I IsK and g IsK to increase in magnitude from 0 to −21 pA and from 107 to 1101 pS. V rc remained unchanged (−2 vs. 1 mV). These data demonstrate that a hypo-osmotic challenge stimulates transepithelial K+ secretion and activates the apical I IsK channel. The hypoosmotically-induced increase in K+ secretion exceeded the estimated amount of K+ release necessary for the maintenance of constant cell volume, suggesting that the rate of basolateral K+ uptake was upregulated in the presence of the hypo-osmotic challenge and that cross-talk exists between the apical membrane and the basolateral membrane.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00234524
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  • 2
    Electronic Resource
    Electronic Resource
    β1-Adrenergic Receptors but not β2-Adrenergic or Vasopressin Receptors Regulate K+ Secretion in Vestibular Dark Cells of the Inner Ear (1999)
    Springer
    The journal of membrane biology 170 (1999), S. 67-77 
    Details
    ISSN: 1432-1424
    Keywords: Key words: Beta1-adrenergic receptors — Vestibular labyrinth — Ussing chamber — RT-PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract. Receptors were identified pharmacologically in functional studies where K+ secretion was monitored as transepithelial current (I sc ). Further, receptors were identified as transcripts by cloning and sequencing of reverse-transcriptase polymerase chain reaction (RT-PCR) products. I sc under control conditions was 796 ± 15 μA/cm2 (n= 329) in gerbilline VDC and 900 ± 75 μA/cm2 (n= 6) in murine VDC. Forskolin (10−5 m) but not 1,9-dideoxy-forskolin increased I sc by a factor of 1.42 ± 0.05 (n= 7). 10−9 m Arg8-vasopressin and 10−9 m desmopressin had no significant effect in gerbilline and murine VDC. Isoproterenol, norepinephrine, epinephrine and prenalterol stimulated I sc maximally by a factor of 1.38 ± 0.04 (n= 7), 1.59 ± 0.06 (n= 6), 1.64 ± 0.03 (n= 8) and 1.37 ± 0.03 (n= 6), respectively. The EC 50 values were (1.4 ± 0.7) × 10−8 m (n= 36), (2.5 ± 1.0) × 10−8 m (n= 31), (1.7 ± 0.7) × 10−7 m (n= 36) and (5 ± 4) × 10−7 m (n= 32), respectively. Propanolol inhibited isoproterenol-induced stimulation of I sc . Atenolol, ICI118551 and CGP20712A inhibited isoproterenol-induced stimulation of I sc with a pKDB of 5.0 × 10−8 m (pK DB = 7.30 ± 0.07, n= 38), 4.4 × 10−8 m (pK DB = 7.36 ± 0.14, n= 37) and 6.8 × 10−12 m (pK DB = 11.17 ± 0.12, n= 37), respectively. RT-PCR of total RNA isolated from microdissected vestibular labyrinth tissue using specific primers revealed products of the predicted sizes for β1- and β2-adrenergic receptors but not for β3-adrenergic receptors. Sequence analysis of the amplified cDNA fragments from gerbilline tissues revealed a 96.4%, 91.5% and 89.6% identity compared to rat β1-, β2- and β3-adrenergic receptors, respectively. These results demonstrate that K+ secretion in VDC is under the control of β1- but not β2- or β3-adrenergic receptors or vasopressin-receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002329900538
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  • 3
    Electronic Resource
    Electronic Resource
    K+ Secretion in Strial Marginal Cells is Stimulated via β1-Adrenergic Receptors but not via β2-Adrenergic or Vasopressin Receptors (2000)
    Springer
    The journal of membrane biology 175 (2000), S. 191-202 
    Details
    ISSN: 1432-1424
    Keywords: Key words: Stria vascularis — Receptor — Adrenergic — Beta — Beta-antagonists — Adrenergic — Atenolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract. Pharmacologic tools were used to identify receptors in functional studies by measuring either transepithelial current (I sc ) in strial marginal cells (SMC) or cAMP production in stria vascularis (SV). Further, receptors were identified in SV as transcripts by cloning and sequencing of reverse-transcriptase polymerase chain reaction (RT-PCR) products. Experiments were performed using tissues isolated from gerbils unless specified otherwise. I sc under control conditions was 1090 ± 21 μA/cm2 (n= 213) in gerbil SMC and 2001 ± 95 μA/cm2 (n= 6) in murine SMC. Direct stimulation of adenylate cyclase with 10-5 m forskolin but not with 10−5 m 1,9-dideoxy-forskolin resulted in an increase in the I sc by a factor of 1.14 ± 0.01 (n= 6). The vasopressin-receptor agonist 10−8 m Arg8-vasopressin had no significant effect on I sc in gerbil and murine SMC. The β-adrenergic agonists isoproterenol, norepinephrine and epinephrine stimulated I sc with an EC 50 of (6 ± 2) × 10−7 m (n= 28), (3 ± 1) × 10−6 m (n= 40) and (7 ± 2) × 10−6 m (n= 38), respectively. Isoproterenol stimulated cAMP production in SV with an EC 50 of (5 ± 2) × 10−7 m (n= 8). The β-antagonist 10−4 m propanolol completely inhibited 2 × 10−5 m isoproterenol-induced stimulation of I sc . The β-antagonists atenolol, ICI118551 and CGP20712A inhibited isoproterenol-induced stimulation of I sc with a K DB of 1 × 10−7 m (pK DB = 6.96 ± 0.15, n= 14), 1 × 10−7 m (pK DB = 7.01 ± 0.14, n= 15), 2 × 10−9 m (pK DB = 8.73 ± 0.13, n = 19), respectively. CGP20712A inhibited isoproterenol-induced cAMP production with a K DB of 1 × 10−10 m (pK DB = 9.94 ± 0.55, n= 9). RT-PCR of total RNA isolated from SV using primers specific for the β1-, β2- and β3-adrenergic receptors revealed products of the predicted sizes for the β1- and β2- but not the β3-adrenergic receptor. Sequence analysis confirmed that amplified cDNA fragments encoded gene-specific nucleotide sequences. These results demonstrate that K+ secretion in SMC is under the control of β1-adrenergic receptors but not β2-adrenergic or vasopressin-receptors and that the β1-subtype is the primary β-adrenergic receptor in SV although SV contains transcripts for both β1- and β2-adrenergic receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s00232001067
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  • 4
    Electronic Resource
    Electronic Resource
    Vestibular Dark Cells Contain an H+/Monocarboxylate− Cotransporter in Their Apical and Basolateral Membrane (1998)
    Springer
    The journal of membrane biology 163 (1998), S. 37-46 
    Details
    ISSN: 1432-1424
    Keywords: Key words: H+/monocarboxylate− cotransporter — BCECF — Vestibular labyrinth — RT-PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract. The transport of lactate and pyruvate across membranes of vestibular dark cells (VDC) may be important under aerobic, ischemic or hypoxic conditions. This study addresses the questions whether VDC from the gerbil contain an H+/monocarboxylate− cotransporter (MCT) and in which membrane, apical or basolateral, MCT is located. Uptake of monocarboxylates into VDC was monitored in functional studies by measuring the cytosolic pH (pH i ) and by measuring the pH-sensitive equivalent short circuit current (I sc ). Subtypes of the functionally identified MCT which are present in vestibular labyrinth tissues were identified as transcripts by cloning and sequencing of reverse-transcriptase polymerase chain reaction (RT-PCR) products. Monocarboxylates but not dicarboxylates induced a transient acidification of pH i which was inhibited by 5 mmα-cyano-4-hydroxycinnamate (CHC) but not by 1 μm DIDS or 500 μm pCMBS. The initial rate of acidification induced by monocarboxylates was dose-dependent in the range between 1 and 20 mm. K m values were for pyruvate 1.3, acetate 3.7, l-lactate 3.8 and d-lactate 7.3 mm. Both apical and basolateral application of monocarboxylates caused a transient increase of I sc which was sensitive to 5 mm CHC. RT-PCR revealed the presence of transcripts for the MCT subtypes MCT1 and MCT2. The identity of transcripts was confirmed by sequence analysis. These observations suggest that VDC contain an MCT in their apical and basolateral membrane and that the vestibular labyrinth contains transcripts for the subtypes MCT1 and MCT2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002329900368
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  • 5
    Electronic Resource
    Electronic Resource
    DIDS increases K+ secretion through an I sKchannel in apical membrane of vestibular dark cell epithelium of gerbil (1995)
    Springer
    The journal of membrane biology 146 (1995), S. 283-291 
    Details
    ISSN: 1432-1424
    Keywords: I sKpotassium channel ; Min K channel ; Disulfonic stilbene ; Inner ear ; Ion-selective vibrating probe ; Macropatch clamp technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Vestibular dark cell epithelium secretes K+ via I sKchannels in the apical membrane. The previous observation that disulfonic stilbenes increased the equivalent short circuit current (I sc) suggested that these agents might be useful investigative tools in this tissue. The present experiments were conducted to determine if the increase in I scwas associated with an increase in K+ flux and if the effect was directly on the I sKchannel or indirectly via a cytosolic intermediary. Measurements of transepithelial K+ flux with the K+-selective vibrating probe and of changes in net cellular solute flux by measurements of epithelial cell height showed that 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) increased K+ flux by a factor of 1.96±0.71 and caused net solute efflux. The apical membrane was partitioned with a macropatch pipette and DIDS was applied either to the membrane outside the pipette, inside the pipette or to the entire apical membrane. DIDS inside the pipette increased the current across the patch, the membrane conductance, the slowly-inactivating (I sK) component of the membrane current and shifted the reversal voltage toward the equilibrium potential for K+. DIDS outside the patch decreased the patch current and conductance, consistent with shunting of current away from the membrane patch. These findings strongly support the notion that DIDS increases K+ secretion through I sKchannels in the apical membrane of vestibular dark cell epithelium by acting directly on the channels or on a tightly colocalized membrane component.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00233948
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  • 6
    Electronic Resource
    Electronic Resource
    Evidence for a Calcium-Sensing Receptor in the Vascular Smooth Muscle Cells of the Spiral Modiolar Artery (2000)
    Springer
    The journal of membrane biology 175 (2000), S. 203-212 
    Details
    ISSN: 1432-1424
    Keywords: Key words: Calcium-sensing receptor — Cerebral arteries — Labyrinth — Thapsigargin — Ryanodine — U73122
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract. The vascular diameter of the gerbilline spiral modiolar artery has been shown to depend on the presence of extracellular Ca2+ but it remained unknown whether the smooth muscle cells of this arteriole contain a Ca2+ sensing receptor (CaSR). The cytosolic Ca2+ concentration ([Ca2+] i ) was monitored as fluo 3 fluorescence and the vascular diameter was measured by video-microscopy in isolated in vitro superfused spiral modiolar arteries. RT-PCR was used to probe for the presence of CaSR transcripts. Increasing the extracellular Ca2+ concentration ([Ca2+] o ) from 1 to 10 mm caused a biphasic increase in [Ca2+] i that was paralleled by a vasoconstriction. The initial rate of this vasoconstriction, 2.01 ± 0.07 μm/sec (n= 131), was inhibited when cytosolic Ca2+ stores were presumably depleted with thapsigargin (IC 50= 3 × 10−9 m, n= 26) or ryanodine (IC 50= 4 × 10−8 m, n= 25) or when PLC was inhibited by 10−6 m U73122 (n= 8). The initial rate of this constriction was not affected by the L-type Ca2+ channel blocker 10−6 m nifedipine (n= 5), by 10−6 m U73343 (n= 6), which is the inactive analogue of U73122, by the T-type Ca2+ channel blocker 10−6 Gd3+ (n= 6) or the Na+/Ca2+ exchanger blocker 10−4 m Ni2+ (n= 5). The agonist rank potency order was Gd3+ 〉 Ni2+ 〉 Ca2+ 〉〉 neomycin = Mg2+. Analysis of RNA isolated from the SMA revealed a RT-PCR product of the appropriate size for the CaSR (448 bp). Sequence analysis of the amplified cDNA fragment revealed a 94–96% amino acid identity compared to other CaSRs. These results demonstrate that the spiral modiolar artery contains a CaSR, which is most likely located in the vascular smooth muscle cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s00232001068
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  • 7
    Electronic Resource
    Electronic Resource
    The pH-sensitivity of transepithelial K+ transport in vestibular dark cells (1995)
    Springer
    The journal of membrane biology 147 (1995), S. 255-262 
    Details
    ISSN: 1432-1424
    Keywords: Labyrinth ; Slowly activating K+ channel ; IsK channel ; MinK channel ; pH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The pH-sensitivity of transepithelial K+ transport was studied in vitro in isolated vestibular dark cell epithelium from the gerbil ampulla. The cytosolic pH (pH iwas measured microfluorometrically with the pH-sensitive dye 2′,7′-bicarboxyethyl-5(6)-carboxyfluorescein (BCECF) and the equivalent short-circuit current (I sc), which is a measure for transepithelial K+ secretion, was calculated from measurements of the transepithelial voltage (V t)and the transepithelial resistance (R t) in a micro-Ussing chamber. All experiments were conducted in virtually HCO 3 − -free solutions. Under control conditions, pH iwas 7.01±0.04 (n=18), V twas 9.1±0.5 mV, R t16.7±0.09 Ωcm2, and I sc was 587±30 μA/cm2 (n=49). Addition of 20 mm propionate− caused a biphasic effect involving an initial acidification of pH i, increase in V tand I sc and decrease in R tand a subsequent alkalinization of pH i, decrease of V tand increase of R t. Removal of propionate− caused a transient effect involving an alkalinization of pH i, a decrease of V tand I sc and an increase in R t. pH iin the presence of propionate− exceeded pH iunder control conditions. Effects of propionate − on V t, R tand I sc were significantly larger when propionate− was applied to the basolateral side rather than to the apical side of the epithelium. The pH i-sensitivityof I sc between pH 6.8 and 7.5 was −1089 μA/(cm2 · pH-unit) suggesting that K+ secretion ceases at about pH i7.6. Acidification of the extracellular pH (pH o)caused an increase of V tand I sc and a decrease of R tmost likely due to acidification of pH i. Effects were significantly larger when the extracellular acidification was applied to the basolateral side rather than to the apical side of the epithelium. The pH osensitivity of I sc between pH 7.4 and 6.4 was −155 μA/(cm2 · pH unit). These results demonstrate that transepithelial K+ transport is sensitive to pH iand pH oand that vestibular dark cells contain propionate− uptake mechanism. Further, the data suggest that cytosolic acidification activates and that cytosolic alkalinization inactivates the slowly activating K+ channel (I sK)in the apical membrane. Whether the effect of pH ion the I sK channel is a direct or indirect effect remains to be determined.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00234523
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  • 8
    Electronic Resource
    Electronic Resource
    Differential effects of ADH on sodium, chloride, potassium, calcium and magnesium transport in cortical and medullary thick ascending limbs of mouse nephron (1988)
    Springer
    Pflügers Archiv 412 (1988), S. 516-523 
    Details
    ISSN: 1432-2013
    Keywords: ADH ; Transepithelial ion net fluxes ; Na+, Cl−, K+, Ca2+ and Mg2+ transport ; Electron microprobe ; Mouse kidney ; Cortical and medullary thick ascending limb of Henle's loop ; In vitro microperfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of antidiuretic hormone (arginine vasopressin, AVP) on transepithelial Na+, Cl−, K+, Ca2+ and Mg2+ net transports was investigated in medullary (mTAL) and cortical (cTAL) segments of the thick ascending limb (TAL) of mouse nephron, perfused in vitro. Transepithelial net fluxes (J Na +,J Cl −,J K +,J Ca 2+,J Mg 2+) were determined by electron probe analysis of the collected tubular fluid. Transepithelial potential difference (PDte) and transepithelial resistance (Rte) were measured simultaneously. cTAL segments were bathed and perfused with isoosmolal, HCO 3 − containing Ringer solutions, mTAL segments were bathed and perfused with isoosmolal HCO 3 − free Ringer solutions. In cTAL segments, AVP (10−10 mol·l−1) significantly increasedJ Mg 2+ andJ Ca 2+ from 0.39±0.08 to 0.58±0.10 and from 0.86±0.13 to 1.19±0.15 pmol·min−1 mm−1 respectively. NeitherJ Na + norJ Cl −, (J Na +: 213±30 versus 221±28 pmol·min−1 mm−1,J Cl −: 206±30 versus 220±23 pmol·min−1 mm−1) nor PDte (13.4±1.3 mV versus 14.1±1.9 mV) or Rte (24.6±6.5Ω cm2 versus 22.6±6.4Ω cm2) were significantly changed by AVP. No significant effect of AVP on net K+ transport was observed. In mTAL segments, Mg2+ and Ca2+ net transports were close to zero and AVP (10−10 mol·l−1) elicited no effect. However NaCl net reabsorption was significantly stimulated by the hormone,J Na + increased from 107±33 to 148±30 andJ Cl − from 121±33 to 165±32 pmol·min−1 mm−1. The rise inJ NaCl was accompanied by an increase in PDte from 9.0±0.7 to 13.5±0.9 mV and a decrease in Rte from 14.4±2.0 to 11.2±1.7 Ω cm2. No K+ net transport was detected, either under control conditions or in the presence of AVP. To test for a possible effect of HCO 3 − on transepithelial ion fluxes, mTAL segments were bathed and perfused with HCO 3 − containing Ringer solutions. With the exception ofJ Ca 2+ which was significantly different from zero (J Ca 2+: 0.26±0.06 pmol·min−1 mm−1), net transepithelial fluxes of Na+, Cl−, K+ and Mg2+ were unaffected by HCO 3 − . In the presence of AVP,J Mg 2+ andJ Ca 2+ were unaltered whereasJ NaCl was stimulated to the same extent as observed in the absence of HCO 3 − . In conclusion our results indicate heterogeneity of response to AVP in cortical and medullary segments of the TAL segment, since AVP stimulates Ca2+ and Mg2+ reabsorption in the cortical part and Na+ and Cl− reabsorption in the medullary part of this nephron segment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00582541
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  • 9
    Electronic Resource
    Electronic Resource
    Cl−-channel blockers in the thick ascending limb of the loop of Henle Structure activity relationship (1986)
    Springer
    Pflügers Archiv 407 (1986), S. S128 
    Details
    ISSN: 1432-2013
    Keywords: Cl−-channel blocker ; Thick ascending limb of the loop of Henle ; Diphenylamine-2-carboxylate ; Cl−-channel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract On the basis of our findings with diphenylamine-2-carboxylate [5] we have searched for compounds which possess an even higher affinity for the Cl−-channels in the basolateral membrane of the thick ascending limb of the loop of Henle. To quantitiy the inhibitory potency, we performed measurements of the equivalent short circuit current, corresponding to the secondary active transport of Cl− [8] and measurements of the voltage across the basolateral membrane. A survey of 219 compounds reveals that relatively simple modifications in the structure of diphenylamine-2-carboxylate led to very potent blockers such as 5-nitro-2-(3-phenylpropylamino)-benzoate which inhibits the short circuit current half maximally (IC50) at 8·10−8 mol/l. A comparison of the structural formula and the respective IC50 values leads to several empirical conclusions: 1. The potent compounds are lipophilic due to the apolar residue (e.g. phenyl- or cycloalkyl group). Replacing this part of the molecule by an aliphatic chain (up to 4 C-atoms) leads to inactive compounds. 2. Most of the inhibitors are secondary amines. Linking other than with-NH- between the phenyl ring and the benzoic acid results in inactive compounds. Tertiary amines, such as in case of 2-(N,N-diphenylamine) benzoic acid or N-methylphenylaminebenzoic acid are poorly active. 3. The carboxylate group of the benzoate moiety must be in ortho position to the amino group. 4. Introduction of substituents into the benzoate moiety e.g.-NO2 (in meta position to the carboxylate group), or by-Cl (in para position to the carboxylate group) results in an increase of inhibitory potency. 5. A-CH2-,-C2H4-,-C3H6-) spacer between the amino bridge and the phenyl ring increases the affinity for the Cl−-channel by several orders of magnitude. The above described structure activity relationship renders it likely that these chloride channel blockers possess several sites of interaction: The negatively charged carboxylate group, the secondary amine group which probably carries a positive partial charge, and for the very potent agents (nos. 130, 143, 144, and 145) an additional negative partial charge at the respective-Cl or-NO2 substituent. Finally, also an apolar interaction with an cycloalkyl or cycloaryl residue seems to be required, and this site of interaction has a defined spacing from the secondary amino nitrogen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00584942
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  • 10
    Electronic Resource
    Electronic Resource
    Analogues of torasemide — structure function relationships —experiments in the thick ascending limb of the loop of Henle of rabbit nephron (1987)
    Springer
    Pflügers Archiv 408 (1987), S. 54-62 
    Details
    ISSN: 1432-2013
    Keywords: Torasemide ; Cortical thick ascending limb of the loop of Henle ; Rabbit ; Na+2Cl−K+ cotransporter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of the present study was to examine compounds related to torasemide with respect to their ability to block the equivalent short circuit current, corresponding to the rate of chloride reabsorption, in isolated in vitro perfused cortical thick ascending limbs of Henle of the rabbit. The torasemide molecule was modified with respect to the anionic sulfonylurea group, and the secondary amine linked to the pyridine ring. Our results indicate that only few of the tested 48 torasemide-related compounds were able to inhibit from both epithelial sides like torasemide. Only few of the tested compounds were equally effective as torasemide from the lumen side. Some analogues were acting only from the luminal side and some only from the peritubular side. The correlations between structure and potency of inhibition from the luminal side allow the following conclusions: a) The secondary amine moiety linked to the pyridine ring (toluidine in case of torasemide) can be replaced by a cycloalkylamine or, with some loss of inhibitory potency, by alkylamines. The inhibitory potency is increased with the number of C-atoms in the cycloalkylamine substituted compounds (optimum C7 to C8), and is also depending on the length of the alkylamines (optimum C4). b) The secondary amine seems to be required since nitrogen cannot be replaced by −S- or −SO2-. c) The sulfonylurea group cannot be substituted by other anionic groups such as −SO 3 − or −COO−. d) If the pyridine ring is replaced by a NO2-substituted phenyl ring, the inhibitory potency from the luminal side is lost. However, these compounds act still (with some loss of potency) from the peritubular side. The data indicate that several of the conclusions drawn from our previous systematic surveys of chloride channel blockers and loop diuretics of the furosemide type, i.e. blockers of the Na+2Cl−K+ carrier, hold also true for compounds related to torasemide. In addition, the pyridine ring is responsible for some specific structure activity correlations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00581840
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