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  • 1
    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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  • 2
    Electronic Resource
    Electronic Resource
    Torasemide inhibits NaCl reabsorption in the thick ascending limb of the loop of Henle (1986)
    Springer
    Pflügers Archiv 407 (1986), S. 611-614 
    Details
    ISSN: 1432-2013
    Keywords: Torasemide ; Na+2Cl−K+ carrier ; Cl−-channel ; Thick ascending limb of the loop of Henle ; Mouse ; Rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Torasemide (1-isopropyl-(4-(3-methylphenylamino)pyrid-3-yl)urea) is a new diuretic. The present study examines the effects of this substance in the isolated perfused thick ascending limb (TAL) of mouse and rabbit kidney. In cortical TAL segments of the rabbit, torasemide added to the lumen perfusate led to a fall in equivalent short circuit current (= transepithelial voltage divided by transepithelial resistance, which corresponds to the rate of chloride reabsorption) with a half maximal inhibition concentration of 3 · 10−7 mol/l. This effect was accompanied by a hyperpolarization of the luminal and basolateral membrane from −78 to −81 mV and from −72 to −81 mV, respectively. A similar hyperpolarization of both membrane voltages was also observed in medullary TAL segments of the mouse. Torasemide, added to the basolateral perfusate of cortical TAL segments of the rabbit, also inhibited the equivalent short circuit current. However, 3 · 10−5 mol/l were necessary for a half maximal inhibition. The fall in the equivalent short circuit current was accompanied by a significant increase in transepithelial resistance from 34 to 38 Ω cm2, by an increase in the fractional resistance of the basolateral membrane, and by a hyperpolarization mainly of the basolateral membrane. Again, similar results were obtained in the medullary TAL segment of the mouse. The strong inhibitory effect of torasemide from the lumen side can be explained by an interference with the Na+ 2Cl−K+ carrier in the luminal membrane. In fact, torasemide apparently is structurally related to furosemide. The weaker effect of torasemide from the peritubular side can, at least in part, be explained as an interference with chloride channels present in the basolateral membrane. Torasemide is also structurally related to chloride channel blockers such as diphenylamine-2-carboxylate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00582640
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    Paper (German National Licenses)
    Fulltext
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