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H J Lang

Publications and source records attributed to H J Lang.

62 records · Page 4Linked to original sources
PubMed1986

Cl(-)-channel blockers in the thick ascending limb of the loop of Henle. Structure activity relationship.

On the basis of our findings with diphenylamine-2-carboxylate 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 quantity the inhibitory potency, we performed measurements of the equivalent short circuit current, corresponding to the secondary active transport of Cl- 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 X 10(-8) mol/l. A comparison of the structural formula and the respective IC50 values leads to several empirical conclusions: 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. 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-methylphenylamine-benzoic acid are poorly active. The carboxylate group of the benzoate moiety must be in ortho position to the amino group. 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. 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.

Animals↗
PubMed1985

2-((2-Pyridylmethyl)sulfinyl)benzimidazoles: acid sensitive suicide inhibitors of the proton transport system in the parietal cell.

2-((2-Pyridylmethyl)sulfinyl)benzimidazoles, selective inhibitors of the H+/K+-ATPase in the parietal cells of the stomach, have been investigated concerning their chemical behaviour in acidic medium. Protonation of the sulfoxide and subsequent elimination of water forms a sulfenium ion or a chemical equivalent thereof. If no external nucleophiles are present, a rearrangement process takes place. In the presence of mercaptans, the sulfenium ion is trapped giving rise to a variety of products. On the basis of these results, a mechanistic scheme is proposed for the inactivation of the H+/K+-ATPase by these compounds.

Adenosine Triphosphatases↗
PubMed1985

Diphenylamine-2-carboxylate, a blocker of the Cl(-)-conductive pathway in Cl(-)-transporting epithelia.

The present study examines the effects of diphenylamine-2-carboxylate (DPC) in Cl(-)-transporting epithelia. This substance blocks reversibly the Cl(-)-conductance present under normal circumstances in the basolateral membrane of the thick ascending limb of the loop of Henle (TAL) and in the apical membrane of shark rectal gland tubules (RGT). This leads to a reduction in active NaCl reabsorption (TAL) and NaCl secretion (RGT) respectively, as measured by the equivalent short circuit current. The cells hyperpolarize as the membrane voltage drifts from the control value (some compromise between the chemical potential of Cl- and K+) towards the chemical potential of K+. The resistance of the basolateral (TAL) or apical membrane (RGT) increases and this leads to a moderate increase in transepithelial resistance. In addition, the Cl(-)-concentration step induced membrane voltage changes, which can be produced under control conditions, disappear in the presence of the blocker. Finally, experiments in excised membrane patches indicate that this substance inhibits the single current events of individual Cl(-)-channels.

Animals↗
PubMed1985

Contraluminal sulfate transport in the proximal tubule of the rat kidney. V. Specificity: phenolphthaleins, sulfonphthaleins, and other sulfo dyes, sulfamoyl-compounds and diphenylamine-2-carboxylates.

In order to evaluate the specificity for the contraluminal sulfate transport system the inhibitory potency of phenol- and sulfonphthaleins, of sulfamoyl-compounds (diuretics) as well as diphenylamine-2-carboxylates (Cl- channel blockers) on the 35SO4(2-) influx from the interstitium into cortical tubular cells in situ has been determined. The following was found: 1) Phenolsulfonphthalein (phenol-red) inhibited with an app. Ki-value of 1.7 mmol/l, while analogs which had additional Br-atoms in position 3 and/or 5, i.e. bromphenol-blue, bromcresol-purple and bromcresol-green, inhibited with an apparent Ki of 0.1 and 0.5 mmol/l respectively. 2) Phenolphthalein and tetrabromphenolphthalein did not inhibit, while the disulfonate dyes bromsulfalein, fuchsin acid and indigocarmine inhibited with a Ki between approximately equal to 1 and 3 mmol/l. The highest inhibitory potency in this class of compounds was seen with orange G (app. Ki 0.07 mmol/l). The monosulfonate dyes tested, fluorescein-sulfonate and orange I inhibited moderately with an app. Ki of approximately equal to mmol/l. 3) The 3-sulfamoyl compounds inhibited to a varying degree, when they had a neighbouring -NH-group (furylmethylamino-group), i.e. in position 6 to the COOH or SO3H-group, or when they had a phenoxy-group in position 4. 4) 4-sulfamoylbenzoate and the related compounds probenecid, acetazolamide and hydrochlorothiazide inhibited with an app. Ki between 4 and 7 mmol/l. 5) All diphenylamine-2-carboxylate analogs inhibited with an app. Ki between 3 and 5 mmol/l, even when the -NH-group was replaced by an = O-group or the benzene ring was replaced by a pyrimidine ring, but not when it was replaced by a thiophen ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

[Analysis of postoperative deaths in colon and rectal cancer (author's transl)].

Analysis of the clinical and autopsy reports of 200 deaths following surgery for colorectal cancer from 1956 to 1974, at the Dept. of Surgery, University of Heidelberg, revealed that pneumonia (24.5%) was the most common cause of death followed by peritonitis (22%), pulmonary embolism (15.5%), advanced tumor disease (14%), cardiac failure (9.5%), ileus (5.5%), and others (9%). The explanation for the postoperative mortality rate of 12% (cancer of colon) and 13.2% (cancer of rectum) lies in the fact that 82.5% of those who died postoperatively were beyond the age of 60, and 40.5% beyond 70 years at the time of surgery. Moreover, in 50.5% advanced tumors with regional and/or distant metastases were found. In 55.5% severe preoperative complications (ileus: 38%, peritonitis: 11%, abscess formation or hemorrhage: 6.5%) required an emergency operation. Only 38.5% of the procedures were considered for cure. Besides the need for early recognition of the cancer, intensification of pre- and postoper treatment appears to be the predominant task in the effort to decrease postoperative mortality.

Adult↗
PubMedDate not supplied

Effects of the Na+/H+-exchange inhibitor Hoe 642 on intracellular pH, calcium and sodium in isolated rat ventricular myocytes.

The inhibitors of the Na+/H+-exchange (NHE1) system Hoe 694 and Hoe 642 possess cardioprotective effects in ischaemia/reperfusion. It is assumed that these effects are due to the prevention of intracellular sodium (Nai) and calcium (Cai) overload. The purpose of the present study was to investigate the effects of Hoe 642 on intracellular pH, Na+ and Ca2+ (pHi, Nai and Cai) in isolated rat ventricular myocytes under anoxic conditions or in cells in which oxidative phosphorylation had been inhibited by 1.5 mmol/l cyanide. In cells which were dually loaded with the fluorescent dyes 2, 7-biscarboxyethyl-5,6-carboxyfluorescein (BCECF) and Fura-2, anoxia caused acidification of the cells (from pHi 7.2 to pHi 6.8) and an increase in Cai from about 50 nmol/l to about 1 micromol/l. The decrease in pHi began before the cells underwent hypoxic (rigor) contracture, whereas Cai only began to rise after rigor shortening had taken place. After reoxygenation, pHi returned to its control value and Cai oscillated and then declined to resting levels. It was during this phase that the cells rounded up (hypercontracture). When 10 micromol/l Hoe 642 was present from the beginning of the experiment, pHi and Cai were not significantly different from control experiments. At reoxygenation, pHi did not recover, but Cai oscillated and returned to its resting level. To monitor Nai, the cells were loaded with the dye SBFI. After adding 1.5 mmol/l cyanide or 100 micromol/l ouabain, Nai increased from the initial 8 mmol/l to approximately 16 mmol/l. Hoe 642 or Hoe 694 (10 micromol/l) did not prevent the increase in Nai. In contrast, the blocker of the persistent Na+ current R56865 (10 micromol/l) attenuated the CN--induced rise in Nai. The substance ethylisopropylamiloride was not used because it augmented considerably the intensity of the 380 nm wavelength of the cell's autofluorescence. In conclusion, the specific NHE1 inhibitor Hoe 642 did not attenuate anoxia-induced Cai overload, nor CN--induced Nai and Cai overload. Hoe 642 prevented the recovery of pHi from anoxic acidification. This low pHi maintained after reoxygenation may be cardioprotective. Other possible mechanisms of NHE1 inhibitors, such as prevention of Ca2+ overload in mitochondria, cannot be ruled out. The increase in Nai during anoxia is possibly due to an influx of Na+ via persistent Na+ channels.

Amiloride↗