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H J Lang

Publications and source records attributed to H J Lang.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes.

OBJECTIVES: The slow component of the delayed rectifier K+ current (IKs) is believed to be important in cardiac repolarization, and may be a potential target for antiarrhythmic drugs, but its study has been limited by a lack of specific blockers. The chromanol derivate 293B blocks currents expressed by minK and not HERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials. We aimed to establish the effects of 293B on K+, Na+ and Ca2+ currents and action potentials in human and guinea pig cardiomyocytes. METHODS: Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36 degrees C. RESULTS: Delayed rectifier current (IK) elicited by pulses to +60 mV from a holding potential of -50 mV in guinea pig myocytes was strongly inhibited by 293B (maximum inhibition 96.9 +/- 0.8%; 50% inhibitory concentration, EC50, 1.02 microM), but IK during pulses to -10 mV was unaffected (3.9 +/- 8.4% inhibition at 50 microM). Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug-sensitive IK correspond to those of IKr and IKs respectively. Inward rectifier K+ current, Na+ current and L-type Ca2+ current were unaffected by 293B. Transient outward current in human ventricular myocytes was inhibited by 293B at an EC50 of 24 microM, less than one twentieth the potency for IKs inhibition in guinea pig myocytes. While dofetilide prolonged action potential duration (APD) with strong reverse use dependence, 293B prolonged guinea pig and human ventricular APD to a similar fractional extent at all frequencies. CONCLUSIONS: 293B is a selective IKs blocker, and the frequency dependence of APD prolongation caused by this IKs blocker is different from that caused by IKr blockade: 293B may be an interesting tool to study the physiologic role of IKs and the antiarrhythmic potential of IKs blockade.

Action Potentials↗
PubMed1998

Effect of inhibitors of Na+/H+-exchange and gastric H+/K+ ATPase on cell volume, intracellular pH and migration of human polymorphonuclear leucocytes.

1. Stimulation of chemotaxis of human polymorphonuclear leucocytes (PMNs) with the chemoattractive peptide fMLP (N-formyl-Met-Leu-Phe) is paralleled by profound morphological and metabolic alterations like changes of intracellular pH (pHi) and cell shape. The present study was performed to investigate the interrelation of cell volume (CV) regulatory ion transport, pHi and migration of fMLP stimulated PMNs. 2. Addition of fMLP to PMNs stimulated directed migration in Boyden chamber assays and was accompanied by rapid initial intracellular acidification and cell swelling. 3. Inhibition of the Na+/H+ exchanger suppressed fMLP stimulated cell migration, accelerated the intracellular acidification and inhibited the fMLP-induced cell swelling. 4. Step omission of extracellular Na+ caused intracellular acidification, which was accelerated by subsequent addition of gastric H+/K+ ATPase inhibitor SCH 28080, or by omission of extracellular K+ ions. In addition Na+ removal caused cell swelling, which was further enhanced by fMLP. 5. H+/K+ATPase inhibitors omeprazole and SCH 28080 inhibited stimulated migration and blunted the fMLP-induced increase in CV. 6. Increasing extracellular osmolarity by addition of mannitol to the extracellular solution caused cell shrinkage followed by regulatory volume increase, partially due to activation of the Na+/H+ exchanger. In fMLP-stimulated cells the CV increase was counteracted by simultaneous addition of mannitol. Under these conditions the fMLP stimulated migration was inhibited. 7. The antibacterial activity of PMNs was not modified by Hoe 694 or omeprazole. 8. Western analysis with a monoclonal anti gastric H+/K+ ATPase beta-subunit antibody detected a glycosylated 35 kD core protein in lysates of mouse and human gastric mucosa as well as in human PMNs. 9. The results indicate that fMLP leads to cell swelling of PMNs due to activation of the Na+/H+ exchanger and a K+-dependent H+-extruding mechanism, presumably an H+/K+ ATPase. Inhibition of these ion transporters suppresses the increase in CV and precludes PMNs from stimulated migration.

Animals↗
PubMed1998

Intracellular pH regulation in bovine aortic endothelial cells: evidence of both Na+/H+ exchange and Na+-dependent Cl-/HCO3- exchange.

Regulation of intracellular pH (pHi) was studied in cultured bovine aortic endothelial cells, an important cell system for cardiovascular research. Suspended cells were acidified by the NH4Cl prepulse technique as well as by exposure to CO2/HCO3-. Subsequent rates of pHi recovery were monitored using the fluorescent dye 2',7'-bis(2-carboxyethyl)-5-(6)-carboxyfluorescein (BCECF). In HCO3(-)-free solutions, an EIPA-sensitive, Na+-dependent mechanism fully accounted for realkalinization, namely the Na+/H+ exchanger (NHE). In the presence of HCO3-, an additional acid efflux mechanism was found. This one was dependent on Na+ and intracellular Cl-, EIPA-insensitive but DIDS-sensitive, and therefore represented a Na+-dependent Cl-/HCO3- exchanger (NCBE). In summary, two acid-extruding mechanisms were identified in bovine aortic endothelial cells: NHE and NCBE.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Effects of bradykinin on NIH 3T3 fibroblasts pretreated with lithium. Mimicking events of Ha-ras oncogene expression.

As shown previously, expression of Ha-ras oncogene in NIH 3T3 fibroblasts (+ ras cells) increases cellular concentrations of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 and enhances bradykinin induced Ca2+ entry [1-3]. These cells respond to low concentrations of serum or bradykinin with sustained oscillations of the cell membrane potential due to pulsatile release of calcium from internal stores and subsequent activation of calcium sensitive K+ channels [1]. Furthermore Ha-ras oncogene expression leads to depolymerization of the actin filament network and delayed increase of cell volume [4-6]. Pretreatment of the same cells not expressing the oncogene (-ras cells) with Li+ similarly increases Ins(1,4,5)P3 and Ins(1,3,4,5)P4 [2]. As shown in the present study, -ras cells pretreated with Li+ similar to Ha-ras oncogene expressing cells respond to bradykinin with sustained oscillations of cell membrane potential, depolymerization of the actin filament network and increase of cell volume. The oscillations of the cell membrane potential and the depolymerization of the actin cytoskeleton can be inhibited by the calcium channel blocker lanthanum and the bradykinin induced increase of cell volume is inhibited by HOE 694, pointing to involvement of Na+/H+ exchange. The data indicate a close functional linkage of the calcium oscillations, cytoskeletal rearrangement and activation of the Na+/H+ exchanger. Thus, Li+ pretreatment mimicks crucial cellular events triggered by expression of the Ha-ras oncogene. However, unlike in cells expressing the Ha-ras oncogene, Li+ pretreatment alone does not allow for growth factor-independent proliferation of the cells.

3T3 Cells↗
PubMed1997

KVLQT channels are inhibited by the K+ channel blocker 293B.

Previous data have indicated that the chromanol 293B blocks a cAMP activated K+ conductance in the colonic crypt, a K+ conductance in pig cardiac myocytes and the K+ conductance induced by IsK protein expression in Xenopus oocytes. We have also shown that cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) up-regulates, apart from the typical Cl- current, a 293B- inhibitable K+ current. Very recently it has been shown that the IsK protein interacts with KVLQT subunits to produce a K+ channel. These data have prompted us to ask the following questions: Is the 293B-inhibitable current in oocytes expressing CFTR and activated by cAMP caused by an endogenous Xenopus KVLQT (XKVLQT), and is mouse KVLQT (mKVLQT) expressed in oocytes inhibited by 293B? Antisense and sense probes for XKVLQT were coinjected with CFTR cRNA into oocytes. After 3-4 days the oocytes were examined by two electrode voltage clamp. It was found that in control oocytes expressing CFTR and stimulated by isobutylmethylxanthine (IBMX, 1 mmol/l) 293B (10 micromol/l) reduced the conductance (Gm). In oocytes coinjected with the sense probe for XKVLQT and pretreated with IBMX 293B still reduced Gm, whilst the 293B-inhibitable Gm was almost completely absent in oocytes coinjected with XKVLQT antisense. In another series a full length clone for mKVLQT was generated by PCR techniques and the cRNA was injected into oocytes. After several days these oocytes, unlike water injected ones, were found to be strongly hyperpolarized and their Gm was increased significantly. The oocytes were depolarized significantly and their Gm was reduced reversibly by 10 micromol/l 293B. These data indicate that CFTR activation by IBMX indeed co-activates an endogenous oocyte XKVLQT channel and that this channel is inhibited by a new class of channel blockers, of which 293B is the prototype.

1-Methyl-3-isobutylxanthine↗
PubMed1997

The role of the IsK protein in the specific pharmacological properties of the IKs channel complex.

IKs channels are composed of IsK and KvLQT1 subunits and underly the slowly activating, voltage-dependent IKs conductance in heart. Although it appears clear that the IsK protein affects both the biophysical properties and regulation of IKs channels, its role in channel pharmacology is unclear. In the present study we demonstrate that KvLQT1 homopolymeric K+ channels are inhibited by the IKs blockers 293B, azimilide and 17-beta-oestradiol. However, IKs channels induced by the coexpression of IsK and KvLQT1 subunits have a 6-100 fold higher affinity for these blockers. Moreover, the IKs activators mefenamic acid and DIDS had little effect on KvLQT1 homopolymeric channels, although they dramatically enhanced steady-state currents through heteropolymeric IKs channels by arresting them in an open state. In summary, the IsK protein modulates the effects of both blockers and activators of IKs channels. This finding is important for the action and specificity of these drugs as IsK protein expression in heart and other tissues is regulated during development and by hormones.

Animals↗
PubMed1997

Taurine reabsorption by a carrier interacting with furosemide in short and long Henle's loops of rat nephrons.

Taurine is net reabsorbed in the proximal convolution by Cl- -stimulated Na+ symport specific for beta-amino acids but not in later nephron segments. However, large unidirectional taurine transport takes place there. To investigate unidirectional taurine reabsorption, we comicroinfused [3H]taurine and [14C]inulin into late proximal (LP), early distal (ED), and late distal (LD) tubule segments, as well as into the tips of long loops of Henle (LLH) of rats in vivo, and determined fractional reabsorption of [3H]taurine (FR) in the ipsilateral urine. FR (9 micromol/l taurine) was 80-93 (LP), 16 (ED), and 8% (LD). At 26 mmol/l taurine, FR decreased to 13 (LP) and 6% (ED). FR also decreased when Na+ or Cl- was absent or furosemide (5 x 10(-5) mol/l) was added. Bumetanide (5 x 10(-5) mol/l) had no effect, whereas aniline-2-sulfonic acid (ASA) inhibited. During LLH microinfusion, FR was 55% at 66 micromol/l and 17% at 228 micromol/l and was again inhibited by furosemide and ASA but not by bumetanide. [14C]taurine reabsorption from microperfused proximal convolutions was not influenced by furosemide. Chronic water diuresis did not affect taurine reabsorption in short Henle's loops. We conclude that taurine can enter cells of the distal nephron from the lumen by an Na+- and partly Cl- -dependent carrier with which C alpha,beta-substituted taurine (ASA) and C alpha,beta- and N-substituted beta-alanine (furosemide) directly interact. Thus proximal and distal taurine carriers seem to be different.

Absorption↗
PubMed1997

Synthesis of the highly selective Na+/H+ exchange inhibitors cariporide mesilate and (3-methanesulfonyl-4-piperidino-benzoyl) guanidine methanesulfonate.

The syntheses of cariporide mesilate ((4-isopropyl-3-methanesulfonyl-benzoyl) guanidine methanesulfonate, HOE 642, CAS 159138-81-5), currently being clinically investigated as a protective drug in cardiac ischemia and reperfusion states, and of HOE 694 ((3-methanesulfonyl-4-piperidino-benzoyl)guanidine methanesulfonate, CAS 149725-40-6), widely used as a physiological and pharmacological research tool in studies comprising Na+/H+ exchange (NHE) inhibition, are described. Additionally, their selectivity on the different subtypes is disclosed.

Amiloride↗
PubMed1996

Specific blockade of slowly activating I(sK) channels by chromanols -- impact on the role of I(sK) channels in epithelia.

Chromanols, which were recently shown to inhibit cAMP-mediated Cl- secretion in colon crypts via a blockade of a cAMP-activated K+ conductance, were analyzed for their effects on distinct cloned K+ channels expressed in Xenopus oocytes. The lead chromanol 293B specifically inhibited I(sK) channels with an IC50 of 7 micromol/l without affecting the delayed rectifier Kv1.1 or the inward rectifier Kir2.1. Moreover, several other chromanols displayed the same rank order of potency for I(sK) inhibition as demonstrated in colon crypts. Finally, we tested the effects of the previously described I(sK) blocker azimilide on cAMP mediated Cl- secretion in rat colon crypts. Similar to 293B azimilide inhibited the forskolin induced Cl- secretion. These data suggest that I(sK) protein induced K+ conductances are the targets for the chromanol 293B and its analogues, and azimilide.

Animals↗
PubMed1996

Studies on the mechanism of swelling-induced lysosomal alkalinization in vascular smooth muscle cells.

Previous studies in renal cells and hepatocytes have shown that cell swelling leads to a rapid and reversible increase in pH in acidic cellular compartments, including lysosomes. Among the consequences are an inhibition of proteolysis. The present study shows that a similar lysosomal alkalinization occurs upon osmotic swelling of vascular smooth muscle cells, as evidenced by acridine orange and fluorescein isothiocyanate fluorescence. Furthermore, we have studied the mechanism underlying lysosomal alkalinization, which had remained unclear. The lysosomal alkalinization was not abolished by inhibition of vacuolar H+-ATPases (100 nM bafilomycin), Cl- channels [100 microM] 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), carbonic anhydrase (100 microM acetazolamide) or Na+/H+ exchange (10 microM HOE 694). The Ca2+ ionophore A23187 (10 microM) led to a slight increase in lysosomal pH, but removal of extracellular Ca2+ and depletion of cellular Ca2+ stores (100 nM thapsigargin) did not appreciably blunt the swelling-induced lysosomal alkalinization. In the presence of bafilomycin the alkalinizing effect of osmotic cell swelling was not reversible, in contrast to that of NH4Cl. In conclusion, osmotic swelling of vascular smooth muscle cells leads to lysosomal alkalinization, presumably in large part through activation of a hydrogen ion leak.

Acridine Orange↗
PubMed1995

A new class of inhibitors of cAMP-mediated Cl- secretion in rabbit colon, acting by the reduction of cAMP-activated K+ conductance.

Previously we have shown that arylaminobenzoates like 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), which are very potent inhibitors of NaCl absorption in the thick ascending limb of the loop of Henle, are only poor inhibitors of the cAMP-mediated secretion of NaCl in rat colon. This has prompted our search for more potent inhibitors of NaCl secretion in the latter system. The chromanole compound 293 B inhibited the equivalent short-circuit current (Isc) induced by prostaglandin E2 (n = 7), vasoactive intestinal polypeptide (VIP, n = 5), adenosine (n = 3), cholera toxin (n = 4) and cAMP (n = 6), but not by ionomycin (n = 5) in distal rabbit colon half maximally (IC50) at 2 mumol/l from the mucosal and at 0.7 mumol/l from the serosal side. The inhibition was reversible and paralleled by a significant increase in transepithelial membrane resistance [e.g. in the VIP series from 116 +/- 16 omega.cm2 to 136 +/- 21 omega.cm2 (n = 5)]. A total of 25 derivatives of 293 B were examined and structure activity relations were obtained. It was shown that the racemate 293 B was the most potent compound within this group and that its effect was due to the enantiomer 434 B which acted half maximally at 0.25 mumol/l. Further studies in isolated in vitro perfused colonic crypts revealed that 10 mumol/l 293 B had no effect on the membrane voltage across the basolateral membrane (Vbl) in non-stimulated crypt cells: -69 +/- 3 mV versus -67 +/- 3 mV (n = 10), whilst in the same cells 1 mmol/l Ba2+ depolarised Vbl significantly. However, 293 B depolarised Vbl significantly in the presence of 1 mumol/l forskolin: -45 +/- 4 mV versus -39 +/- 5 mV (n = 7). Similar results were obtained with 0.1 mmol/l adenosine. 293 B depolarised Vbl from -40 +/- 5 mV to -30 +/- 4 mV (n = 19). This was paralleled by an increase in the fractional resistance of the basolateral membrane. VIP had a comparable effect. The hyperpolarisation induced by 0.1 mmol ATP was not influenced by 10 mumol/l 293 B: -75 +/- 6 mV versus -75 +/- 6 mV (n = 6). Also 293 B had no effect on basal K+ conductance (n = 4). Hence, we conclude that 293 B inhibits the K+ conductance induced by cAMP. This conductance is apparently relevant for Cl- secretion and the basal K+ conductance is insufficient to support secretion.

Amiloride↗
PubMed1995

Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion.

OBJECTIVE: The aim was to characterise the new compound HOE642 as a selective and cardioprotective Na+/H+ exchange inhibitor in various models. METHODS: The effect of HOE642 was tested in the osmotically activated Na+/H+ exchange of rabbit erythrocytes and in propionate induced swelling of human thrombocytes. Recovery of pH after an NH4Cl prepulse and effects on other ion transport systems by patch clamp technique were investigated in rat cardiomyocytes. NHE subtype specifity of the compound was determined by 22Na+ uptake inhibition in a fibroblast cell line separately expressing subtype isoforms 1-3. Protective effects of HOE642 in cardiac ischaemia and reperfusion by ligation of coronary artery were investigated in isolated working rat hearts and in anaesthetised rats. RESULTS: HOE642 concentration dependently inhibited the amiloride sensitive sodium influx in rabbit erythrocytes, reduced the swelling of human platelets induced by intracellular acidification, and delayed pH recovery in rat cardiomyocytes. In the isolated working rat heart subjected to ischaemia and reperfusion HOE642 dose dependently reduced the incidence and the duration of reperfusion arrhythmias. It also reduced the the release of lactate dehydrogenase and creatine kinase, and preserved the tissue content of glycogen, ATP, and creatine phosphate. In anaesthetised rats undergoing coronary artery ligation intravenous and oral pretreatment with HOE642 caused a dose dependent reduction or a complete prevention of ventricular premature beats, ventricular tachycardia, and ventricular fibrillation. The compound was well tolerated and neutral to circulatory variables. Other cardiovascular agents tested in this model were not, or were only partly, effective at doses showing marked cardiodepressive effects. CONCLUSIONS: HOE642 is a very selective NHE subtype 1 inhibitor showing cardioprotective and antiarrhythmic effects in ischaemic and reperfused hearts. Further development of well tolerated compounds like HOE642 could lead to a new therapeutic approach in clinical indications related to cardiac ischaemia and reperfusion.

Animals↗
PubMed1995

Visual short-term memory of stimulus velocity in patients with unilateral posterior brain damage.

Neurophysiological studies indicate the existence of an area in the extrastriate monkey cortex specialized for the processing of stimulus motion. The present investigation was conducted to determine whether a homologous area exits in the human cortex that underlies the processing and short-term storage of velocity information. Contrast detection and velocity discrimination thresholds were measured in a group of 23 patients with unilateral focal damage to either the lateral occipital, temporal, or posterior parietal cortex. Their results were compared to those of 23 age-matched control subjects. Detection and discrimination thresholds were determined for spatially truncated sinewave gratings presented 4 degrees eccentric of fixation randomly in either the left and right visual fields. Contrast detection thresholds were measured in a spatial two-alternative forced-choice paradigm for three different drift rates (1, 2, and 4 Hz) for leftward and rightward drift directions. Simultaneous velocity discrimination thresholds were determined for reference and test gratings presented 4 degrees left and right of fixation. Sequential velocity discrimination thresholds were measured using a delay, with a interstimulus interval (ISIs) of 1, 3, and 10 sec. In a subset of five patients with superior temporal lobe damage, spatial frequency discrimination thresholds for stationary gratings were also determined. The results indicate the following: (1) contrast detection thresholds for drifting gratings did not significantly differ between the patient and control groups; (2) velocity discrimination thresholds were significantly elevated in the patients; (3) velocity discrimination thresholds significantly increased with increasing ISI in the patients; (4) velocity discrimination thresholds were elevated most when the patients had a lesion in the superior temporal cortex; (5) in the subgroup of five patients with superior temporal lobe damage, spatial frequency discrimination thresholds were not significantly elevated. The results suggest that there is a visual area in the human posterior temporal cortex that is involved in the processing and short-term storage of the velocity of moving visual stimuli.

Adolescent↗
PubMed1995

Effects of calcium channel blockers on NIH 3T3 fibroblasts expressing the Ha-ras oncogene.

NIH 3T3 fibroblasts expressing the ras oncogene (+ras cells) respond to bradykinin, bombesin or serum with sustained oscillations of cell membrane potential reflecting oscillations of intracellular calcium activity and subsequent activation of calcium-sensitive K+ channels. In contrast, identical cells not expressing the oncogene (-ras cells) respond to bradykinin with a single, transient hyperpolarization of the cell membrane. Furthermore, +ras cells are characterized by a serum-independent proliferation, an increase in cell volume and a marked reorganization of the cytoskeleton. It has been shown previously that the calcium channel blocker nifedipine, but not verapamil and diltiazem, inhibits oscillations of cell membrane potential as well as proliferation. In this study, we have examined the effect of several calcium channel blockers (bepridil, nifedipine, verapamil, diltiazem) on the proliferation, volume and cytoskeletal reorganization of +ras cells. Bepridil (10 mumol/l), which is also shown here to inhibit oscillations of cell membrane potential, and nifedipine (10 mumol/l) caused a decrease in cell number, whereas verapamil and diltiazem (10 mumol/l each) resulted in growth rates which did not differ from untreated +ras cells. The increase in cell volume as observed in untreated +ras cells was also observed for cells treated with verapamil and diltiazem, whereas cell volumes of +ras cells treated with bepridil and nifedipine were markedly reduced and similar to the values obtained for -ras cells. In addition, bepridil and nifedipine markedly inhibited cytoskeletal rearrangement, i.e depolymerization of actin-containing stress fibers. This inhibitory effect was not observed for verapamil and diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗
PubMed1994

Effects of a new Na+/H+ antiporter inhibitor on postischemic reperfusion in pig heart.

We investigated the effects of a new compound (3-methylsulfonyl-4-piperidinobenzoyl) guanidine hydrochloride (HOE 694) known to inhibit the Na+/H+ exchanger in a porcine model of ischemia/reperfusion. Ischemia was induced by coronary occlusion (twice for 10 min, with a 30-min reperfusion interval) followed by a 4-h reperfusion period. Treated animals (n = 8) received HOE 694 as a bolus (7 mg/kg) 20 min before ischemia and subsequently as a continuous infusion (0.07 mg/kg) throughout the experiment. Control pigs (n = 11) received vehicle. Regional wall function (percentage of segment shortening, % SS) of the treated animals was significantly improved as compared with that of controls after the 4-h reperfusion period (74.1 +/- 2.5 vs. 50.9 +/- 5.4, p < 0.005). Ventricular fibrillation (VF) could be prevented completely in treated pigs but occurred in 9 of 11 control animals (p < 0.001). Ultrastructural changes after ischemia and reperfusion were moderate and slightly abnormal in controls but much milder and completely recovered in the treated group, respectively. The tissue content of high-energy phosphates did not show a significant difference between groups. Inhibition of the sarcolemmal Na+/H+ antiporter with HOC 694 is antiarrhythmic and diminishes myocardial ischemic cell injury by preventing Na+ overload.

Adenine Nucleotides↗
PubMed1994

Sorbitol-accumulating pyrimidine derivatives.

The novel compounds SDI 157 (2-methyl-4(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimid ine, CAS 131816-54-1) and SDI 158 (2-hydroxymethyl-4-(4-N,N-dimethylaminosulfonyl-1- piperazino) pyrimidine, CAS 140687-51-0) have been found to be inhibitors of sorbitol dehydrogenase. In normal and diabetic animals both compounds induced a dose-dependent increase of tissue sorbitol, especially in the peripheral nerve, without alteration of the blood glucose. In contrast to SDI 158, SDI 157 does not act in vitro. However, in the isolated perfused rat liver SDI 157 induced a high sorbitol release and plasma samples of animals treated with SDI 157 induced a sorbitol accumulation in vitro in erythrocytes like SDI 158. SDI 157 seems to be a prodrug. In accordance with the polyol theory, the chronic administration of SDI 157 to diabetic rats accelerated the cataract development and depleted the lens of total and oxidized glutathione. Surprisingly, however, it accelerated the motor nerve conduction velocity in normal and diabetic rats, normalized the glomerular filtration rate in diabetic rats and did not induce retinal capillary lesions in normal rats or aggravate those in diabetic rats. At single oral doses up to 100 mg/kg, SDI 157, was well tolerated by diabetic and normal rats. Except for a reduction of drinking water consumption, the chronic administration of SDI 157 in drinking water at doses up to 100 mg/kg per day had no side effects in normal, diabetic and galactoselfructose-rich diet rats.

Animals↗
PubMed1993

Effects of HOE 694--a novel inhibitor of Na+/H+ exchange--on NIH 3T3 fibroblasts expressing the RAS oncogene.

Among the sequelae of ras oncogene expression are intracellular alkalinization and increase of cell volume, both phenomena attributed at least in part to activation of the Na+/H+ exchanger. The present study was performed to elucidate the effects of HOE 694--a novel inhibitor of the Na+/H+ exchanger--on intracellular pH, cell volume, cytoarchitecture and cell proliferation of ras oncogene expressing NIH 3T3 fibroblasts. Following transient exposure of the cells to 20 mmol/l NH3/NH4+, intracellular pH decreases sharply. The following slow realkalinization is completely blocked by 10 mumol/1 HOE 694. Half-maximal inhibition is achieved by 100 nmol/l HOE 694. Cell proliferation is inhibited by HOE 694 with similar potency, whereas the increase in cell volume and cytoskeletal transformation are not prevented, even by 10 mumol/l HOE 694.

3T3 Cells↗