Biomedical subjects

K Turnheim

Publications and source records attributed to K Turnheim.

At least 37 records · Page 2Linked to original sources

PubMed1991

Intrinsic regulation of apical sodium entry in epithelia.

In the past 30 years the basic features of Na+ absorption by epithelia have been unraveled and generally accepted cell models have been established. However, these cell models of transepithelial Na+ transport represent, for the most part, a static view of cell function, i.e., all transport parameters are assumed to be in a steady state. Today the focus is on the dynamic properties of epithelia, the non-steady-state condition, and the adaptation to environmental or transport changes. This review deals with mechanisms intrinsic to the epithelium that regulate apical membrane Na+ permeability in response to changes in transport load and ambient conditions. Together with parallel autoregulatory events concerning the basolateral K+ conductance, the described mechanisms controlling apical membrane Na+ permeability serve to maintain the intracellular ionic composition within the limits that are compatible with cell function and survival. Extraepithelial factors that influence epithelial Na+ transport such as mineralocorticoids and glucocorticoids, ADH, catecholamines, and other neurotransmitters are discussed elsewhere. Apical membrane Na+ permeability appears to be determined by several intrinsic or autoregulatory mechanisms. The PmNa of epithelia with channel-mediated apical Na+ entry is downregulated by increases in the Na+ concentration of the apical bathing solution (self-inhibition) and by procedures that inhibit basolateral Na+ extrusion (feedback inhibition). The underlying mechanisms of both regulatory systems are unclear. With the use of current-noise (fluctuation) analysis, on the one hand, and single-channel recordings, on the other hand, conflicting results were obtained concerning the saturability of single-channel conductance with increasing external Na+ concentrations. Results from Na(+)-uptake studies in apical membrane vesicles from amiloride-sensitive epithelia render it unlikely that cell Na+ itself is the mediator of feedback inhibition. Both self-inhibition and feedback inhibition of PmNa are prevented by titrating superficial sulfhydryl groups in the apical membrane. Elevations of cell Ca2+ decrease apical Na+ entry, possibly via an indirect mechanism involving protein kinase C. The PmNa is markedly dependent on cell metabolism and pHc; inhibition of ATP supply and lowering cell pH reduce PmNa. Additionally, PmNa may be altered by exocytotic expansion and endocytotic retrieval of the apical membrane area or by insertion of channel proteins into the apical membrane without increasing the apical membrane area. The diversity of regulatory systems may insure the high degree of flexibility and plasticity of epithelia in their response to environmental changes.

Animals↗

PubMed1990

Calcium-activated potassium channels in basolateral membranes of colon epithelial cells; reconstitution and functional properties.

Using differential sedimentation, isopycnic and Ficoll-400 barrier centrifugation, basolateral membrane vesicles of surface and crypt cells of the rabbit distal colon were enriched 34- and 9-fold, respectively. 86Rb(+)-uptake into these vesicles, driven by an electrical potential difference, was stimulated by submicromolar Ca2+ activities and inhibited by Ba2+. These findings indicate the presence of Ca2(+)-activated K+ channels. The K+ channels in surface and crypt cell membranes differed with respect to inhibition by the bee venom apamin, the scorpion venom charybdotoxin and tetraethylammonium and exhibited a different pH dependence. Fusion of basolateral membrane vesicles with planar phospholipid bilayers revealed the presence of high-conductance Ba2(+)-sensitive K+ channels which were activated by micromolar Ca2+ and inhibited by crude scorpion venom and trifluoperazine. These K+ channels may be involved in the coupling of apical and basolateral membrane conductances during Na+ absorption and Cl- secretion, but they may also play a role in cell volume regulation.

Animals↗

PubMed1990

[Biological availability of different oral cimetidine preparations in the dog].

Bioavailability of Different Oral Dosage Forms of Cimetidine in Dogs. The bioavailability of cimetidine (200 mg) after oral administration to awake dogs was increased significantly by using tablets containing alginate. In addition the timespan was prolonged during which therapeutic plasma concentrations were maintained. Release and absorption of cimetidine were retarded from tablets containing methacrylic acid-copolymers, but the bioavailability was decreased from this dosage form and therapeutic plasma concentrations were not reached.

Acrylates↗

PubMed1989

Rabbit distal colon epithelium: I. Isolation and characterization of basolateral plasma membrane vesicles from surface and crypt cells.

A method has been developed for the simultaneous isolation of basolateral plasma membrane vesicles from surface and crypt cells of rabbit distal colon epithelium by sequential use of differential sedimentation, isopycnic centrifugation and Ficoll 400 barrier centrifugation. The protein yield was high (total 0.81 mg/g mucosa) and surface and crypt cell-derived basolateral membrane fractions have been purified 34- and 9-fold with respect to the homogenate. The pattern of marker enzyme enrichments revealed only minor contamination by subcellular organelles. Latency of ouabain-sensitive (Na+,K+)-ATPase activity prior and after trypsin treatment of membranes indicated a vesicle configuration of sealed right side-out: sealed inside-out: leaky of approximately 2:1:1. The presence of sealed vesicles was also evident from the osmotic sensitivity of the D-[1-14C] mannitol equilibrium space determined with either fraction. Although considerably different in protein profile, surface and crypt basolateral membranes were similar in cholesterol to phospholipid molar ratio and membrane fluidity as determined by steady-state fluorescence polarization. Stopped-flow light scattering experiments revealed a rather low water permeability of the membranes with a permeability coefficient of 6 microns/sec at 35 degrees C, which is one order of magnitude lower than reported for small intestinal plasma membranes. Both membrane fractions have been shown to effectively generate outward uphill potassium ion gradients, a process that is energized by ATP and inhibited by the membrane-permeant cardiac-glycoside digitoxin. These characteristics are consistent with the activity of a (Na+,K+) pump operating in inside-out vesicles.

Animals↗

PubMed1989

Reconstitution of a calcium-activated potassium channel in basolateral membranes of rabbit colonocytes into planar lipid bilayers.

A highly enriched preparation of basolateral membrane vesicles was isolated from rabbit distal colon surface epithelial cells employing the method described by Wiener, Turnheim and van Os (Weiner, H., Turnheim, K., van Os, C.H. (1989) J. Membrane Biol. 110:147-162) and incorporated into planar lipid bilayers. With very few exceptions, the channel activity observed was that of a high conductance. Ca2+-activated K+ channel. This channel is highly selective for K+ over Na+ and Cl-, displays voltage-gating similar to "maxi" K(Ca) channels found in other cell membranes, and kinetic analyses are consistent with the notion that K+ diffusion through the channel involves either the binding of a single K+ ion to a site within the channel or "single-filing" ("multi-ion occupancy"). Channel activity is inhibited by the venom from the scorpion Leiurus quinquestriatus, Ba2+, quinine, and trifluoperazine. The possible role of this channel in the function of these cells is discussed.

Analog-Digital Conversion↗

PubMed1989

[Antidiarrheal agents: tools and therapeutic agents].

A host of chemically diverse compounds have antidiarrheal potency, however, only a fraction of these agents has gained clinical acceptance. But regardless of their therapeutic status, the effects of these drugs have enhanced our understanding of the physiology and pathophysiology of the intestinal mucosa. Fluid- and electrolyte substitution are the primary therapeutic measures in severe diarrhea, for that purpose oral rehydration using glucose-sodium solutions has proven simple and effective. In addition gut-selective opiates, for instance loperamide, are indicated. Opiates not only decrease propulsive motor activity of the bowel but also increase intestinal water and electrolyte absorption, both effects are neuronally mediated. Antimicrobial drugs are necessary in only a small fraction of patients with diarrhea. Experimental findings have indicated possible future candidates for treatment of diarrhea: Besides opiates and glucose-electrolyte solutions water and electrolyte absorption is enhanced by alpha 2-adrenergic agents, corticosteroids, and somatostatin. Inhibitors of electrolyte secretion include phenothiazines and opiates, possibly because of binding to calcium-calmodulin, calcium-channel blockers, membrane-stabilizing agents for instance propranolol and inhibitors of prostaglandin-synthesis such as non-steroidal antirheumatic agents.

Antidiarrheals↗

PubMed1988

Essentials of insulin pharmacokinetics.

Pharmacokinetic methods are a powerful tool for the investigation of the insulin system in health and disease; the underlying formalisms are simple and straight-foreward. Following intravenous injection the plasma concentration of insulin declines with at least two exponentials, the rapidly disappearing component (half-time 2.4 min) represents elimination from the intravascular space, whereas the most slowly disappearing component (half-time 50-130 min) reflects elimination from the interstitial fluid and the tissues that utilize insulin. Total clearance of insulin, which is the result of metabolic degradation, ranges between 700 and 800 ml/min. The sites of degradation are primarily the liver (hepatic insulin clearance: 320-400 ml/min) and the kidneys (renal insulin clearance: 190-270 ml/min), hence insulin disposal depends on the function of these organs. The apparent volume of distribution for insulin is approximately equal to the extracellular space. Insulin absorption from the subcutaneous tissue is slow (half-times of 0.5-2.7, 6.6-13.8, and 15-48 hours for fast-, intermediate-, and long-acting insulins, respectively). The bioavailability of insulin after subcutaneous administration is variable. Insulin kinetics appear not to be altered in diabetes mellitus, except in cases with insulin antibodies or in insulin-resistant patients, in which insulin removal may be retarded. Optimization of functional insulin replacement requires knowledge of the pharmacokinetic properties of the insulin preparation used.

Humans↗

PubMed1988

Sodium pump quantity and turnover in rabbit descending colon at different rates of sodium absorption.

3H-Ouabain binding to isolated epithelia and basolateral membrane vesicles of Na+-transporting epithelial cells of rabbit descending colon was determined to quantify the number of operative Na+-pump sites at different rates of transcellular Na+ transport which was varied over a wide range by chronic dietary Na+ restriction or Na+ loading. Both in intact epithelia and in basolateral membrane vesicles the maximal number of specific ouabain binding sites was higher in preparations from animals transporting Na+ at high rates than in preparations from animals transporting Na+ at low rates. The affinity of ouabain to its binding site and the association and dissociation rate constants were not dependent on the rate of Na+ transport. In intact epithelia the Na+ turnover rate per pump unit was twice as high in tissues with high Na+ transport than in tissues with low Na+ transport. In basolateral membrane vesicles the Na+ turnover rate was considerably higher than in intact epithelia and there was no difference in turnover rate between vesicle preparations obtained from tissues transporting Na+ at high or low rates. Hence, factors within the intact cell appear to control the turnover rate of the Na+-pump.

Animals↗

PubMed1987

[The placebo as a nonspecific treatment factor].

Nonspecific drug actions result from the social interaction between physician and patient and the medical environment. Positive (therapeutic) placebo effects are produced in approximately 30-35% of treated patients, especially in cases of vegetative and psychic disturbances. There appears to be no distinct group of individuals with specific personality features that can be classified as "placebo responders". Negative (toxic) placebo effects, which are usually minor, are reported in 4-50% of treated patients. The occurrence of side effects may cause the patient to assume treatment with an active agent, thus increasing the therapeutic efficiency of the treatment (placebo amplification by side effects). On the other hand, the lack of a certain side effect may diminish the therapeutic effect of an active drug. The notion that placebo-induced analgesia is endorphin-mediated is not established. Hence at present psychological mechanisms have to be assumed for the placebo effect. The conscious use of a placebo as a therapeutic agent is problematic for ethical reasons, whereas the placebo component of drugs with specific actions should be exploited to enhance their therapeutic efficiency.

Humans↗

PubMed1987

[Pharmacotherapy in the aged].

The relatively high incidence of adverse drug reactions in the aged is a consequence of polypharmacy on the one hand and of altered pharmacokinetics on the other, changes of intrinsic or receptor properties (pharmacodynamic factors) are usually not of primary importance. Plasma half-lives increase and total clearance rates of many drugs are reduced due to diminished drug metabolism and renal excretion. With the exception of actively transported substances the amount absorbed from the gastrointestinal tract is not altered. Total body water declines with age, whereas the relative content of adipose tissue increases. Hence, the volume of distribution of hydrophilic drugs may be decreased, that of lipophilic drugs increased. The maintainance dose in old age can be calculated from the changes in plasma half-lives or, preferably, total clearance rates, the initial dose is determined by the changes in the volume of distribution. At present there is no rational basis for the use of geriatric drugs, i.e. agents claimed to retard the process of aging.

Aged↗

PubMed1987

Cell Na+ activities and transcellular Na+ absorption by descending colon from normal and Na+-deprived rabbits.

The relation between intracellular Na+ activities, (Na)c, determined employing Na+-selective microelectrodes, and the rates of active Na+ absorption, INa, by rabbit descending colon was examined when INa was varied over a wide range by chronic dietary Na+ deprivation. (Na)c averaged 13 mM and was independent of INa over a sixfold range. Further, the ratios of the slope resistance of the apical membrane (rm) to that of the basolateral membrane (rs) (i.e. rm/rs) in low-transporters (control diet) and high-transporters (Na+-deprived) did not differ significantly inspite of the fact that the Na+ conductance of the apical membranes of high-transporters was, on the average, three times greater than that of the low-transporters. These findings, together with the results reported by other laboratories, strongly suggest that the aldosterone-induced increase in the conductance of the apical membrane to Na+ and, in turn, the rate of entry of Na+ into the absorptive cells are followed by parallel increases in the ability of cells to extrude Na+ across the basolateral membrane in the absence of a sustained increase in (Na)c as well as the conductance of that barrier.

Animals↗

PubMed1986

[Pharmacology of nonionic roentgen contrast media].

The non-ionic X-ray contrast media metrizamide, iopamidol, iohexol, and iopromide do not bind calcium and are less hyperosmolar than the conventional ionic contrast media, for instance amidotrizoate (diatrizoate), iothalamate, or ioglicate. Hence the use of non-ionic contrast media is associated with less undesirable side-effects that are attributable to hypertonicity such as an increase in circulating plasma volume, decreased deformability of red blood cells, damage of vascular endothelium with consequent activation of blood coagulation, the complement system and fibrinolysis, increased release of bradykinin and histamine, cardiac arrhythmias, diuresis, vasodilation and decreased blood pressure, pain and heat sensation. Because of less dilution the quality of imaging is also better. According to the intravenous LD50 in experimental animals the acute toxicity of non-ionic contrast media is lower than that of ionic media. With respect to contrast quality and the rate of side-effects the various non-ionic contrast media appear to be equivalent. Despite their higher price and higher viscosity it is probable that the non-ionic contrast media will replace the classical ionic media, especially in angio- and myelography.

Animals↗

PubMed1986

Absorption and secretion of potassium by rabbit descending colon.

Measurements of K fluxes under a variety of conditions have provided an internally consistent set of data that demonstrate active absorption and active secretion of K by rabbit descending colon in vitro. The properties of K diffusion across the paracellular pathway are those of a free solution shunt. With Na and Cl present on both sides of short-circuited tissues the two opposing active K transport systems balance each other, so that there is no net K transport. Net K absorption results when the transcellular secretory K flux is inhibited by 1. serosal addition of ouabain, 2. serosal addition of furosemide, or 3. omission of either Na or Cl from the serosal solution. Hence basolateral K uptake appears to be mediated by a furosemide-sensitive Na-Cl-K cotransport system in addition to the Na-K exchange pump. Luminal addition of mersalyl or orthovanadate inhibits active K absorption. The adenosine analogue 5'-N-ethylcarboxamide adenosine and the beta-adrenergic agent isoproterenol, added to the serosal solution, cause net K secretion which is inhibitable by furosemide. The secretory K fluxes, both under stimulated and nonstimulated conditions, are abolished by an opposing electrical gradient, suggesting conductive K exit across the apical cell membrane, whereas K absorption appears to be an electroneutral process.

Absorption↗

PubMed1986

Sodium absorption and potassium secretion in rabbit colon during sodium deficiency.

Reducing the daily Na intake of rabbits from approximately 4.4 to 0.1 meq/kg body wt increases plasma aldosterone levels and the rate of amiloride-sensitive Na transport in the descending colon two- to threefold. The stimulation of Na transport is a result of an increase in the maximum transport capacity of the epithelium, whereas the affinity of Na to its transport system is not altered. Simultaneous with enhanced Na absorption, there is statistically significant K secretion of 0.25 mu eq . cm-2 . h-1 under short-circuit conditions. Transepithelial current-voltage relations in the absence and presence of amiloride were used to determine the Na permeability of the apical membrane and the intracellular Na activity of the Na-transporting cells. The Na content of the amiloride-sensitive cells was estimated from the kinetics of absorptive Na tracer fluxes. The stimulation of active Na transport under conditions of dietary Na restriction is associated with parallel increases in apical membrane Na permeability and the Na content of the amiloride-sensitive cells, but the intracellular Na activity and the activity of the epithelial Na-K-ATPase are not significantly altered. Taken together, these results suggest that endogenous aldosterone increases the number of conducting Na entry sites in the apical membrane of colonic epithelium and that there is activation of additional Na pump units in the basolateral membrane, brought about by cell swelling and possibly by an increase in the fraction of epithelial cells that participate in active Na transport.

Absorption↗

PubMed1985

Determination of the sodium transport pool in epithelia from tracer fluxes: a simplified approach.

The epithelial content of tracer Na can be calculated either from the exponential increase of unidirectional transepithelial Na tracer fluxes observed after addition of labeled Na to the solution bathing the luminal side of isolated epithelia or from the linear portion of the rate of accumulation of label in the serosal solution. The second method is not only simpler, because fewer data points are required and no logarithmic transformations are necessary, but also more accurate, as shown in experiments with stripped epithelia of rabbit descending colon. From the difference in tissue Na tracer content in the absence and presence of amiloride, which blocks luminal Na uptake, a Na concentration in the transport pool of 8-10 mM is obtained, assuming that all cells participate in active transport. From a comparison of the intracellular Na concentration derived from current-voltage relations of the apical Na entry step with the Na concentration in the epithelial Na transport pool, an estimate may be obtained of what fraction of the cell mass is involved in active Na transport.

Amiloride↗

PubMed1984

Stimulation of electrolyte secretion in rabbit colon by adenosine.

Serosal addition of adenosine after inhibition of adenosine deaminase with deoxycoformycin increases short-circuit current (Isc) and tissue conductance of isolated epithelia of rabbit descending colon. In the presence of Cl this increase in Isc results from a reversal of electrically neutral Cl absorption to rheogenic Cl secretion. When Cl is absent the stimulating effect of adenosine on Isc is reduced to one-third and appears to be brought about by HCO3 secretion. Under all conditions active Na transport remains unaltered. Adenosine-induced electrolyte secretion is markedly decreased by serosal addition of furosemide and depends on the presence of Na on the serosal side of the tissue. The stoichiometry of the interaction of Na and Cl with the basolateral Cl entry mechanism appears to be 1:1. Under Na-free conditions adenosine elicits a current transient which is carried by Cl ions and which is not inhibited by furosemide. Hence this current transient seems to be brought about by rheogenic apical Cl efflux. All these findings suggest that the conductive step in transepithelial Cl secretion resides in the apical membrane. Hyperpolarization of the Na-transporting cells by luminal addition of amiloride does not enhance electrolyte secretion. The site of action of adenosine is the extracellular surface of the basolateral membrane, because (a) luminal addition of adenosine is ineffective, (b) nitrobenzylmercaptopurineriboside, a blocker of cellular nucleoside uptake, augments the effect of serosal adenosine, and (c) the intracellular metabolites of adenosine do not mediate the effect. From the rank-order of potency of adenosine and its analogues 5'-N-ethylcarboxamide adenosine and N6-cyclohexyladenosine it is concluded that the adenosine receptors involved in electrolyte secretion are of the Ra subtype. Theophylline partially inhibits the secretory effect. The intracellular mediator of adenosine appears to be cyclic AMP and/or cyclic GMP, since the tissue levels of both compounds are rapidly elevated after addition of adenosine and both cyclic AMP and cyclic 8-bromo-GMP are able to mimic the adenosine action.

Adenosine↗

PubMed1983

Relation between intracellular sodium and active sodium transport in rabbit colon: current-voltage relations of the apical sodium entry mechanism in the presence of varying luminal sodium concentrations.

The current-voltage relations of the amiloride-sensitive Na entry pathway across the apical membrane of rabbit descending colon, exposed to a high K serosal solution, were determined in the presence of varying mucosal Na activities, (Na)m, ranging from 6.2 to 99.4 mM. These relations could be closely fit to the "constant field" flux equation yielding estimates of the permeability of the apical membrane to Na, PmNa, and the intracellular Na activity, (Na)c. The following empirical relations emerged: (Na)c increased hyperbolically with increasing (Na)m; PmNa decreased hyperbolically with increasing (Na)m and linearly with increasing (Na)c; spontaneous variations in Na entry rate at constant (Na)m could be attributed entirely to parallel, spontaneous variations in PmNa; the rate of Na entry increased hyperbolically with increasing (Na)m obeying simple Michaelis-Menten kinetics; the relation between (Na)c and "pump rate," however, was sharply sigmoidal and could be fit by the Hill equation assuming strong cooperative interactions between Na and multiple sites on the pump; the Hill coefficient was 2-3 and the value of (Na)c at which the pump-rate is half-maximal was 24 mM. The results provide an internally consistent set of relations among Na entry across the apical membrane, the intracellular Na activity and basolateral pump rate that is also consistent with data previously reported for this and other Na-absorbing epithelia.

Animals↗

PubMed1982

Does tissue ATP content limit active sodium transport across intestinal epithelia in vitro?

The ATP content of isolated epithelia of rabbit descending colon, incubated in oxygenated Ringer solution containing glucose, is increased by addition of 1 mM adenosine from 10.9 +/- 1.4 to 22.2 +/- 2.3 pmoles/mg, but the transport rate of the Na pump is not altered. It is therefore concluded that epithelial ATP synthesis is not rate-limiting for Na transport in this tissue under conditions of in vitro aerobic incubation.

Adenosine↗