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U Quast

Publications and source records attributed to U Quast.

At least 55 records · Page 3Linked to original sources
PubMed1997

[Oral vaccines against poliomyelitis and vaccination-related paralytic poliomyelitis in Germany. Do we need a new immunization strategy?].

Oral vaccination against poliomyelitis, which was carried out worldwide, lead to eradication of poliomyelitis in the United States, in South America and parts of Europe; in other parts of the world, paralytic poliomyelitis is still a severe risk of health. In those countries where poliomyelitis has been eradicated, it is presently discussed whether the vaccination schedules should be changed to an inactivated polio vaccine (IPV), as in polio-free countries only cases of paralytic poliomyelitis after vaccinations have been reported. Behringwerke's data from a 30-year period of analysing adverse drug reaction reveal the following: using the trivalent oral polio vaccine (OPV), based on WHO case definition, the risk for vaccine-associated paralytic poliomyelitis with permanent damage is approximately 1 case for 4.5 million vaccinations (0.22 per million) in vaccinees, and approximately 1 case for 11 million (0.09 per million) in contact persons. This low risk is in line with the data ascertained worldwide.

Adolescent↗
PubMed1996

Binding of [3H]-P1075, an opener of ATP-sensitive K+ channels, to rat glomerular preparations.

ATP-sensitive K+ channels (KATP channels) in the kidney have been found in the tubular system and in the afferent arteriole. In this study we have examined the binding of [3H]-P1075 ([3H]-N-cyano-N'-(1, 1-dimethylpropyl)-N"-3-pyridylguanidine), a selective opener of KATP channels, in rat glomerular preparations. Equilibrium (saturation, competition) and kinetic experiments indicated that [3H]-P1075 binds to a single class of sites with a dissociation constant of about 3 nM and a maximum binding capacity of 10 fmol mg-1 glomerular protein. The association rate constant of the complex was 6,5 x 10(7) M-1 min-1; dissociation occurred with a half-time of 6.2 min. Specific [3H]-P1075 binding was strongly reduced when the metabolic state of the glomerular preparation was impaired during the preparation procedure or the binding assay or when the preparation was subjected to mild collagenase treatment. In different metabolically competent preparations, the amount of specific [3H]-P1075 binding correlated well with the number of vascular endings adherent to the glomeruli; no specific binding was found in mesangial cells in culture. Specific [3H]-P1075 binding was inhibited by representatives of the different classes of KATP channel openers and by sulphonylurea-type blockers with inhibition constants similar to those obtained in rat aortic rings. It is concluded that rat glomerular preparations possess specific binding sites for KATP channel openers with vascular characteristics. The sensitivity of binding to mild collagenase treatment suggests that these sites are located on a membrane protein; in addition, the data suggest that these sites are localized on smooth muscle and/or renin secreting cells of the afferent vascular endings attached to some of the glomeruli. Their estimated density (1,500 microns-2) is much higher than that of KATP channels in smooth muscle.

Adenosine Triphosphate↗
PubMed1995

Ba2+ differentially inhibits the Rb+ efflux promoting and the vasorelaxant effects of levcromakalim and minoxidil sulfate in rat isolated aorta.

The K+ channel openers activate ATP-sensitive K+ channels (KATP) in vascular smooth muscle and induce relaxation. In this study, the relationship between these two effects was examined in rings of rat aorta using levcromakalim and minoxidil sulfate as the openers and Ba2+ as the K+ channel blocker; K+ channel opening was assessed by determining the rate constant of 86Rb+ efflux from the preparation. Ba2+ inhibited the 86Rb+ efflux stimulated by levcromakalim in a noncompetitive manner with an IC50 value of 29 microM and a Hill-coefficient of 1.2. At concentrations >300 microM, Ba2+ increased the tension of rat aortic rings concentration-dependently. Levcromakalim relaxed contractions to Ba2+ (0.5 and 1 mM) with potencies similar to those determined against KCl (25 mM) or noradrenaline as spasmogens (EC50 values 15-40 nM). The vasorelaxant effect against Ba2+ was inhibited by the KATP channel blockers, glibenclamide and tedisamil, and abolished in depolarizing medium (55 mM KCl). At 3 mM Ba2+, levcromakalim was still able to transiently induce complete relaxation; however, within 1 h oscillations in tension developed, leading to a stable level of only 15% relaxation. A similar level of relaxation was achieved against 10 mM Ba2+ whereas the combination of 0.5 mM Ba2+ and 3 microM tedisamil blocked the relaxant effect of levcromakalim completely. With minoxidil sulfate as the KATP channel opener the results of the 86Rb+ efflux and tension experiments were similar to those obtained with levcromakalim. It is concluded that Ba2+ is more potent in inhibiting the K+ channel opening than the vasorelaxant effects of the openers. On the basis of the 86Rb+ efflux experiments it is estimated that at least 97% of the channels opened by the activators can be blocked without major effects on vasorelaxation suggesting a dissociation between the two effects. However, if the block is pushed to extremes (> or = 99.95%) the vasorelaxant effect of the openers is also abolished suggesting a link between both effects. This paradoxon remains to be solved.

Animals↗
PubMed1995

Potentiation of P1075-induced K+ channel opening by stimulation of adenylate cyclase in rat isolated aorta.

1. The effects of analogues and stimulators of cyclic AMP on the 86Rb+ efflux-stimulating and binding properties of P1075, an opener of ATP-dependent potassium channels, were studied in rat aortic rings. The increase in 86Rb+ efflux stimulated by P1075 was taken as a qualitative measure of K+ channel opening. 2. Forskolin, a direct activator of adenylate cyclase, isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, and dibutyryl-cyclic AMP (db-cyclic AMP), a membrane permeant cyclic AMP-analogue, relaxed rat aortic rings contracted by noradrenaline with EC50 values of 0.06, 2 and 10 microM, respectively. 3. Forskolin, IBMX and db-cyclic AMP produced concentration-dependent increases of the 86Rb+ efflux induced by P1075 (50 nM) by up to twofold with EC50 values of about 0.1, 1.7 and 81 microM. At these concentrations the agents had little effect on the basal rate of 86Rb+ efflux. 4. The 86Rb+ efflux produced by P1075 in the presence of the cyclic AMP stimulators was inhibited by glibenclamide, a blocker of ATP-sensitive potassium channels. 5. IBMX (100 microM) induced a leftward shift of the concentration-86Rb+ efflux curve of P1075 without increasing the maximum. The enhancements of P1075-stimulated 86Rb+ efflux produced by combinations of forskolin and IBMX were either additive or less than additive. 6. The protein kinase A inhibitor, H-89, inhibited P1075-stimulated 86Rb+ efflux in the presence of IBMX significantly more than in the absence of IBMX, suggesting that the effect of increased cyclic AMP levels is mediated by protein kinase A. 7. At high concentrations, forskolin and IBMX slightly increased basal 86Rb+ efflux and inhibited the tracer efflux induced by P1075.8. Binding of [3H]-P1075 to rat aortic rings was either unaffected or inhibited by forskolin, IBMX and db-cyclic AMP.9. This study shows that moderate stimulation of the cyclic AMP system potentiates the K+ channel opening effect of P1075 by activation of protein kinase A. The fact that binding of [3H]-P1075 remains unchanged or is diminished favours the hypothesis that the K'channel openers activate ATP-dependent K+ channels by an indirect mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1995

[Tuberculosis].

Explore the source record for details and available documents.

BCG Vaccine↗
PubMed1994

A fast and sensitive TLD method for measurement of energy and homogeneity of electron beams using transmitted radiation through lead.

A simple and fast, but sensitive TLD method for the measurement of energy and homogeneity of therapeutically used electron beams has been developed and tested. This method is based on the fact that when small thicknesses of high-Z absorbers such as lead are interposed in the high-energy electron beams, the transmitted radiation increases with the energy of the electron beams. Consequently, the ratio of readouts of TLDS held on the two sides of a lead plate varied sharply (by factor of 70) with a change in energy of the electron beam from 5 MeV to 18 MeV, offering a very sensitive method for the measurement of the energy of electron beams. By using the ratio of TL readouts of two types of TLD ribbon with widely different sensitivities, LiF TLD-700 ribbons on the upstream side and highly sensitive CaF2:Dy TLD-200 ribbons on the downstream side, an electron energy discrimination of better than +/- 0.1 MeV could be achieved. The homogeneity of the electron beam energy and the absorbed dose was measured by using a jig in which the TLDS were held in the desired array on both sides of a 4 mm thick lead plate. The method takes minimal beam time and makes it possible to carry out measurements for the audit of the quality of electron beams as well as for intercomparison of beams by mail.

Algorithms↗
PubMed1994

Cellular pharmacology of potassium channel openers in vascular smooth muscle.

Potassium channel opening is a physiological mechanism which excitable cells exploit to maintain or restore their resting state. Thus drugs that open vascular potassium channels have the potential to restrain or prevent contractile responses to excitatory stimuli or clamp the vessel in a relaxed condition. Hence, potassium channel openers, such as aprikalim and levcromakalim, relax agonist precontracted vascular preparations in vitro and lower systemic and regional vascular resistances in intact animals. Glibenclamide, a blocker of ATP sensitive potassium (KATP) channels, antagonises these effects. The main vasorelaxant mechanism of the potassium channel openers is to increase the potassium efflux through opening plasmalemmal potassium channels, which repolarises and/or hyperpolarises the membrane. This effect lowers the opening probability of voltage dependent calcium channels, restrains agonist induced calcium release from intracellular sources through inhibition of inositol trisphosphate formation, decreases the sensitivity of intracellular contractile elements to calcium, and accelerates the clearance of intracellular calcium via the Na+/Ca+ exchanger. Experimental evidence indicates that mechanisms not linked to potassium channel opening may also contribute to the potassium channel opener induced vasorelaxation; these remain to be clearly defined (for example, inhibition of the refilling of intracellular calcium stores). Potassium channel openers displace the binding of 3H-P1075, a potent potassium channel opener, in myocytes and intact rings from the rat aorta. In patches from vascular myocytes, potassium channel openers primarily open a small conductance (10-20 pS) KATP channel which is gated by [ATP]i and particularly by nucleotide diphosphates and magnesium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Synthesis of and radioligand binding studies with a tritiated pinacidil analogue: receptor interactions of structurally different classes of potassium channel openers and blockers.

The synthesis of N-cyano-N'-[1,1-dimethyl-[2,2,3,3-3H]propyl]-N"-(3- pyridinyl)guanidine, [3H]-15, is described. The utility of this tritiated radioligand in characterizing the interactions of potassium channel openers and blockers with their receptors is demonstrated. Potassium channel openers of the pinacidil, cromakalim, aprikalim, diazoxide, and minoxidil types, as well as KATP channel blockers of the glibenclamide and eosine types, are all capable of displacing [3H]-15 from its receptor. The results indicate that all of these compounds interact with the same target protein, but that several different allosterically coupled receptor binding sites are probably involved. The highly significant correlation between the ability of the structurally diverse potassium channel openers to inhibit [3H]-15 binding and to relax vascular smooth muscle is consistent with their receptor binding sites being closely associated with the potassium channel protein which is the functional target of this class of drugs.

Animals↗
PubMed1993

The individual enantiomers of cis-cromakalim possess K+ channel opening activity.

Cromakalim (BRL 34915), a racemic trans-3,4-disubstituted benzopyran, is the prototype of a novel group of vasorelaxants which act by opening K+ channels in the cell membrane, the K+ channel openers. The enantiomers of cis-cromakalim were synthesized and their biological activity compared to that of the enantiomers of (trans-)cromakalim. Both the (+)-(3R,4R) enantiomer and its (-)-(3S,4S) antipode inhibited binding of the K+ channel opener [3H]P1075 in strips of rat aorta with pKi values of 5.4 and 5.2, respectively. They relaxed noradrenaline-induced contractions of rat isolated aorta under control conditions with pD2 values of 5.7 and 5.2; their vasorelaxant potency was greatly diminished under depolarized conditions (KCl = 55 mmol/l). Both compounds increased the permeability of the cell membrane for K+ as suggested by their ability to stimulate 86Rb+ efflux from rat aortic strips. The vasorelaxant and the 86Rb+ efflux-stimulating effects of the compounds were inhibited by the sulfonylurea, glibenclamide. These results show that the enantiomers of cis-cromakalim are genuine K+ channel openers. The (R,R) enantiomer is 50 times weaker than the (-)-(3S,4R) enantiomer of cromakalim (= levcromakalim, BRL 38227) but 3 times more potent than the (+)-(3R,4S) enantiomer. These data highlight the importance of the stereochemistry at both the 3 and 4 position of the benzopyran ring.

Anesthesia↗
PubMed1993

Do the K+ channel openers relax smooth muscle by opening K+ channels?

During the past decade, a group of chemically heterogeneous compounds known as the K+ channel openers has emerged. These compounds open a certain class of K+ channels (ATP-sensitive K+ channels) in the sarcolemma of vascular smooth muscle cells, which leads to hyperpolarization of the cell membrane and relaxation of the tissue. The mechanisms by which hyperpolarization affects smooth muscle contraction and contractility can thus be examined. Hyperpolarization induced by these K+ channel openers prevents Ca2+ entry through voltage-operated Ca2+ channels. Surprisingly, and by mechanisms not yet defined, hyperpolarization of the cell also reduces agonist-induced accumulation of inositol 1,4,5-trisphosphate (and consequently, Ca2+ mobilization from intracellular stores), and the Ca2+ sensitivity of the contractile apparatus. In addition, recent evidence reviewed here by Ulrich Quast suggests that the K+ channel openers possess further mechanisms of vasorelaxation not linked to the opening of plasmalemmal K+ channels.

Adenosine Triphosphate↗
PubMed1993

Binding of the K+ channel opener [3H]P1075 in rat isolated aorta: relationship to functional effects of openers and blockers.

P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine], an analogue of the K+ channel opener pinacidil, was shown to be a K+ channel opener in rat aorta, based on (i) its ability to stimulate 86Rb+ efflux, (ii) its ability to relax contractions in response to noradrenaline under normal conditions (5 mM KCl) but not under depolarized conditions (55 mM KCl), and (iii) the sensitivity of these effects to inhibition by the sulfonylurea glibenclamide. In these assays, P1075 was approximately 20 times more potent than cromakalim. Using a tritiated derivative, [3H] P1075, specific binding could not be detected in microsomal preparations from various tissues. However, in rat aortic strips specific binding of [3H]P1075 has been observed and was reduced by lowering the temperature or by decreasing intracellular ATP levels via metabolic inhibition. Specific [3H]P1075 binding was influenced neither by depolarization (55 mM KCl) nor by lowering the pH from 7.4 to 6.0. Binding was inhibited by representatives from all major families of K+ channel openers, with potencies that correlated well with the potencies obtained in 86Rb+ efflux and relaxation studies. However, stimulation of 86Rb+ efflux occurred at 40 times higher concentrations than did binding (and vasorelaxation). Of the various inhibitors of the K+ channel openers tested, only the sulfonylureas inhibited [3H] P1075 binding with the same rank order of potencies as that required for inhibition of P1075-induced 86Rb+ efflux, although at higher concentrations. The results show that binding of [3H] P1075 is independent of membrane potential but decreases concomitantly with the intracellular ATP level. The excellent correlation between the potencies of the openers and sulfonylurea blockers in binding assays and functional studies suggests that the 'drug receptor' labeled by [3H]P1075 in rat isolated aorta is of functional relevance. However, the fact that binding of the openers occurred at concentrations considerably lower than those required for K+ channel opening and that binding of the sulfonylureas was only reflected at concentrations higher than those needed to block the channel requires complex models to link binding and effect, possibly involving two agonist binding sites coupled by negative cooperativity.

Adenosine Triphosphate↗