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Biomedical subjects

U Quast

Publications and source records attributed to U Quast.

At least 73 records · Page 4Linked to original sources
PubMed1992

Analysis of the relaxant action of SDZ PCO 400 in airway smooth muscle from the ox and guinea-pig.

SDZ PCO 400 (30 nM-100 microM) suppressed the spontaneous tone of guinea-pig isolated trachealis. Glibenclamide (1-10 microM), phentolamine (100 microM), guanethidine (50 microM) and bretylium (50 microM) each antagonized SDZ PCO 400 without antagonizing isoprenaline or theophylline. Charybdotoxin (100 nM) failed to antagonize SDZ PCO 400 but antagonized theophylline. The relaxant action of SDZ PCO 400 was ablated when spasm was induced by a K(+)-rich (120 mM) medium. In bovine and guinea-pig trachea, SDZ PCO 400 (10 microM) suppressed spasm evoked by lower (less than 40 mM) but not higher (greater than 40 mM) concentrations of KCl. In guinea-pig trachea the relaxant action of SDZ PCO 400 was associated with suppression of electrical slow waves and with marked cellular hyperpolarisation. SDZ PCO 400 (0.5 and 10 microM) promoted the efflux of 86Rb+ from bovine trachealis, an effect inhibited by glibenclamide (1 microM). It is concluded that the tracheal relaxant action of SDZ PCO 400 is associated with the opening of a plasmalemmal K(+)-channel analogous to the ATP-sensitive K(+)-channel observed in insulin-secreting cells.

Animals↗
PubMed1992

A specific binding site for K+ channel openers in rat aorta.

The K+ channel openers, including cromakalim, pinacidil, minoxidil sulfate, diazoxide, and nicorandil, form a chemically heterogeneous group of compounds, which relax smooth muscle by opening plasmalemmal K+ channels. At present it is not known whether these drugs elicit their effects by binding to the same target, presumably the K+ channel. In order to address this question, a binding assay for K+ channel openers has been developed in vascular smooth muscle. The novel tritiated K+ channel opener, [3H]P1075, an analogue of pinacidil, binds with high affinity (KD = 6 +/- 1 nM) to endothelium-denuded rings of rat aorta. Inhibition studies indicate that the different families of K+ channel openers bind to a common target. Evidence is presented to suggest that the binding site for the sulfonylurea, glibenclamide, the major blocker of the K+ channel openers, is coupled in a negative allosteric manner to the binding site(s) for the openers. The binding assay described here may open the way to the biochemical characterization of the drug receptor for the K+ channel openers.

Animals↗
PubMed1992

Structure-activity studies of potassium channel opening in pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas.

Potassium channel opening activity for pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas, has been assessed through simultaneous measurement of spontaneous contractile activity and stimulation of 86Rb+ efflux from rat portal veins loaded with 86Rb+. The good correlation between these two effects suggests that the vasodilator activity of the compounds is directly attributable to an increased opening of potassium channels. The resulting quantitative in vitro data has been used to analyze the structure-activity relationships for potassium channel opening, allowing the biological activity to be rationalized in terms of a pharmacophore involving a hydrogen-bond-acceptor element, a hydrogen-bond-donor element, and a lipophilic binding group. A model for the binding of pinacidil-related compounds to their potassium channel receptor has been developed, and compounds designed to test this model have been synthesized and tested. Prototropic equilibria are implicated as playing a fundamental role in determining the hydrogen-bonding ability of the compounds, and conformational changes in the receptor are invoked to explain disparities in the chiral recognition of lipophilic groups in different compounds.

Animals↗
PubMed1992

Differential inhibition by tedisamil (KC 8857) and glibenclamide of the responses to cromakalim and minoxidil sulphate in rat isolated aorta.

The effects of the K+ channel blockers tedisamil and glibenclamide on cromakalim- and minoxidil sulphate-induced 42K+ and 86Rb+ efflux and vasorelaxation in rat aorta, were investigated. In aortic strips preloaded with 42K+ or 86Rb+, cromakalim (1 mumol/l) induced increases in tracer efflux, which were concentration-dependently inhibited by tedisamil with similar potencies (pD2 approximately 7.3) but different amplitudes (maximum inhibition of 86Rb+ efflux to 0% of control, 42K+ efflux to 10 +/- 1%). The 42K+ efflux elicited by a low concentration of cromakalim (100 nmol/l) was, however, fully inhibited by tedisamil. The tracer effluxes induced by minoxidil sulphate were fully inhibited by tedisamil and glibenclamide (300 nM). Cromakalim and minoxidil sulphate, produced a concentration-dependent inhibition of noradrenaline (100 nmol/l)-induced tone, with pD2 values of approximately 7.3. Tedisamil (300 nmol/l) and glibenclamide (300 nmol/l), which inhibited cromakalim- and minoxidil sulphate-induced 42K+ and 86Rb+ efflux by greater than or equal to 80%, produced 2-fold and 40-fold shifts in the concentration-relaxation curve for cromakalim, and 3.5-fold and 2200-fold shifts in the concentration-relaxation curve for minoxidil sulphate, respectively. Similar shifts of the cromakalim concentration-relaxation curve in the presence of tedisamil and glibenclamide were also observed when the tissues were precontracted with potassium chloride (25 mmol/l). The results show that tedisamil and glibenclamide inhibit the cromakalim- and minoxidil sulphate-induced tracer effluxes with similar potencies whereas they differ greatly in their ability to inhibit the vasorelaxant effects of the two K+ channel openers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Potassium channel openers: pharmacological and clinical aspects.

Opening of plasmalemmal K+ channels leads to cellular hyperpolarization which, in excitable tissues possessing voltage-dependent Ca2+ channels, prevents the opening of such channels and thus prevents excitation. In the last few years, an increasing number of compounds have been identified which elicit their effects by opening K+ channels, preferentially in smooth muscle, but also in other excitable tissues. These include the novel benzpyrans, cromakalim and bimakalim, the thioformamide aprikalim, and also well known antihypertensives such as minoxidil sulphate, diazoxide and pinacidil. After a short overview of the various families of K+ channel openers (KCOs), their basic pharmacological properties, including inhibition by the sulfonyl ureas (such as glibenclamide) are presented. The actual discussion concerning the type of K+ channel(s) opened by these compounds and their mechanism(s) of vasorelaxation will be reported. The therapeutic potential of these compounds in the cardiovascular field (as antihypertensives and, in particular, as anti-ischemic agents in heart and skeletal muscle), and in asthma (where they reverse established airway hyperreactivity) will also be discussed. Improved tissue selectivity may be the essential pre-requisite for true clinical success of this class of compounds.

Animals↗
PubMed1992

On the role of Ca++ binding proteins as possible targets for Ca++ sensitizing agents.

We describe the effects of various cardioactive compounds on the Ca++ activation of force production and ATPase activity in isolated contractile structures from mammalian heart and, in some cases, skeletal muscle. We show that: 1) the Ca++ sensitizing activity of APP 201-533 does not discriminate between cardiac and skeletal muscle and is, therefore, not based on interaction with cardiac troponin I phosphorylation at serine 20. 2) compounds like trifluoperazine or bepridil, both known to interact with calmodulin, increase the Ca++ sensitivity of the contractile structures of the heart, in high concentrations, as expected from the high natural abundance of troponin C. 3) DPI 201-106 interacts with calmodulin (and presumably with the structurally closely related troponin C) in the microM concentration range. Its high Ca(++)-sensitizing potency in skinned cardiac muscle and a certain sensitivity of this effect to the detergent Triton X-100 suggest accumulation of the hydrophobic compound in the myofibrillar protein lattice.

Amrinone↗
PubMed1992

Chronic adriamycin treatment and its effect on the cardiac beta-adrenergic system in the rabbit.

Treatment of male rabbits with adriamycin at a cardiotoxic dose (1 mg/kg intravenously, i.v., twice a week for 9 weeks) caused cardiovascular disturbances characteristic of chronic heart failure. The severity of symptoms varied, indicating differences in the individual sensitivity of the animals to adriamycin. Thus, cardiac output (CO) was decreased by greater than 40% in only 4 of the 7 animals in which it was measurable at 9 weeks. Elevated levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA), as well as pulmonary congestion, hydrothorax, and ascites were also evident. The baroreflex response to sodium nitroprusside (NPS) was blunted. The response to the inotropic drug dobutamine was depressed by 50% as compared with the control animals. Right ventricular beta-adrenoceptor density was significantly reduced in these animals (22.9 +/- 3.1 as compared with 31.8 +/- 1.0 fmol/mg protein in control animals) owing to a selective downregulation of the beta 1-adrenoceptor population. The loss of beta-adrenoceptors was highly correlated with severity of heart failure symptoms: i.e., baroreflex dysfunction as indicated by the NPS slope (r = 0.91), decrease in CO during the previous weeks (r = 0.88), and plasma norepinephrine (NE) levels (r = 0.96). However, when all adriamycin-treated animals were compared collectively regardless of the severity of heart failure, with the controls, no difference in the beta-adrenoceptor density was detectable, a finding in agreement with previous observations in this model. Chronic treatment of rabbits with adriamycin thus causes low-output failure, reflecting some of the findings reported for the human disease; however, individual sensitivity to adriamycin varies considerably between rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

[Bullous poikilodermatitic amyloidosis of the skin with junctional bulla development in IgG light chain plasmacytoma of the lambda type. Histology, immunohistology and electron microscopy].

A 75-year-old patient presented with bullae, poilokilodermatic skin and nail dystrophy as signs of systemic amyloidosis 1 year before an IgG myeloma of the lambda type was diagnosed. The skin lesions appeared at mechanically irritated locations on the trunk and at the tensor sites of the extremities. Histology showed a subepidermal blister and necrotic keratinocytes in the epidermis. There were amyloid deposits in the papillary dermis perivascular, and in the deep dermis around eccrine glands and in arrectores pilorum muscles. Polyclonal antibodies allowed classification of the deposits as amyloid composed of lambda light-chain immunoglobulins. Electron microscopy revealed globoid deposits of non-branching filaments typical of amyloid. The blister was formed at the level of the lamina lucida, with the lamina densa at the base of the bottom of the bulla. So far, junctional blister formation in bullous amyloidosis of the skin has been described only once. Our case is the second report of this blister type, and to our knowledge the first published report of a junctional blister in myeloma-associated systemic amyloidosis.

Actin Cytoskeleton↗
PubMed1991

Cromakalim inhibits contractions of the rat isolated mesenteric bed induced by noradrenaline but not caffeine in Ca(2+)-free medium: evidence for interference with receptor-mediated Ca2+ mobilization.

The effects of the K+ channel opener cromakalim on phasic contractions induced by noradrenaline and caffeine were studied in the rat isolated mesenteric bed. In the presence of 1.4 mM Ca2+, 1-s pulses of noradrenaline increased the perfusion pressure of the preparation concentration dependently (midpoint at 92 +/- 10 microM noradrenaline). Cromakalim (0.3 and 1 microM) inhibited these contractions in a non-competitive manner. Contractions elicited by 1-s pulses of noradrenaline (100 microM) were inhibited by the dihydropyridine Ca2+ antagonist isradipine by maximally 24 +/- 1%, indicating that only a minor component of this contraction depended on Ca2+ entry via dihydropyridine-sensitive Ca2+ channels. Cromakalim was a much more effective inhibitor of these contractions (maximum inhibition by 80%, midpoint of the inhibition curve at 171 +/- 15 nM). The effect of cromakalim was stereoselective, inhibited by the sulphonylurea glibenclamide, and abolished in partially depolarizing media (KCl = 35 and 50 mM). In Ca(2+)-free medium, cromakalim inhibited the contraction induced by noradrenaline (100 microM) by maximally 69 +/- 4%, with a midpoint at 58 +/- 14 nM. The effect of cromakalim was again stereoselective, inhibited by glibenclamide, and abolished in the presence of 50 mM KCl. Contractions induced by caffeine (10 and 100 microM) were not affected by cromakalim (1 microM). The results indicate that, in rat mesenteric resistance vessels, cromakalim interferes with the ability of noradrenaline, but not caffeine, to mobilize Ca2+ from intracellular stores. The antivasoconstrictor effect of cromakalim against noradrenaline is inhibited by glibenclamide and appears to be linked to the ability of cromakalim to hyperpolarize the cell membrane.

Animals↗
PubMed1991

Tedisamil (KC 8857) differentially inhibits the 86Rb+ efflux-stimulating and vasorelaxant properties of cromakalim.

Tedisamil, a blocker of cardiac K+ channels, potently inhibited cromakalim-induced 86Rb+ efflux from rat aorta with a pIC50 = 7.3, a value similar to that obtained with the sulphonylurea glibenclamide. However, tedisamil was approximately 30 times less potent than glibenclamide in inhibiting the vasorelaxant effects of cromakalim. The data suggest that tedisamil can dissociate between the efflux-inducing and vasorelaxant effects of cromakalim and may therefore prove to be an important tool in elucidating the mechanism of action of this vasorelaxant.

Animals↗
PubMed1991

[Maintenance of remission in acute myeloid leukemia by allogeneic or autologous bone marrow transplantation].

Over a 10-year period 120 patients (58 women, 62 men; median age 33 [14-53] years) with acute myeloid leukaemia were treated by allogenic (n = 90) or autologous bone marrow transplantation to maintain remission. After a median observation time of 41 (11-126) months 64 patients (53%) remain alive without recurrence of leukaemia. Ten years after allogenic transplantation performed during the first complete remission the probability of disease-free survival is 50 +/- 8%, as compared with 50 +/- 9% at 4.5 years after autologous transplantation. Significant factors influencing disease-free survival after allogenic transplantation during the first complete remission were the time interval up to the onset of remission and the length of the remission before transplantation. The chance of disease-free survival after allogenic transplantation in the second complete remission does not so far differ from the results achieved by transplantation in the first complete remission. The risk of recurrence after autologous transplantation in the first complete remission (47 +/- 10%) is significantly higher than that following allogenic transplantation (18 +/- 10%, P less than 0.0001). Acute graft versus host reactions occurred in 16% and chronic reactions in 36% of patients after allogenic transplantation. The mortality was 38% after allogenic transplantation and 7% after autologous transplantation.

Acute Disease↗
PubMed1991

Some degree of overlap exists between the K(+)-channels opened by cromakalim and those opened by minoxidil sulphate in rat isolated aorta.

The effects of the K+ channel opening drugs minoxidil sulphate and cromakalim, on 42K+ and 86Rb+ efflux and on vasorelaxation in rat isolated aorta, were compared. In rat aortic rings precontracted with noradrenaline (100 nmol/l), minoxidil sulphate and cromakalim concentration-dependently inhibited induced tension by up to 90%, with pD2 values of 7.35 +/- 0.1 and 7.17 +/- 0.1, respectively. Glibenclamide (300 nmol/l), produced 2200- and 19-fold rightward shifts in the concentration-relaxation curves to minoxidil sulphate and cromakalim, respectively, without an effect on the maximum relaxation. Both minoxidil sulphate and cromakalim increased the efflux of 42K+ and 86Rb+ from aorta in a concentration-dependent manner, with midpoints in the mumol/l range; the maximum efflux induced by minoxidil sulphate being approximately one tenth of that induced by cromakalim. The ratio of stimulated 86Rb+/42K+ efflux increased from 0.22 to 0.48 with increasing cromakalim concentrations, but was approximately constant (approximately 0.39) when the minoxidil sulphate concentration was varied. In the presence of minoxidil sulphate, the effects of cromakalim on 42K+ and 86Rb+ efflux were inhibited in a concentration-dependent manner, by up to 60%. In the continuing presence of cromakalim (300 nmol/l), minoxidil sulphate (10 mumol/l)-induced increases in 42K+ and 86Rb+ efflux were inhibited by 45%, whereas conditioning with cromakalim (1 mumol/l) inhibited the 86Rb+ efflux stimulated by additional superfusion of cromakalim (1 mumol/l) by 85%. Glibenclamide inhibited minoxidil sulphate (10 mumol/l)- and cromakalim (1 mumol/l)-induced increases in 42K+ and 86Rb+ efflux in a concentration-dependent manner with IC50 values of approximately 80 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Postexposure rabies prophylaxis: when the guidelines are not respected.

Fifteen spontaneously reported cases of alleged lack of drug effect of postexposure antirabies prophylaxis using PCEC vaccine were analysed. The most striking finding was that in no case were the WHO guidelines for postexposure treatment of injuries caused by rabid animals respected. Therefore nothing points to insufficient vaccine efficacy. Better information for both the medical profession and the public about the treatment of exposed patients is needed.

Adult↗
PubMed1991

Vaccination of patients with encephalomyelitis disseminata.

The aetiopathogenesis of Encephalomyelitis disseminata (multiple sclerosis) is not yet fully understood. It is thought to involve an immunopathological process, with various exogenic factors considered to be possibly responsible for inducing the disease or causing acute exacerbations. In the literature the following factors are described as having the capacity to interfere directly or indirectly in immunoregulatory mechanisms: infectious diseases, gravidity, various types of trauma, non-infectious diseases, and drugs, but also physical strain and vaccinations.

Adolescent↗
PubMed1991

Differences in the K(+)-channels opened by cromakalim, acetylcholine and substance P in rat aorta and porcine coronary artery.

1. The effects of acetylcholine and substance P on the efflux of 86Rb+ and 42K+ from rat aorta and pig coronary artery, respectively, were compared with those of the K+ channel opening agent, cromakalim. 2. In rat aorta preloaded with 86Rb+ and/or 42K+, acetylcholine produced transient, concentration-dependent increases in the efflux rate coefficients of these tracers (maximum approximately 35%). These effects were abolished by endothelial cell removal. 3. Donor/acceptor experiments with rat aorta suggested that at least some of the efflux of 86Rb+ seen in the presence of acetylcholine was not derived from the endothelium, but came from the smooth muscle itself. 4. Acetylcholine (10 microM)-induced 86Rb+ efflux was reduced by tetraethylammonium (TEA, 10 mM) to 33% and ouabain (300 microM) to 54% of control. Preincubation with Ba2+ (100 microM) did not significantly inhibit acetylcholine-induced efflux. 5. Acetylcholine-induced 42K+/86Rb+ efflux was unaffected by preincubation with glibenclamide (10 microM). In contrast, the 42K+/86Rb+ efflux induced by cromakalim was inhibited by glibenclamide (50 nM) by 50%. 6. Acetylcholine (0.3-10 microM)-induced inhibition of phenylephrine (1 microM)-induced tone was abolished by endothelial cell removal but unaffected by glibenclamide. Cromakalim-induced relaxations were endothelium-independent and were inhibited by glibenclamide in a concentration-dependent manner. 7. LG-monomethyl L-arginine (L-NMMA, 250 microM) produced a significant (37 +/- 14%) inhibition of acetylcholine-induced 86Rb+ efflux whereas DG-monomethyl L-arginine was without effect. In the tissue bath L-NMMA inhibited relaxations produced by acetylcholine (0.3-10 microM), but was without effect on responses to cromakalim. 8. In the pig coronary artery, substance P induced an endothelium-dependent efflux of 86Rb+ and 42K+, which was unaffected by preincubation with glibenclamide (10 microM) or L-NMMA (250 microM). 9. The present study shows that acetylcholine and substance P each open K(+)-channels in arterial smooth muscle. However, the insensitivity of the stimulated 86Rb/42K+ efflux to inhibition by glibenclamide suggests that the K(+)-channel opened by these agents is different from the K(+)-channel opened by cromakalim. In addition, the inability of L-NMMA to inhibit fully the acetylcholine- and substance P-stimulated 86Rb+ efflux suggests that in rat aorta and pig coronary artery the endothelium-derived hyperpolarizing factor(s) (EDHF) is different from endothelium-derived relaxing factor (EDRF).

Acetylcholine↗
PubMed1991

The dose to lung in TBI.

Many physical problems are associated with TBI prior to BMT. Determination of the dose to lung, the organ at risk in TBI, is the most demanding task the DGMP working group on "Physical Aspects of TBI" has to solve. At an international workshop held at Essen in May 1990 the 50 participants discussed the problems and possibilities to measure, calculate, plan, modify, confirm, verify, and report the dose to lung. Some highlights are discussed here. The review lectures are summarized as abstracts in this issue. Details are published separately in the proceedings.

Algorithms↗
PubMed1990

Clinical results and the Essen concept of TBI.

Total body irradiation (TBI) prior to bone marrow transplantation (BMT) is applied for treatment of 230 patients in the period 1975-1988. The clinical results of 169 patients treated by four different TBI dosage and treatment techniques are analysed. The risk of leukemic relapse is low after fractionated TBI (9%) as well as after single dose TBI (14%). The lowest frequency of interstitial pneumonitis (21%) occurred when the patient translation technique was used for fractionated homogeneous pa/ap TBI with 10 Gy (8 Gy lung dose) in 4 fractions in 4 days. Prophylaxis of GVHD and the modus of protective environment were two other factors which influence the risk of IP.

Adult↗