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W Bartsch

Publications and source records attributed to W Bartsch.

At least 37 records · Page 2Linked to original sources
PubMed1987

Metabolism of androgens in human benign prostatic hyperplasia: aromatase and its inhibition.

As an extension of our studies on androgen metabolism in epithelium and stroma of human benign prostatic hyperplasia (BPH) tissue our attempts to demonstrate the presence of aromatase are described. Additionally, the question is raised whether the aromatase inhibitor 17 alpha-oxa-D-homoandrosta-1.4-diene-3.17-dione (testolactone) might also act by inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSDH). In vitro metabolism and inhibition were analyzed by TLC. The main results were: (1) Two aromatase assays (estrone formation and tritium release) were tested with placenta microsomes. Identical results were obtained (Km = 43 +/- 7 nmol/l n = 5; Vmax = 100 resulted in recovery of the aromatase activity added. (3) In BPH tissue alone, formation of estrone from androstenedione could not be detected (less than 7 x 10(-17) mol/min per mg protein, n = 8). (4) 4-Hydroxyandrostenedione inhibited placental aromatase (Ki = 37 nmol/l) distinctly better than 17 beta-HSDH from human BPH (Ki = 18 mumol/l), whereas the Ki values for testolactone (3.7 and 29 mumol/l, respectively) were more similar. It is concluded that aromatization of androgens is not an important pathway in BPH tissue. An alternative mode of action of testolactone by inhibition of 17 beta-HSDH is discussed.

17-Hydroxysteroid Dehydrogenases↗
PubMed1987

Pharmacological profile of carvedilol as a beta-blocking agent with vasodilating and hypotensive properties.

Carvedilol is a new beta-receptor blocking and vasodilating drug that is presently undergoing clinical trials in hypertension and coronary heart disease. In this article, the pharmacodynamic properties of carvedilol are compared with those of standard drugs. The beta-blocking activity was characterized in isolated organs and in conscious rats, rabbits, and dogs. For the beta 1-blockade in guinea pig atria, the pA10 values were 7.44 +/- 0.16 for carvedilol and 6.77 +/- 0.08 for propranolol. Carvedilol is a noncardioselective beta-blocker. The i.v. doses that inhibited the tachycardia by 50% induced by 1 microgram/kg isoprenaline were 62 micrograms/kg in dogs, 138 micrograms/kg in rabbits and 841 micrograms/kg in rats. In rabbits carvedilol was slightly more active and in rats less active than propranolol. In all models, carvedilol was much more active than labetalol or prizidilol. In contrast to propranolol, carvedilol relaxed rat aortic strips. A dose-dependent decrease in arterial blood pressure was seen in different in vivo models. The total peripheral and coronary resistance were decreased in conscious dogs. The doses required for both beta-blockade and decrease in blood pressure were in the same range. The drug was also active after oral administration. There is no hint for development of tolerance.

Adrenergic beta-Antagonists↗
PubMed1987

[The role of tissue steroids in benign hyperplasia and prostate cancer].

This paper presents a large body of data relating to benign prostatic hyperplasia, which have been derived from fundamental endocrinological research. For the urologist, the data open up interesting aspects of the pathomorphology of prostatic hyperplasia. The most interesting findings can be summed up as follows: 1. Testosterone is the circulating androgenic prohormone that mediates the intracellular message leading to androgen secretion, though by way of its metabolite dihydrotestosterone, which is really the active substance. 2. This metabolic conversion is catalyzed by 5 alpha-reductase, which is predominantly a stromal enzyme. 3. The estrogen metabolism in the stromal cells of the prostate may be associated with the abnormal growth of the prostate. 4. In the presence of benign prostatic hyperplasia dihydrotestosterone and 17 beta-estradiol accumulate in the nuclei of the stromal cells. 5. Adrenal androgens are also metabolized in the human prostate, yielding some substances with androgenic and some with estrogenic potency. 6. Changes in sex hormone binding globulins (SHBG) are found with age whether benign prostatic hyperplasia is present or not. It is therefore questionable whether it has any influence on the development of prostatic hyperplasia. 7. Although in some cases it is not yet possible to determine whether the findings presented in this paper have any causal significance, the data can be used as a rational basis for hormonal treatment of prostatic disease.

Adrenal Glands↗
PubMed1987

Pharmacological profile of carvedilol, a compound with beta-blocking and vasodilating properties.

We found compounds in the class of "phenoxyethylamines" that in addition to a beta-blocking activity also showed vasodilatation. Using screening investigations in rabbits, substances were sought that possess both properties in the same dose or concentration range. These conditions were fulfilled, for example, by carvedilol. In further, more detailed, pharmacological investigations it was found that the substances are also active after oral administration. The cause of the hypotensive action of carvedilol is a fall in total peripheral vascular resistance resulting from a direct vasodilating action. This direct vasodilating action is demonstrable in aortic strips independently of whether the preparation has been previously contracted with noradrenaline, potassium chloride, or a thromboxane agonist. Carvedilol behaves in this respect more like glyceryl trinitrate and less like the alpha 1-blocker prazosin. Because of the additional beta-blocking action, there is only a slight activation of reflex mechanisms even at clearly hypotensive doses in comparison with equipotent doses of other vasodilators (dihydralazine and nicardipine). With respect to its beta-blocking action, carvedilol is very similar to propranolol. It does not have any intrinsic sympathomimetic activity or any cardioselectivity, and its membrane-stabilizing property is approximately the same as that of propranolol. The balanced ratio of the vasodilatation and beta-blocking actions makes this substance an interesting choice for the treatment of various cardiovascular diseases.

Administration, Oral↗
PubMed1987

Studies on the mode of vasodilating action of carvedilol.

Investigations were performed on isolated rat aortic strips and in pithed rats in order to elucidate the mechanism of vasorelaxation or the acute blood pressure lowering effect induced by carvedilol. In particular, the possible role of the beta-receptor-stimulating activities or alpha-blocking properties has been investigated. beta 2-stimulation can be ruled out, since preincubation of isolated vessels with the beta 2-receptor blocker ICI 118.551 does not influence the vasorelaxing activity of carvedilol. Additionally, its optical enantiomers also induce the same vasorelaxing effect in vitro. In contrast to the standard alpha-blocking agents phentolamine or prazosin, carvedilol does not inhibit effects of alpha-receptor agonists at hypotensive doses, but inhibition of the effects of alpha-receptor agonists has been found in vitro and in vivo at high concentrations or doses and indicates a potential alpha-blocking activity of carvedilol. For example, the dose required for a specific inhibitory effect on norepinephrine responses observed in pithed rats is at least 20 times higher than that required for a decrease in blood pressure in spontaneously hypertensive rats. Furthermore, the alpha-blocking activity is at least 20 times lower than the beta-blocking activity, whereas hypotension and beta-blockade can be observed in intact animals after acute administration in the same dose range of carvedilol. It can therefore be assumed that the alpha-blocking activity does not contribute substantially to the decrease in blood pressure at doses normally used. It is suggested that a not yet defined postreceptor mechanism is involved in the vasorelaxing and acute blood pressure lowering activity of carvedilol.

Animals↗
PubMed1987

Evaluation of the risk for drug-induced postural hypotension in an experimental model: investigations with carvedilol, prazosin, labetalol, and guanethidine.

Postural hypotension is a common side effect observed in the treatment of hypertension with various drugs. Carvedilol, a vasodilating beta-blocker, was compared with prazosin, labetalol, and guanethidine for its ability to induce orthostatic hypotension. The comparison was carried out using doses of the drugs required to lower baroreceptor reflex hypertension in anesthetized rabbits by 30 mm Hg (ED -30 mm Hg). The following doses were found in independent investigations to be equipotent in this rabbit model: ED -30 mm Hg (mg/kg i.v.): prazosin = 0.03; labetalol = 1.8; guanethidine = 0.12; carvedilol = 0.12. These doses did not markedly inhibit the orthostatic reaction in rabbits after tilting stress, so 10-fold higher doses were used and clear discrimination between the drugs was found. The orthostatic index was reduced after prazosin and labetalol by about 24%, after guanethidine by about 30%, and after carvedilol by about 13%. The 50-fold dose of carvedilol (6 mg/kg i.v.) does not lead to any greater inhibition of the orthostatic index. From these results it is concluded that a relatively lower risk of postural hypotension is to be expected after carvedilol treatment than with the other drugs presented here. Furthermore, these results do not provide any indication that carvedilol exerts its vasodilator properties via alpha-blockade.

Animals↗
PubMed1986

Concentrations of 3 beta-hydroxy androgens in epithelium and stroma of benign hyperplastic and normal human prostate.

Androgen metabolites with 3 beta-hydroxy configuration--ie, dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one, DHEA), 5-androstene-3 beta-17 beta-diol (A-Diol), and 5 alpha-androstane-3 beta, 17 beta-diol (3 beta-Diol)--were measured by radioimmunoassay in the homogenate, in the mechanically separated epithelium and stroma, and in the nuclear fractions of epithelium and stroma of benign hyperplastic (BPH) and normal human prostatic tissue, in muscle homogenates and in plasma. The main results were: 1) Mean prostatic DHEA, A-Diol and 3 beta-Diol were 6-7 times as high as plasma values (1 g = 1 ml). Compared to muscle, prostatic values were more than tenfold higher. 2) The values in homogenates of BPH and normal prostate were not statistically different (pmol/mg DNA, mean +/- SEM, BPH: DHEA 46.8 +/- 7.2, n = 11; A-Diol 5.7 +/- 1.2, n = 12; 3 beta-Diol 3.7 +/- 0.6, n = 13; normal prostate: DHEA 56.0 +/- 5.5, n = 2; A-Diol 7.4 +/- 2.4, n = 5; 3 beta-Diol 5.8 +/- 1.7, n = 5). 3) In the nuclear fractions of epithelium and stroma the values were low compared to the homogenates and could not be discriminated from unspecific retention. Although we could not demonstrate either a specific retention of the 3 beta-hydroxysteroids in the nuclei or conclusive differences in steroid accumulation between epithelium and stroma of BPH and normal prostate, which could explain the development of the disease, the high levels in the tissue particularly of A-Diol would be compatible with estrogenic action at the prostate level.

Adult↗
PubMed1986

Intratissular androgens in benign prostatic hyperplasia and prostatic cancer.

The well-known hormone dependency of the normal human prostate and of BPH and prostatic carcinoma stimulated the study of cellular events which would possibly lead to specific steroid hormone patterns under the respective prevailing condition. In extending earlier observations on a significant DHT and E2 accumulation especially in stromal nuclei of BPH recent data on the uptake and metabolism of adrenal androgens clearly underline the important differential role of either stromal or epithelial cells. Epithelium and stroma of BPH contained a quantitatively different pattern of steroid metabolizing enzymes. This dualism of enzyme activity favours the conversion of testosterone to DHT in the stroma while androgens of adrenal origin are metabolized mainly in BPH epithelium. Further to quantitative data on the intracellular distribution of the three sex steroid classes (estrogens, androgens, adrenal androgens) and to Km and Vmax values of the respective steroid metabolizing enzymes in question (5 alpha-reductase, 3 alpha/beta-HSDH, 17 beta-HSDH, sulfatase, aromatase) the impact of antihormones (cyproterone acetate) on the intratissular distribution and on the in vivo cytosolic and nuclear binding of DHT as well as on its biological implications will be discussed. The data present a complicated picture, which points to special roles of epithelial and stromal cells and allow speculations on the relative importance of testicular and adrenal androgens and estrogens for the development and maintenance of both normal and diseased human prostates. Furthermore, the determination of intratissular steroid concentrations can be an important tool to understand and to ground a rational basis for a hormonal treatment of prostatic tumors.

Adrenal Glands↗
PubMed1985

Interactions of an anti-androgen (cyproterone acetate) with the androgen receptor system and its biological action in the rat ventral prostate.

Male Wistar rats were castrated and implantated with testosterone-filled silastic depots (in vitro release rate: 60 micrograms/24 h) prior to treatment with 10 mg cyproterone acetate (CyAc) on day 1, and 5 mg on days 4, 7, 10 and 13. Animals were sacrificed on day 14. Control animals were treated identically, with the exception of CyAc administration. Blood was collected and the ventral prostates of 6-8 animals were pooled, homogenized and processed into cytosol and purified nuclei. Steroid determinations (CyAc, testosterone, 5 alpha-dihydrotestosterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol)) were performed by RIA. Specifically bound DHT (charcoal resistant DHT = CR-DHT) represents DHT values (RIA) following treatment of cytosol or nuclear extract with dextran coated charcoal. The androgen receptor was determined in cytosol and nuclear extract by 'exchange assay' using [3H]methyltrienolone (MT) (18 h, 15 degrees C). The main results were: 1) The steroid levels in plasma (testosterone, DHT, 3 alpha-diol) were in the range of untreated adult animals and not significantly influenced by the CyAc treatment. Final CyAc levels were 305 +/- 58 nmol/l (mean +/- SD, n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen Antagonists↗
PubMed1985

Comparison of the haemodynamic profiles of the hypotensive action of verapamil and carvedilol.

Comparative haemodynamic investigations with carvedilol and verapamil were carried out on conscious, instrumented dogs. Arterial blood pressure, right atrial pressure (RAP), cardiac output (CO), heart rate, stroke volume and total peripheral resistance (TPR) were determined after intravenous (i.v.) injection of incremental doses (0.01-3 mg/kg) of the drugs. Carvedilol reduced the blood pressure in a dose-dependent manner, concomitant with a reduction in TPR. The RAP and the CO were not affected, indicating that arterial vasodilatation was induced by carvedilol. Verapamil showed a decrease in the blood pressure with a reduction of CO and SV. Moreover, at high doses the RAP was increased, indicating a reduction of the cardiac performance. Thus, in our experimental model remarkable differences between the haemodynamic effects of i.v. injections of carvedilol and verapamil have been observed, whereas after oral administration blood pressure also decreases after verapamil due to a reduction of TPR.

Animals↗
PubMed1984

Differences in the nitrite ion formation and the toxicological findings between isosorbide dinitrate and isosorbide-5-mononitrate.

In the metabolism of isosorbide dinitrate (ISDN), fast denitration with the formation of nitrite ions and a mononitrate plays an important role. In contrast, the denitration of isosorbide-5-mononitrate (IS-5-MN) to isosorbide is very slow. Accordingly po administration of high doses of ISDN (92.5 and 236 mg/kg) in conscious dogs led to maximum nitrite concentrations in the blood of 0.9 and 3.3 mg/liter, respectively. In contrast, with equimolar doses of IS-5-MN (75 and 191 mg/kg) we were able to detect nitrite ions reliably only at the higher dose and this gave a maximum blood concentration of 0.4 mg/liter. The rise in nitrite ion concentration is followed by the formation of methemoglobin. As is known from the literature, there is a rise in the activity of alkaline phosphatase in the serum of rabbits in addition to methemoglobin formation following repeated administration of sodium nitrite. So we have specifically investigated whether this is also the case following ISDN and IS-5-MN administration. On po administration of 236 mg/kg ISDN/day to dogs, there was a continuous rise in alkaline phosphatase from about the 20th day onward which we did not observe after the equimolar dose of IS-5-MN (191 mg/kg). NaNO2, 35 mg/kg po, led to a comparable maximal rise in methemoglobin to that obtained with 236 mg/kg ISDN. Repeated po administration of 35 mg/kg NaNO2/day also caused a rise in alkaline phosphatase. It is concluded that the formation of nitrite ions from ISDN is the reason for the rise in methemoglobin and alkaline phosphatase. The lower formation of nitrite ions from IS-5-MN can also be of clinical importance, at least in certain cases.

Alkaline Phosphatase↗
PubMed1984

Pharmacokinetic aspects of isosorbide-5-mononitrate in dogs.

The aim of this study was to determine pharmacokinetic data of isosorbide-5-mononitrate (IS-5-MN) in dogs and to correlate them with the hemodynamic effects of this drug. Beagle dogs (n = 7) were given 3 mg/kg of IS-5-MN, the main metabolite of isosorbide-dinitrate, by i.v. injection and oral administration. At defined times blood samples were withdrawn from the vena cava caudalis for assaying IS-5-MN. In the experiments with oral administration the decrease in systolic blood pressure was monitored as a measure of hemodynamic response. The pharmacokinetic parameters were calculated from the plasma concentrations on the basis of an open two-compartment model. The half-life for the distribution phase was about 6 min, for the elimination phase about 1.5 hr. The latter is about one-third of that obtained in man. From the comparison of the areas under the curve, a bioavailability of 71.5% was estimated. In a second series of investigation dogs were given five different doses of IS-5-MN orally (3.125-50 mg/dog). These experiments showed a rise in the peak plasma concentration and the area under the curve proportional to the dose, whereas the terminal half-life did not differ markedly. A close correlation has been found in both series of investigations between the log concentration and the decrease in blood pressure. The minimum plasma concentration for a hemodynamic effect was estimated to be 100 ng/ml.

Administration, Oral↗
PubMed1984

Electrocardiographic analysis of the effects of isosorbide-5-mononitrate on regional myocardial ischemia in conscious dogs.

Whereas the clinical efficacy of isosorbide-5-mononitrate (IS-5-MN) in angina pectoris has been demonstrated unequivocally, the action of the substance on acute myocardial ischemia in animal models has not been investigated yet. Therefore, IS-5-MN and, for comparison in some experiments, isosorbide dinitrate and isosorbide-2-mononitrate were studied on a model of a brief intermittent myocardial ischemia in dogs. Ischemia was produced by occlusion of a coronary artery. Simultaneously, the dogs were loaded by treadmill exercise (model I) or injection of isoprenaline (model II). Local S-T segment changes were derived with epicardial electrodes. The action of orally administered IS-5-MN, isosorbide-2-mononitrate and isosorbide dinitrate of S-T segment elevations was studied with model I. A dose of 20 mg/dog produced a significant lowering of the S-T elevations (17, 13 and 15%). With 40 mg of IS-5-MN and isosorbide dinitrate per dog, similar effects were obtained (18 and 21%, with no statistical significant differences in comparison with 20 mg/dog). The time course of the action of IS-5-MN and the dose-response curve after i.v. injection were evaluated with model II. Even 5 hr after 20 mg of IS-5-MN per dog, a significant reduction of S-T elevations could be demonstrated. Significant effects on the epicardially derived S-T elevations have already been observed at doses of IS-5-MN that do not yet lead to a lowering of the systolic blood pressure in conscious dogs. Higher doses that lower the systolic blood pressure do not lead to any further lowering of the observed S-T elevations.

Administration, Oral↗
PubMed1983

Regulation and compartmentalization of androgens in rat prostate and muscle.

Male rats were castrated and treated with various doses of testosterone (T) or 5 alpha-dihydrotestosterone (DHT) by implantation of steroid releasing polydimethylsiloxane depots. After 14 days, the animals were killed and the concentration of T, DHT and 5 alpha-androstane-3 alpha,17 beta-diol (Diol) was measured by radioimmunoassay in plasma, in the homogenates of the prostate (PR), the bulbocavernosus/levator ani muscle (BCLA), skeletal muscle (SM) and heart muscle (HM), as well as in the cytosol and the nuclear fraction of these tissues. Additionally, the weight and DNA content of PR and the levator ani muscle were measured. The main results were: After T or DHT administration the main androgens in plasma were T or Diol, respectively, the concentration of each being linearly dependent from the administered steroid dose (T after T-: r = 0.97, P less than 0.001. Diol after DHT administration: r = 0.97, P less than 0.001). T in a dose of 60 micrograms/24 h maintained the concentrations of T, DHT and Diol in plasma in the range of untreated controls. Irrespective of the T doses administered, its concentration in PR tissue was comparatively low. T administration resulted in a significant accumulation of DHT in PR, when compared to plasma T. The steepest increase of DHT in PR was found with low doses of T administered (0.6-12 micrograms/24 h). At higher doses (12-600 micrograms/24 h) the further increase in the tissue was rather parallel to that of plasma T. A comparable picture was found for the DHT concentration in cytosol and in nuclei. The Diol concentration in the cytosol was linearly related to the administered T dose (r = 0.80, P less than 0.001). This steroid could not be detected in nuclei (less than 0.5 pmol/mg DNA). Administration of DHT in principle mimicked the DHT data observed after T treatment. In muscle homogenates no accumulation of neither T, DHT nor Diol was observed. In the nuclear fractions only after the highest doses of T measurable amounts of T and DHT were found. Whereas a positive correlation between DHT values in nuclei and weight increases in prostate was present, no such parallelism could be demonstrated in muscular tissue. The data are discussed with respect to the present knowledge of androgen binding and metabolism in different organs and to a possible specific role of nuclear DHT accumulation in mediating androgen dependent processes.

Androgens↗
PubMed1983

Androgens and estrogens: their interaction with stroma and epithelium of human benign prostatic hyperplasia and normal prostate.

Growth and integrity of human prostatic epithelium is strongly dependent upon the adjacent stroma. Furthermore, the human prostate is under the control of sex hormones. Both facts prompted us to compare epithelium with stroma of human benign prostatic hyperplasia (BPH) and normal prostate (NPR) concerning their metabolism, binding and tissue concentrations of androgens and estrogens. In vitro metabolism was analyzed by t.l.c., androgen and estrogen binding sites were determined by a charcoal adsorption technique, androgen and estrogen tissue concentrations were measured by RIA. The main results are--(1) Metabolism: BPH stroma shows 2-3 times higher 5 alpha-reductase activity than epithelium. This high 5 alpha-reductase activity in BPH stroma dictates the differences between unseparated BPH and NPR, in the former the 5 alpha-reductase activity being 2 times higher. The 3 alpha(beta)-hydroxysteroid dehydrogenase (HSDH) activity is more evenly distributed between stroma and epithelium of BPH and NPR. The ratios of 5 alpha-reductase to HSDH activity in the various tissue fractions indicate that the highest enzymatically regulated 5 alpha-dihydrotestosterone (DHT) enrichment must occur in BPH stroma. (2) Tissue concentrations: unseparated BPH contains 2.2 times more DHT than NPR. About 70% of the total DHT content is found in nuclear fractions, whereby the nuclear DHT content of BPH stroma is significantly higher than that of BPH epithelium. In addition, nuclei of BPH stroma contain significantly more estradiol than epithelial nuclei. (3) Binding: the androgen receptor is evenly distributed between epithelium and stroma of BPH, while the estrogen receptor is preferably assayed in BPH stroma. These studies indicate that the BPH stroma is not only a preferential tissue for 5 alpha-reductase activity and DHT enrichment but also for nuclear estradiol accumulation.

3-Hydroxysteroid Dehydrogenases↗
PubMed1982

Nuclei of stroma: site of highest estrogen concentration in human benign prostatic hyperplasia.

In an earlier publication we found significantly more estrogen receptor-positive cases in the stroma if compared with the epithelium of human benign prostatic hyperplasia (BPH). We were therefore interested to find out whether this preferential assay of estrogen receptor in stroma is reflected by a higher estrogen content in this tissue fraction. Estradiol (E2) and estrone (E1) were measured by RIA in whole BPH tissue, stroma, and epithelium as well as in the nuclear fraction of stroma and epithelium. For comparison, E2 and E1 were measured in blood also. The main results are as follows: 1) In all BPH samples the E2 (26.0 +/- 3.5 (SEM) pg/g (n = 20)) and E1 (53.5 +/- 7.4 (14)) content was significantly higher than in the corresponding plasma (E2: 17.5 +/- 2.3 pg/ml (11); E1: 26.5 +/- 4.4(7)), the mean ratio of E2/E1 was 0.52 and 0.69 for BPH and plasma, respectively; 2) in stroma significantly more E2 (53.6 +/- 7.8 fmol/mg DNA (18)) and E1 (55.9 +/- 8.4 (12)) were measured than in epithelium (E2: 15.7 +/- 1.9 (16); E1: 20.7 +/- 3.2 (13)); 3) in nuclei of stroma significantly higher E2 (38.0 +/- 5.3 fmol/mg DNA (20)) and E1 (19.2 +/- 4.8 (14)) concentrations were present than in epithelium (E2: 6.8 +/- 3.1 (19); E1: 2.5 +/- 0.5 (13)), the mean ratio of E2/E1 for the nuclear fractions of stroma (2.3) and epithelium (2.7) increased dramatically if compared with the respective ratio in whole BPH tissue. In conclusion, there is a distinct accumulation of estrogens in the nuclei of stroma, E2 concentration being significantly higher than E1. These data support the hypothesis that E2 could play a preferential role in stimulating the growth of the BPH stroma.

Aged↗