Biomedical subjects
M Stimpel
Publications and source records attributed to M Stimpel.
[Mechanism of action of calcium antagonists].
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[Nitrendipine, a new calcium antagonist, as basis therapy in essential hypertension].
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[The hypertensive emergency and severe hypertension: experiences with nifedipine].
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Captopril before and after spironolactone therapy in primary aldosteronism. Pathogenetic and therapeutical aspects.
In three patients with primary aldosteronism, the acute effect of a single dose of captopril on the elevated mean arterial blood pressure (MAP) was studied before and after 4 weeks of treatment with spironolactone. Before spironolactone therapy, captopril did not cause any drop in MAP. Four weeks later, after an oral daily dose of 400 mg spironolactone, MAP was still elevated in all three patients, though electrolyte abnormalities were fully corrected. Since plasma renin activity (PRA) was increased to values above the normal range, the acute effect of captopril on MAP was tested again. A single dose of 25 mg captopril then caused a fall in MAP to normal. These data reveal the conversion from a renin-independent to a renin-dependent kind of hypertension after spironolactone therapy in three patients with primary aldosteronism syndrome. This might be of pathogenetic and therapeutic interest.
[Fatigue, muscle weakness].
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Stereospecific modulation of the calcium channel in human erythrocytes by cholesterol and its oxidized derivatives.
To study the effect of cholesterol and its pathophysiologically important oxidized derivatives (OSC) on the calcium entry channel, the human red blood cell was used as a model system. The calcium ejecting adenosinetriphosphatase (ATPase) was inhibited by vanadate. The cells were loaded with OSC at concentrations between 1.25 X 10(-5) and 25 X 10(-5) mol/l. 22-Hydroxycholesterol, cholestan-3 beta,5 alpha,6 beta-triol, 5 alpha-cholestan-3 beta-ol,3 beta,5 alpha-dihydroxycholestan-6-one and 3 beta-hydroxy-5 alpha-cholestan-7-one stimulated 45Ca2+ influx by up to almost 90%, whereas 25-hydroxycholesterol, 7 beta-hydroxycholesterol, 20 alpha-hydroxycholesterol and 7-oxocholesterol inhibited influx by up to 75%. Both stimulation and inhibition were dependent on the amount of OSC incorporated into the membrane. More than 90% of the total modification of calcium influx by OSC was accounted for by an influence on the nitrendipine-inhibitable part of influx. Enrichment of cholesterol in the membrane greatly stimulated, and cholesterol depletion inhibited, Ca2+ influx. These results demonstrate that cholesterol and its oxidized derivatives are able to modulate the calcium channel in human red blood cells in a highly stereospecific manner.
[Divisible tablets--source of error in therapeutic drug dosages].
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Adrenalectomy in primary aldosteronism: a long-term follow-up study.
The effect of unilateral adrenalectomy in primary aldosteronism was analyzed in 38 patients with unilateral adenoma, 12 cases with idiopathic bilateral hyperplasia and 1 patient suffering from an aldosterone-producing carcinoma. Responses to surgery differed markedly. In all 38 adenoma cases plasma aldosterone dropped to normal levels and remained within normal range during a mean follow-up period of 75 +/- 12 months. 23 (61%) of these patients became normotensive without medication and thus could be classified as definitely cured. 34% (13 patients) improved (normotensive under medical treatment) and only 2 cases (5%) remained hypertensive despite sufficient medical treatment. In the hyperplasia group, however, the effect of adrenalectomy was disappointing. None of these subjects showed a long-lasting normalization of aldosterone secretion. A temporary remission for no more than 3-4 months was achieved in only 3 patients. In a fourth case with macronodular hyperplasia, primary aldosteronism relapsed after a 6-year period of normal blood pressure and aldosterone values. Therefore, 6 years after adrenalectomy no hyperplasia patient was definitely cured in contrast to 61% of the adenoma cases. The problems in the management of hypertension in adrenal hyperplasia are furthermore documented by a poorer blood pressure control despite antihypertensive medication and a high rate of vascular complications. During the follow-up, 3 of 12 hyperplasia patients experienced a cerebrovascular event and 1 a myocardial infarction.
High density lipoproteins--modulators of the calcium channel?
It has recently been shown that human red blood cells possess a voltage-independent calcium channel which can be influenced by in vitro modification of the membraneous cholesterol content. To determine whether there is also a link between plasma lipids and the calcium influx through this channel under in vivo conditions, the calcium influx was measured in red blood cells from 51 male donors (aged 41 +/- 5 years). The influx through the channel was defined as the nitrendipine (15 mumol/l)-inhibitable part of 45Ca2+ influx. The Ca(2+)-ejecting ATPase was inhibited by vanadate. The results demonstrate a strong inverse relationship (r = -0.81; P < 0.001) between the plasma concentration of high density lipoproteins (HDL) and 45Ca2+ influx. No significant correlation was found between 45Ca2+ influx and triglycerides, low density lipoproteins (LDL), very low density lipoproteins (VLDL), total plasma cholesterol or extracellular electrolytes (K+, Na+, Ca2+, Mg2+). The results indicate that HDL are involved in the modulation of the calcium channel and provide a link between the cellular cholesterol turnover and the calcium influx in the pathogenesis of atherosclerosis and hypertension.
The scored tablet--a source of error in drug dosing?
To determine the weight deviation of scored tablets after breaking we took 100 tablets of each of 34 brands of commercially available antihypertensive drugs and broke them into two, using the scored line. We graded the weights of the tablet halves according to their deviation from the expected weight (1 = less than or equal to +/- 5%, 11 = +/- 6-10%, 111 = greater than or equal to +/- 10%). The brands were ranked by the proportion of tablet halves (n = 200) in each category. Only seven brands divided very accurately and 11 brands divided reasonably accurately. Despite the scored line the remainder were either moderately (n = 10) or absolutely (n = 6) unsuitable for breaking, by hand or otherwise. A high proportion of these tablet halves showed weight deviations of 6-10% or more than 10% when compared to the expected weight. These findings show that a great number of antihypertensive drugs do not break evenly despite a scored line. This leads to inaccuracy of dosage.
The spectrum of renovascular hypertension.
This review briefly summarizes pathological findings that may cause renovascular hypertension. Though atherosclerosis is the most common cause of renovascular hypertension, one third of all renovascular disorders has to be contributed to one of the arterial dysplasias. In contrast to atherosclerotic lesions which occur predominantly in older, male patients, fibrodysplastic alterations occur rather in younger, female patients. In very few cases malformations of the renal arteries or generalized diseases may cause renovascular hypertension.
The cholesterol content of the human erythrocyte influences calcium influx through the channel.
In order to study the influence of the cholesterol content on the calcium entry channel, the human red blood cell was used as a model system. The cholesterol to lecithin ratio (C/L ratio) of the membrane was modified experimentally by incubating the cells (15h, 25 degrees) with liposomes of defined C/L ratios. Subsequently, net 45Calcium-influx into the cell was measured by inhibiting the Ca-ejecting ATPase with vanadate. Additionally, the use of nitrendipine, a potent calcium channel inhibitor, during incubation allowed the determination of Ca-influx through the calcium channel. A positive correlation between the 45Ca++-influx and the molar C/L ratio of the membrane was found over a wide C/L range. A molar C/L ratio of 1.4 in the membrane increased calcium influx by 150 % compared to controls (molar C/L ratio = 0.8, calcium influx rate = 100 %), while a molar C/L ratio at less than 0.75 decreased calcium influx by 50 %. We conclude, that the cholesterol content of the membrane greatly influences the calcium channel and thus plays a pivotal role for the availability of calcium as a second messenger. These findings may provide a link between high plasma cholesterol and the development of atherosclerosis as well as enhanced platelet aggregability.
Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant Echinacea purpurea.
Purified polysaccharides (EPS) prepared from the plant Echinacea purpurea are shown to strongly activate macrophages. Macrophages activated with these substances develop pronounced extracellular cytotoxicity against tumor targets. The activation is brought about by EPS alone and is independent of any cooperative effect with lymphocytes. Also the production and secretion of oxygen radicals and interleukin 1 by macrophages is increased after activation with EPS. Cells of the macrophages lineage seem to be the main target for the action of these polysaccharides. EPS has no effect on T lymphocytes. B lymphocytes show a comparatively modest proliferation after incubation with E. purpurea EPS. Thus, these compounds, which are at least in tissue culture completely nontoxic, may be suited to activate in vivo cells of the macrophage system to cytotoxicity. They may therefore be of relevance in tumor and infectious systems.
Human red blood cells--an ideal model system for the action of calcium agonists and antagonists.
To characterize the pharmacological properties of the slow calcium channel of human red blood cells, we studied the action of various calcium antagonists and two agonists on the 45Ca2+-influx. The Ca2+-ejecting ATPase was inhibited by vanadate. All dihydropyridine derivatives tested showed their inhibiting or stimulating effect on the channel at concentrations attainable in vivo (nitrendipine:Ki = 2.5; Bayer K 6244:Ki 5 microM; nicardipine:Ki = 15 microM, Ks = 0.5 microM; Ciba 28 392:Ki = 20, Ks = 0.3 microM; Ki = inhibition constant, Ks = stimulation constant). Of special interest was the biphasic behaviour (stimulation and inhibition) of the calcium antagonist nicardipine and the agonist Ciba 28 392. The maximum inhibition by the phenylalkylamine derivative verapamil was obtained at much higher concentrations (250 microM; Ki = 100). These data suggest that the calcium channel of human red blood cells has pharmacological properties very similar to the channel in heart and smooth muscle cells with respect to dihydropyridine action. Therefore, human red blood cells are an ideal model to study the action of calcium agonists and antagonists.
Cholesterol and its oxidized derivatives modulate the calcium channel in human red blood cells.
The human red blood cell was used as a model system in order to study the effect of cholesterol and its medically important oxidized derivatives (OSC = oxidized sterol compounds) on the calcium entry channel. The calcium-ejecting adenosine triphosphatase (ATPase) was inhibited by vanadate and the influx of 45Ca2-into the cells measured. The cells were loaded with OSC at concentrations between 0.075 and 1.5 micrograms OSC/10(7) cells. Two classes of OSC could be distinguished: one stimulating Ca2+ influx dose-dependently by almost 100% at maximum concentrations, the other inhibiting it dose-dependently by up to 80%. The calcium channel blocker nitrendipine inhibited influx by 70% at 15 microM. More than 90% of the total stimulation or inhibition was accounted for by an influence on the nitrendipine-inhibitable part of influx, i.e. the calcium channel. Cholesterol (incorporated using liposomes) had a stimulatory (+288%), cholesterol depletion an inhibitory effect on calcium influx (-18%). These results demonstrate that cholesterol and its oxidized derivatives modulate the calcium channel in a highly stereospecific manner and provide new insights into the mechanism of action and the atherogenic effect of these compounds.
Moexipril as add-on therapy to hydrochlorothiazide in moderate to severe hypertension.
This double-blind study was conducted to investigate the efficacy, safety and tolerability of three dose levels of moexipril in comparison to placebo as add-on therapy to hydrochlorothiazide (HCTZ) in patients with moderate to severe hypertension. Two hundred patients who did not respond adequately to a 4-week monotherapy with HCTZ-sitting diastolic blood pressure between 95 and 114 mm Hg- entered the 8-week double-blind period. Patients were randomized to once daily placebo or moexipril 3.75, 7.5 or 15 mg as add-on therapy to open-label HCTZ 25 mg. At biweekly visits, blood pressure and heart rate measurements were obtained and the occurrence of adverse experiences was documented. At the 8-week endpoint, adjusted mean reductions from baseline were significantly (p = 0.003) greater in patients receiving moexipril 3.75, 7.5 and 15 mg compared to placebo (-8.4, -8.8 and -8.9 vs. -4.6 mm Hg). No significant differences between the three dose levels of moexipril could be observed. Moexipril was generally well tolerated. The most frequently reported adverse events for moexipril and placebo were headache, flu syndrome and dizziness (6, 7, 5 vs. 4, 0, 4%). The results indicate that the combination of moexipril and HCTZ is a clinically valuable combination in the treatment of patients with moderate to severe hypertension.