Biomedical subjects

M Wehling

Publications and source records attributed to M Wehling.

At least 145 records · Page 8Linked to original sources

PubMed1990

Effects of aldosterone on intralymphocytic sodium and potassium in patients with essential hypertension.

In vitro binding of aldosterone to mineralocorticoid receptors on human mononuclear leukocytes (HML) and its effects on the intracellular sodium and potassium concentrations of HML have already been described. In the present paper this easily accessible human cell model was investigated in 13 patients with essential hypertension. In only four patients sodium in HML without incubation was elevated compared with the range for normal persons. A decrease of intracellular sodium or potassium occurred during incubation without aldosterone (P less than 0.02). The addition of 1.4 nM aldosterone did not prevent this loss of electrolytes as observed in normal persons. Plasma renin activity and aldosterone were not correlated with the electrolyte response and were within the normal limits. The number of mineralocorticoid receptors/cell were within or close to the normal range (n = 9). The independence of intracellular electrolytes from aldosterone despite a normal number of mineralocorticoid receptors may reflect an impairment of the mineralocorticoid effector mechanism in the HML of patients with essential hypertension.

Adolescent↗

PubMed1990

Aldosterone influences free intracellular calcium in human mononuclear leukocytes in vitro.

Mineralocorticoid receptors have been detected in human mononuclear leukocytes (HML) and a physiological effector mechanism was demonstrated subsequently by which aldosterone is able to prevent the loss of intracellular sodium, potassium and cell water during incubation in an aldosterone-free medium. In the present paper, free intracellular calcium, [Ca2+]i, was measured in HML from normal subjects by Quin-2 and Fura-2 fluorescence after incubation for 1 h at 37 degrees C in RPMI-1640 medium. In fresh HML, [Ca2+]i was 54 +/- 15 nM (Fura-2, mean +/- SD, n = 26). After incubation without aldosterone, [Ca2+]i in HML was 118 +/- 27 nM (Quin-2, n = 11) and 50 +/- 13 nM (Fura-2). After incubation with 1.4 (Fura-2) or 2.8 nM (Quin-2) aldosterone, [Ca2+]i was 139 +/- 38 nM (Quin-2, P less than 0.05 compared with value after incubation without aldosterone) and 57 +/- 11 nM (Fura-2, P less than 0.00001). The Kd-value for dose-response curve was 0.4 nM. The effect of aldosterone was antagonized by N-ethyl-isopropylamiloride, but not by canrenoate, canrenone, cycloheximide and actinomycin D. It was absent in a sodium-free buffer. Corticosterone and hydrocortisone were active as agonists. These results show that aldosterone exerts an effect on the [Ca2+]i in HML in vitro which could be involved in hemodynamic responses to mineralocorticoids if also present in cardiovascular tissues.

Adolescent↗

PubMed1990

Extracardial effects of oral ibopamine versus furosemide in patients with mild or moderate heart failure. A double-blind, randomized trial.

Ibopamine is a novel oral dopamine analogue with vasodilatory, positive inotropic and diuretic effects. In a double-blind, randomized study, the drug was investigated in 12 patients (mean age 49 +/- 10 years, 8 male, 4 female) with mild or moderate heart failure (NYHA classes II:8 patients, III:4 patients). Effects of single oral doses of 200 mg ibopamine, of 40 mg furosemide and of 200 mg ibopamine + 40 mg furosemide were compared in each patient at 3-day intervals. 1 h after administration, systolic and diastolic blood pressure increased from 120 +/- 11 to 124 +/- 9 and from 76 +/- 5 to 81 +/- 6 mm Hg in the ibopamine group. During 4 h after drug ingestion, urinary flow was significantly raised from 124 +/- 81 to 228 +/- 166 ml/2 h in the ibopamine group (p less than 0.05), while the administration of furosemide (with or without ibopamine) resulted in several folds increases of urinary flow. After ibopamine, the 2-h creatinine clearance rose from 123 +/- 73 to 131 +/- 85 ml/min (not significant). Sodium and potassium excretion remained essentially unchanged by ibopamine, while effects of furosemide were several folds of those of ibopamine. Plasma renin activity was lowered to 65% by ibopamine (p less than 0.01). No additive effects of ibopamine in the presence of furosemide were observed for all parameters tested. These results indicate that ibopamine has smaller renal effects than furosemide with regard to water diuresis and kaliuresis. These effects of ibopamine could reflect direct changes of renal function or secondary effects of neurohumoral origin. Ibopamine does not produce undesirable renal side effects, but affects the neurohumoral status favourably. This drug, thus, could be useful as an adjuvant therapy in mild heart failure.

Administration, Oral↗

PubMed1990

Extrarenal receptor-effector-mechanisms for aldosterone: the sequence of effects on the cellular electrolyte transport in human lymphocytes and their implications for disorders of the water and electrolyte balances.

High affinity aldosterone binding sites have not only been described in the classic target tissues such as the renal tubules, but also in non-classic target tissues such as the hippocampus, mammary gland, endothelial cells and, recently, human mononuclear leukocytes. An in vitro effect of aldosterone on intracellular sodium, potassium and calcium concentrations and cell volume was shown in human mononuclear leukocytes. In the absence of aldosterone, the intracellular Na+, K+ and Ca2+ concentrations and the cell volume decreased significantly, but remained constant when aldosterone (1.4 nmol/l) was added to the incubation medium. These effects of aldosterone were blocked by the aldosterone antagonist canrenone (140 nmol/l). The sodium/proton exchanger of the cell membrane could be identified as the primary target of the aldosterone action, possibly non-genomically mediated through membrane receptors. The clinical significance of this model was underlined by the demonstration of absent or a decreased number of mineralocorticoid receptors and the lack of electrolyte response to aldosterone in human mononuclear leukocytes of patients with pseudohypoaldosteronism and aldosteronism. Additionally, an abnormal effector mechanism could be demonstrated in human mononuclear leukocytes from essential hypertensives. These studies are the first to demonstrate the significance of extrarenal, nonepithelial mineralocorticoid receptors and the related effector mechanism in different disorders of the water and electrolyte balance in man.

Aldosterone↗

PubMed1990

[Renal effects of ibopamine in comparison with furosemide in patients with mild heart failure].

Ibopamine is a novel oral dopamine analogue with positive inotropy and diuretic effects. In a double-blind, randomized study, the drug was investigated in 10 patients (mean age 49 +/- 10 years, six male, four female) with mild heart failure (NYHA classes II: six patients, III: four patients). Effects of single oral doses of 200 mg ibopamine, of 40 mg furosemide, and of 200 mg ibopamine plus 40 mg furosemide were compared in each patient at 3-day-intervals. One h after application, systolic and diastolic blood pressure increased from 119 +/- 11 to 124 +/- 8, and from 75 +/- 4 to 80 +/- 6 mm Hg (p less than 0.01) in the ibopamine group, while changes in both other groups and changes of the heart rate were insignificant. During 2 h after drug ingestion urinary flow was raised from 124 +/- 81 to 227 +/- 166 ml/2 h in the ibopamine group (p less than 0.05), while the application of furosemide (with or without ibopamine) resulted in several fold increases of urinary flow. After ibopamine, the 2-h-creatinine-clearance rose from 123 +/- 73 to 130 +/- 85 ml/min (not significant). Sodium excretion remained unchanged by ibopamine, potassium excretion was increased from 2.9 +/- 1.7 to 4.0 +/- 3.3 mmol/h (p less than 0.05), while effects of furosemide were several fold of those of ibopamine. Atrial natriuretic factor concentrations in plasma increased significantly after ibopamine and after ibopamine plus furosemide (p less than 0.01), but remained constant after furosemide alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗

PubMed1989

Fast effects of aldosterone on electrolytes in human lymphocytes are mediated by the sodium-proton-exchanger of the cell membrane.

An in vitro effect of aldosterone on intracellular sodium, potassium and calcium concentrations and cell volume was shown in human mononuclear leukocytes (HML). In the present paper the effect of aldosterone on propionate-induced swelling of HML and, thereby, the Na+/H+-exchanger of the cell membrane was investigated. Aldosterone in physiological concentrations stimulated the cell swelling from 3 min on significantly. This effect had to be attributed to an increased activity of the Na+/H+-exchanger since amiloride blocked it almost completely. The inhibitor of protein synthesis actinomycin D prevented this action, cortisol had an intermediate effect. These data are the first to identify the Na+/H+-exchanger as a primary target of mineralocorticoid action in HML.

Aldosterone↗

PubMed1989

[Receptor-effector relations in the effect of adosterone on mononuclear leukocytes: validation and application to various water and electrolyte imbalances in humans].

Mineralocorticoid receptors were found in cells from extrarenal tissues such as spleen, hippocampus, smooth muscle, heart, hypophysis and mammary gland. Recently, mineralocorticoid receptors and effects of aldosterone on intracellular sodium and potassium have been described for human mononuclear leukocytes (HML). Both intracellular sodium and potassium concentrations decreased when HML from normal subjects were incubated for 1 h in a medium without aldosterone. In the presence of 1.4 nM aldosterone this loss of intracellular sodium and potassium from HML was absent, with values similar to those found in freshly prepared cells before incubation. The clinical significance of this model was underlined by the demonstration of absent or a decreased number of mineralocorticoid receptors and the lack of electrolyte response to aldosterone in HML of patients with pseudohypoaldosteronism. For patients with primary and secondary aldosteronism a reduced number of mineralocorticoid receptors has been shown on HML, thus indicating a "down-regulation" in response to chronically elevated serum levels of aldosterone. Additionally, an abnormal effector mechanism could be demonstrated in HML from these patients. These studies are the first to demonstrate the significance of extrarenal, nonepithelial mineralocorticoid receptors and the related effector mechanism for different disorders of the water- and electrolyte-balance in man.

Aldosterone↗

PubMed1989

Mineralocorticoid effector mechanism of liquorice derivatives in human mononuclear leukocytes.

The mineralocorticoid effector mechanism of glycyrrhetinic acid and of its ester derivative carbenoxolone was evaluated in human mononuclear leukocytes by radioreceptorassay and measurement of intracellular sodium and potassium after incubation of the cells with or without the drugs. The affinity of both compounds for mineralocorticoid receptors in this human model was also compared with that found in kidney cytosol from adrenalectomized rats. Glycyrrhetinic acid possesses a measurable affinity for mineralocorticoid receptors in mononuclear leukocytes, which is 1:3,000 that of aldosterone itself. Carbenoxolone does not bind to the receptors in mononuclear leukocytes, in contrast with kidney cytosol where the drugs show a parallel affinity. The mean intracellular content of sodium in mononuclear leukocytes from 7 volunteers was 35% higher (p less than 0.05) after incubation with 3 mumol glycyrrhetinic acid than after incubation with an equivalent amount of carbenoxolone, or in medium alone. The effect of glycyrrhetinic acid was completely reversed by addition of canrenone for the period of incubation. We conclude that the syndrome of pseudohyperaldosteronism from carbenoxolone is thus probably not related to a direct agonist effect of the drug at the level of mineralocorticoid receptors, but that any action must follow in vivo conversion into glycyrrhetinic acid by hydrolysis.

Adrenalectomy↗

PubMed1989

Correlations between ST-segment depressions in patients with arterial hypertension and changes in arterial blood pressure and the heart rate.

In 10 treated hypertensives without coronary heart disease we carried out 24-h monitoring of the ST-segment and blood pressure. Twenty-four periods with ST-segment depressions of greater than 0.1 mV were recorded in nine of 10 patients. In nine of 24 periods with ST-segment depressions blood pressure was elevated. The heart rate was increased in 20 of 24 ST-segment depressions. During nine periods with ST-segment depressions angina pectoris was reported, and 27 anginal attacks without ST-segment depressions were observed. These results indicate that only 38% of ST-segment depressions in hypertensive heart disease are paralleled by increases in blood pressure, but 83% are paralleled by increases in the heart rate (P less than 0.001), which shows a better correlation with ST-segment depressions than blood pressure.

Angina Pectoris↗

PubMed1989

Inheritance of mineralocorticoid effector abnormalities of human mononuclear leucocytes in families with pseudohypoaldosteronism.

In-vitro effects of aldosterone on intracellular sodium and potassium concentrations have been described for normal human mononuclear leucocytes (HML). After incubation for 1 h at 37 degrees C, intracellular sodium and potassium in HML are significantly higher in the presence of 1.4 nM aldosterone than after incubation without aldosterone. As published earlier, these effects were absent in patients with pseudohypoaldosteronism. In the present paper, the families of seven patients with pseudohypoaldosteronism (index cases) were studied. In the first family, two siblings were affected by the disease and had a reduced number of mineralocorticoid (MC) receptors on HML. Intracellular sodium and potassium in HML from these patients did not show a response to 1.4 nM aldosterone. The parents, who were first cousins, had no history of disease and normal receptor data, but in the mother, the response of HML electrolytes to aldosterone was abnormal. In the second family, the mother of a child with pseudohypoaldosteronism, the mother's sister, and her son, had low numbers of MC receptors. Only the aunt of the index case had an uncertain history of the disease. The MC effector mechanism was abnormal in both children and both mothers studied. In a third family, the effector defect was present only in HML of the father. In three further families the abnormality of the effector mechanism was detected in HML of the patient's mother. These data suggest an autosomal dominant inheritance of pseudohypoaldosteronism with variable expression of the gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1989

Volume regulation of human lymphocytes by aldosterone in isotonic media.

In vitro binding of aldosterone to mineralocorticoid receptors on human mononuclear leukocytes (HML) and its effects on the intracellular sodium and potassium concentrations of HML have already been described. In the present paper this easily accessible human cell model was investigated with regard to the regulation of the cell volume by aldosterone, since the concordant changes of sodium and potassium were expected to be accompanied by water and volume shifts. As determined by the measurement of cell diameter and the planimetric estimation of cell area in photographs, cell volume decreased by approximately 16% when cells were incubated in RPMI-1640 medium without aldosterone added for 1 h at 37 degrees C, a decrease not seen when 1.4 nM aldosterone was added to the incubation medium; the effect was half maximal at a concentration between 0.07 and 0.14 nM. One hundred forty nanomoles canrenone antagonized the action of aldosterone, but cortisol was ineffective. The results indicate concordant changes of intracellular sodium and potassium and cell volume, if studied under the same conditions. These data are the first to demonstrate that aldosterone is a major physiological determinant of lymphocyte volume in isotonic media.

Aldosterone↗

PubMed1989

Effects of clonidine and dihydralazine on atrial natriuretic factor and cGMP in humans.

The effects of a 1-wk treatment with clonidine (75 micrograms/day twice a day) and dihydralazine (25 mg/day twice a day) on base-line levels of plasma atrial natriuretic factor (ANF) and plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and their changes by acute saline infusion (2 liters) in eight normal subjects were evaluated. Basal ANF was decreased to 65% in the clonidine group compared with both the control and dihydralazine groups. Volume loading increased plasma ANF levels by 30-40% of base-line values in the control and the dihydralazine groups and by 15% in the clonidine group. Basal plasma and urinary cGMP levels were raised by 30 and 90% in the dihydralazine group compared with both other groups. Volume loading increased plasma cGMP levels by 40% in the control and clonidine-treated groups and by 25% in the dihydralazine-treated group. It is concluded that ANF may contribute to hemodynamic effects of clonidine but not to those of dihydralazine. Dihydralazine increases plasma and urinary cGMP, supposedly by direct activation of the soluble guanylate cyclase.

Adult↗

PubMed1988

Lack of effect of aldosterone on intracellular sodium and potassium in mononuclear leucocytes from patients with pseudohypoaldosteronism.

In three patients with pseudohypoaldosteronism the effects of aldosterone on intracellular sodium and potassium were studied and compared with normal controls in whom aldosterone prevents the loss of sodium and potassium in vitro. Mononuclear leukocytes were incubated with or without aldosterone (1.4 nM) in RPMI-1640 for 1 h at 37 degrees C. After two washes in isotonic MgCl2 the wet cell pellets were weighted and intracellular sodium and potassium determined by flame photometry, results are expressed as mmol/kg wet cells. In the patients intracellular sodium fell from 18, 23 and 29 mmol/kg to 14, 18 and 11 mmol/kg, respectively, in the absence of aldosterone. With aldosterone added to the incubation medium sodium was not different from values obtained without aldosterone (15, 20 and 13 mmol/kg). Corresponding values for potassium were 89, 48 and 75 mmol/kg before and 68, 32 and 51 mmol/kg after incubation without and 69, 36 and 54 mmol/kg after incubation with aldosterone. Thus, incubation with aldosterone did not show an effect on intracellular sodium and potassium as seen in normals. Baseline values of sodium and potassium before the incubation were within the normal range. From these results it is concluded that in patients with pseudohypoaldosteronism the absent or decreased number of mineralocorticoid receptors in mononuclear leucocytes are accompanied by a lack of response of intracellular sodium and potassium to aldosterone in vitro. However, normal baseline intracellular electrolyte concentrations in these patients may indicate that mineralocorticoids are not involved in the maintenance of normal levels of intracellular sodium and potassium.

Adult↗

PubMed1988

Magnesium release from red blood cells of hypertensive man by the ionophore A 23187.

Free intracellular magnesium in red blood cells (RBC) of 9 normotensives and 7 essential hypertensives was estimated from the amount of magnesium released by an incubation with the ionophore A 23187 (8 microM). In hypertensives, Mg released to the suspension medium was 0.42 +/- 0.10 mmol/l, thus being significantly lower than in normotensives (0.52 +/- 0.09 mmol/l; p less than 0.05). Total RBC Mg and serum Mg were not different in both groups. The chloride distribution ratio between the extracellular and intracellular concentrations was insignificantly increased in hypertensives, thus indicating a depressed intracellular chloride concentration as reported earlier. This ratio is essential for the calculation of the free intracellular Mg from equilibrated extracellular Mg. Taking the latter finding into account, no significant depression of free intracellular Mg can be detected in RBC of hypertensives in this study.

Calcimycin↗

PubMed1987

Altered calcium metabolism in red blood cells of hypertensives: persistent marker or sequel of essential hypertension?

The characteristics of the increased calcium (Ca) influx observed in metabolically depleted red blood cells (RBCs) of hypertensive patients were investigated. Twenty-four normotensives, 16 untreated essential hypertensives, and 10 essential hypertensives under sufficient blood pressure control by 50-100 mg/day atenolol were studied. Free intracellular concentrations of Ca, sodium (Na), and potassium (K) were assessed using ion-selective electrodes in freeze-thawed RBCs, which were metabolically depleted by 30 mM desoxy-glucose at 37 degrees C for 48 h. In the treated hypertensives values for Ca and K at 24 and 48 h were not different from values for the normotensives, whereas elevated Ca was found in RBCs of untreated hypertensives. Na in treated hypertensives was significantly increased at 0 and 48 h, thus, being similar to values for untreated hypertensives. Additionally, RBCs of six normals were stressed in a glass/teflon potter. Before metabolic depletion electrolytes were not affected by this procedure, while Ca at 24 and 48 h of metabolic depletion increased to significantly higher values for the hypertensive patients as compared to the controls. These results suggest that the altered Ca metabolism in the RBCs of hypertensives may reflect a secondary phenomenon due to the mechanical damage to RBCs by the elevated blood pressure.

Atenolol↗

PubMed1987

Mineralocorticoid effector mechanism in human mononuclear leukocytes.

Mineralocorticoid receptors and mineralocorticoid effector mechanism were determined in mononuclear leukocytes (MNL) from normal subjects. The hierarchy of affinities of competitors for the receptor was similar to that described in other non-classical target tissues for aldosterone. In spite of the relative high affinity of cortisol for the receptor, these binding sites are occupied in vivo by aldosterone and play a mineralocorticoid effect in terms of electrolyte content of the cells. The effect of aldosterone is to prevent the loss of electrolytes due to incubation in medium alone and this action is reversed by addition of actinomycin D. In addition, the incubation of the MNL with aldosterone plus human alpha ANP leads to complete block of the action of aldosterone alone. This effect is not mediated by binding of alpha ANP to mineralocorticoid receptors but is probably related to a some postereceptorial effect of aldosterone at the level of plasma membrane. We conclude that the model of MNL is a good tool for studying mineralocorticoid receptors regulation and consequent effector mechanism in humans.

Aldosterone↗

PubMed1987

Effect of aldosterone on sodium and potassium concentrations in human mononuclear leukocytes.

The in vitro effect of aldosterone on intracellular sodium and potassium concentration was investigated in human mononuclear leukocytes (HML). HML were separated from blood by a Percoll gradient and intracellular Na+ and K+ were determined before and after incubation for 1 h at 37 degrees C. The intracellular (ic) Na+ and K+ concentrations after separation of HML were 17 +/- 5 and 59 +/- 18 mmol/kg wet cells (mean +/- SD, n = 6), respectively. In the absence of aldosterone the ic Na+ concentration decreased to 12 +/- 4, whereas the ic Na+ concentration remained constant at 18 +/- 8 mmol/kg wet cells when aldosterone (1.4 nM) was added to the incubation medium. In parallel, the ic K+ concentration decreased without added aldosterone but remained constant with aldosterone. The effect of aldosterone on the ic Na+ and K+ concentrations of HML was blocked by the aldosterone antagonist canrenone (140 nM). Cortisol at a physiological concentration (40 nM) did not alter ic Na and K concentrations in these cells. The results suggest that aldosterone binding to specific receptors in human mononuclear leukocytes significantly contributes to the regulation of monovalent cation levels in these cells. Thus, this easily accessible model of HML allows study of the effects of mineralocorticoids in relation to their receptors in intact cells in normal and pathological states.

Aldosterone↗

PubMed1987

Aldosterone receptors in different types of primary hyperaldosteronism.

The number of mineralocorticoid-binding sites on mononuclear leukocytes and plasma aldosterone (aldo) concentrations were measured in patients with different types of primary hyperaldosteronism. Patients with unilateral adenoma and patients with bilateral adrenal hyperplasia had a significantly lower (P less than 0.001) mean number of binding sites for aldo [144 +/- 36 (+/- SD; n = 6) and 140 +/- 28 sites/cell (n = 4), respectively] compared with normal subjects (292 +/- 110 sites/cell; n = 25). In four patients with dexamethasone-suppressible hyperaldosteronism, mineralocorticoid-binding sites in mononuclear leukocytes were normal (291 +/- 108 sites/cell). In all patients undergoing surgery for unilateral adenoma, the receptors normalized 3 months after the operation. In two patients the reduction in receptors persisted for a short time after surgery even though the plasma aldo level had already normalized. We conclude that mineralocorticoid excess produces down-regulation of mineralocorticoid receptors, which, in turn, might contribute to the genesis of the aldo escape phenomenon.

Adult↗