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Biomedical subjects

M Wehling

Publications and source records attributed to M Wehling.

At least 127 records · Page 7Linked to original sources
PubMed1994

Novel aldosterone receptors: specificity-conferring mechanism at the level of the cell membrane.

Functional studies in extra-renal, nonepithelial cells such as smooth muscle cells and more recently circulating human lymphocytes have provided increasing evidence that aldosterone produces not only classical genomic effects, but also rapid non-genomic effects on transmembrane electrolyte movements. These involve activation of the sodium/proton-exchanger of the cell membrane at very low, physiological concentrations of aldosterone with an acute onset within 1-2 minutes. A second messenger cascade involved is the inositol-1,4,5-trisphosphate/calcium pathway which responds over the same rapid time course. Such changes clearly cannot be explained by genomic mechanisms, which are responsible for later effects than the membrane-related rapid responses. In addition to its rapid time course the unique characteristics of this new pathway for steroid action include a 10000-fold selectivity for aldosterone over cortisol and the ineffectiveness of spironolactones, classical mineralocorticoid antagonists, as antagonists of the response. Subsequently binding sites have been demonstrated in the plasma membrane of human lymphocytes which show pharmacological (aldosterone specificity) and kinetic (high turnover) properties identical with those of the rapid aldosterone effects in the same cells. SDS-PAGE analysis of the receptor protein has shown a molecular weight of approximately 50 kD. The present paper reviews the data supporting a new, two-step model for non-genomic and genomic aldosterone effects. It also suggests a novel specificity-conferring mechanism for mineralocorticoid action at the membrane level.

Animals↗
PubMed1994

Non-classical receptors for aldosterone in plasma membranes from pig kidneys.

Rapid, nongenomic in vitro effects of aldosterone on intracellular electrolytes, cell volume and the sodium-proton antiporter have been found in human mononuclear leukocytes (HML), as have related membrane receptors. In the present study, binding of 125I-labeled aldosterone to plasma membrane preparations from pig kidneys was studied, since nongenomic in vitro effects of aldosterone have also been described in cultured kidney cells. In this preparation, binding of aldosterone shares important features with both functional and binding data in HML. These include a very low apparent Ki of approximately 0.1 nM for aldosterone, a high turnover rate and binding selectivity for aldosterone and fludrocortisone. Desoxycorticosterone acetate and corticosterone show intermediate affinity, with apparent Ki values of approximately 1 and 100 nM, with hydrocortisone even less active. Thus binding of aldosterone to kidney plasma membranes is compatible with the major features of its nongenomic renal effects.

Aldosterone↗
PubMed1994

Novel membrane receptors for aldosterone in human lymphocytes: a 50 kDa protein on SDS-PAGE.

Fast in vitro effects of aldosterone on the Na+/H(+)-exchanger, inositoltrisphosphate generation and corresponding specific binding to plasma membranes at Kd-values of approximately 0.1 nM have been found in human mononuclear leukocytes and vascular smooth muscle cells. The novel aldosterone membrane receptor was analyzed on SDS-PAGE after labeling of microsomal membranes from human mononuclear leukocytes with a [125I]-aldosterone-derivative by use of BASED as a photoactivatable crosslinker. Binding of 1 nM [125I]-aldosterone was found at a molecular weight of approximately 50 kDa which was absent with 1 microM cold aldosterone, but not cortisol in the binding media. This aldosterone-selectivity is typical and discriminatory for the new aldosterone membrane receptor. Solubilization of the receptor protein from membranes by high salt concentrations (1 M NaCl, 1 mM EDTA) was not achieved. It, thus, appears as an integral membrane protein. Dithiothreitol, a sulfhydryl agent, does not reduce specific aldosterone binding indicating the absence of SH-groups in the binding domain or sensitive structures of the receptors. The results are the first to characterize the novel membrane receptor for aldosterone with regard to molecular weight and basic properties. These findings and other related results are reviewed here.

Aldosterone↗
PubMed1993

Aneurysms of coronary arteries in a patient with adult polycystic kidney disease: arteriosclerosis or involvement by the primary disease?

Adult polycystic kidney disease is frequently associated with gastrointestinal and cardiovascular abnormalities. These include hypertension, mitral valve prolapse, mild dilation of the aortic root, abdominal aneurysms, and predisposition to aortic, mitral, and tricuspidal valve regurgitation reminiscent of Marfan's syndrome. Although the exact molecular mechanisms of adult polycystic kidney disease are not well established, a generalized defect of collagen structure is hypothesized. The most severe vascular problems, however, are typical intracranial aneurysms with a high incidence of subarachnoid hemorrhage and a high mortality rate. We report a case of dilated coronary arteries found incidentally in a patient with adult polycystic kidney disease and stress-induced angina pectoris. The typical angina pectoris of the patient is explained by left ventricular hypertrophy and coronary heart disease. Multiple liver cysts, mitral valve prolapse, and the coronary aneurysms in this patient with adult polycystic kidney disease appear to reflect the manifestation of a generalized connective tissue disorder in this syndrome.

Adult↗
PubMed1993

The inositol-1,4,5-trisphosphate system is involved in rapid effects of aldosterone in human mononuclear leukocytes.

There is increasing evidence for rapid steroid action on electrolyte transport in human mononuclear leukocytes (HML). In HML, aldosterone stimulates the Na+/H+ antiporter within a few minutes. Because a variety of hormones and growth factors activate the Na+/H+ antiporter via protein kinase C and inositol phospholipids, a possible involvement of inositol-1,4,5-trisphosphate (IP3) in the rapid effects of aldosterone in HML was investigated. The stimulation of IP3 generation was started by the addition of aldosterone, concanavalin A, or other steroids. A significant increase in IP3 levels by aldosterone (1 nmol/L, P < 0.05) was found after 1 min, similar to that found after concanavalin A (25 micrograms/mL). Aldosterone caused a concentration-dependent elevation of IP3 levels, with an apparent EC50 of approximately 0.1 nmol/L. Fludrocortisone stimulated IP3 generation at similar concentrations, whereas a weaker IP3 stimulation by glucocorticoids (hydrocortisone, dexamethasone) occurred at micromolar concentrations only. Canrenone, a potent inhibitor of classical aldosterone action, was not effective up to a concentration of 100 nmol/L. These findings show kinetic and pharmacological similarities with both the functional data on Na+/H+ antiport stimulation by aldosterone and the studies of 125I-aldosterone binding to plasma membranes of HML. Thus, these data are the first to indicate an involvement of the phosphoinositide pathway in the rapid membrane effects of aldosterone.

Adult↗
PubMed1992

Photoaffinity labeling of plasma membrane receptors for aldosterone from human mononuclear leukocytes.

Non-genomic effects of aldosterone on the sodium-proton-antiport have been shown in human mononuclear leukocytes which could be related to a new aldosterone membrane receptor. In the present paper plasma membranes from human mononuclear leukocytes were covalently photolabeled with a [125I]-aldosterone derivative. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed significant aldosterone binding at a molecular weight of approximately 50000 Dalton which was absent with 1 microM cold aldosterone, but not cortisol in the binding media. The presence of the sulfhydryl agent dithiothreitol did not affect results suggesting the absence of disulfide bridges in the steroid binding domain of the receptor. These data are the first to define the molecular weight of the membrane receptor for aldosterone.

Affinity Labels↗
PubMed1992

Aldosterone-specific membrane receptors and rapid non-genomic actions of mineralocorticoids.

Functional studies in extrarenal, non-epithelial cells such as smooth muscle cells and more recently circulating human lymphocytes have provided increasing evidence that aldosterone produces not only classical genomic effects, but also rapid, non-genomic effects on transmembrane electrolyte movements. These involve activation of the sodium/proton exchanger of the cell membrane at very low, physiological concentrations of aldosterone with an acute onset within 1-2 min. A second messenger cascade involved is the inositol 1,4,5-trisphosphate/calcium pathway which responds over the same rapid time course. Such changes clearly cannot be explained by genomic mechanisms, which are responsible for later effects than the membrane related rapid responses. The mechanisms underlying these rapid effects of aldosterone on electrolytes have been extensively studied in human lymphocytes, which thus may represent valuable tools in the delineation of the receptor-effector mechanisms involved. The unique characteristics of this new pathway for steroid action include its rapid time course, 10,000-fold selectivity for aldosterone over cortisol and the ineffectiveness of spironolactones, classical mineralocorticoid antagonists, as antagonists of the response.

Aldosterone↗
PubMed1992

The early mineralocorticoid effector mechanism, the sodium-proton exchanger, is sensitized in lymphocytes from patients with Cushing's syndrome.

OBJECTIVE: In-vitro binding of aldosterone to mineralocorticoid receptors on human mononuclear leucocytes and its effects on the intracellular sodium and potassium concentrations, the sodium-proton exchanger and cell volume of human mononuclear leucocytes have been described for normals. In the present paper this easily accessible human cell model was studied in Cushing's syndrome to detect abnormalities of the mineralocorticoid effector mechanism. DESIGN: The rate of cell swelling in isotonic sodium propionate reflecting the activity of the sodium-proton exchanger and the stimulatory activity of 1.4 nM aldosterone were determined in a Coulter Channelyzer. PATIENTS: Nine female patients with pituitary-dependent (7) and adrenal hypercortisolism (2) were included in the study. MEASUREMENTS: Compared with controls from matched normals, the cell volume of human mononuclear leucocytes in a physiological buffer was significantly increased in the patients. The increment of cell size in isotonic sodium propionate was elevated in the presence of 1.4 nM aldosterone only. RESULTS: These findings are equivalent to an excess stimulation of the sodium-proton exchanger by aldosterone in these patients. Plasma cortisol was inversely correlated with the cell swelling in propionate. CONCLUSIONS: These data indicate that the early mineralocorticoid effector mechanism in human mononuclear leucocytes from patients with Cushing's syndrome has an increased sensitivity to aldosterone compared with that from normals. This could reflect an adaptation of the cellular electrolyte metabolism to the decreased mineralocorticoid activity balancing the increased glucocorticoid activity. If representative of other cell systems, e.g. renal tubular cells, these findings would identify accompanying electrolyte disorders in these patients not as a side-effect of glucocorticoids, but as a result of an increased sensitivity to endogenous mineralocorticoids.

Adolescent↗
PubMed1992

Membrane receptors for aldosterone: a novel pathway for mineralocorticoid action.

Rapid nongenomic in vitro effects of aldosterone on intracellular electrolytes, cell volume, and Na(+)-H+ antiport have been found in human mononuclear leukocytes (HML). Binding of 125I-labeled aldosterone to plasma membranes of HML shares important features with these functional data. This includes a very low apparent dissociation constant (Kd) of 0.1 nM for both aldosterone and the effect on the Na(+)-H(+)-antiport, a high turnover rate, and the almost exclusive binding selectivity for aldosterone. Dexamethasone, RU 26988, corticosterone, ouabain, amiloride, and 18-hydroxyprogesterone were inactive as ligands. Deoxycorticosterone acetate had an intermediate activity with an apparent Kd of 100 nM. These findings are the first to demonstrate membrane binding of aldosterone being compatible with major aspects of its nongenomic effects.

Aldosterone↗
PubMed1992

[ST-segment depressions and spontaneous changes in blood pressure and heart rate in simultaneous 24-hour recording in hypertensive patients].

In 15 patients with essential hypertension (but without coronary heart disease) simultaneous 24-h monitoring of the ST-segment and blood pressure was performed. Twenty-six periods with significant ST-segment depressions were recorded. In 10/26 periods with ST-segment depressions blood pressure was elevated, heart rate was increased in 20/26 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 data show ischemic episodes in hypertensive patients without coronary heart disease being associated with spontaneous increases of blood pressure and/or heart rate.

Angina Pectoris↗
PubMed1991

High affinity aldosterone binding to plasma membrane rich fractions from mononuclear leukocytes: is there a membrane receptor for mineralocorticoids?

In vitro effects of aldosterone on the intracellular concentrations of sodium, potassium and calcium, cell volume and the sodium-proton-antiport have been described in intact human mononuclear leukocytes (HML). In the present paper, the binding of a [125I]-labeled aldosterone derivative to plasma membrane rich fractions of HML was studied. High affinity binding of the radioligand with an apparent Kd of approximately 0.1 nM was found. Aldosterone displaced the tracer at a similar Kd. Both canrenone and cortisol were inactive as ligands up to concentrations of 0.1 microM. The findings are the first to demonstrate membrane binding sites with a high affinity for aldosterone, but not for cortisol. These data are perfectly compatible with major properties of steroidal effects on the sodium-proton-antiport in HML and thus very likely represent membrane receptors for aldosterone.

Aldosterone↗
PubMed1991

Pseudohypoaldosteronism and mineralocorticoid receptor abnormalities.

Pseudohypoaldosteronism is a rare inherited disease characterized by renal salt loss, hyperkalemia and metabolic acidosis despite highly elevated aldosterone values. We previously reported absent or reduced numbers of mineralocorticoid receptors in mononuclear leukocytes and defective effector mechanism as shown by no response in vitro to the incubation of aldosterone in terms of intracellular electrolyte content. We have studied the inheritance of this disorder in ten families and found two different kinds of inheritance: autosomal recessive--often in interrelated families--and autosomal dominant in unrelated families. Parallel studies in the families with the autosomal dominant form of inheritance demonstrated in addition that the effector mechanism of aldosterone is impaired in vitro both in the affected patients and in the carrier relatives characterized by a low number of mineralocorticoid receptors.

Aldosterone↗
PubMed1991

The Na(+)-H+ exchanger is stimulated and cell volume increased in lymphocytes from patients with essential hypertension.

A stimulation of the Na(+)-H+ exchanger has been shown in platelets of hypertensive man and lymphocytes of spontaneously hypertensive rats. In the present paper, human mononuclear leukocytes (HML) were investigated in 12 patients with essential hypertension with regard to the activity of the Na(+)-H+ exchanger and HML volume. The swelling of HML in isotonic sodium propionate was determined using a Coulter Channelyzer. Compared with matched normotensives, the cell volume of HML in a physiological buffer was significantly increased in essential hypertension (P less than 0.05). The amiloride-inhibitable rate of cell swelling in isotonic sodium propionate was also increased in HML from hypertensives. Amiloride (400 mumol/l) abolished the difference in cell volume within 1 min. These data show a functional swelling of HML in essential hypertension, probably due to an activation of the Na(+)-H+ exchanger. If also representative of smooth muscle cells, these findings could explain hypertensive vessel wall hypertrophy, in part, as functional cell swelling.

Amiloride↗
PubMed1991

Rapid effects of mineralocorticoids on sodium-proton exchanger: genomic or nongenomic pathway?

High-affinity aldosterone binding sites have been described in human mononuclear leukocytes (HML), and in vitro effects of aldosterone on intracellular sodium, potassium, and calcium concentrations and cell volume have been shown in HML. In the present paper, the response of the sodium-proton exchanger of the cell membrane to agonists and antagonists was studied by determining the kinetics of HML swelling in isotonic sodium propionate. Within 1-2 min of incubation, aldosterone significantly stimulated propionate-induced swelling by an additional 30-50% at concentrations as low as 0.07 nM. This effect was not blocked by the classical aldosterone antagonists potassium canrenoate or canrenone at concentrations of 140 or 700 nM. Hydrocortisone and dexamethasone were effective agonists only at much higher concentrations (4,000 nM). These data are not well explained by a mechanism of steroid action involving the interaction of a steroid receptor complex with nuclear DNA, since the effect on the sodium-proton exchanger is too fast. The findings could indicate distinct membrane receptors with a high affinity for aldosterone, but not hydrocortisone, and rapid direct membrane effects of aldosterone. These putative novel receptors may in turn bind novel aldosterone antagonists with possible diuretic and vasodilator effects distinct from those of spironolactones.

Aldosterone↗
PubMed1991

[Ibopamine--acute hemodynamic, renal and neurohumoral effects].

Ibopamine (IP) is a novel dopamine analogue for which beneficial effects have been shown in chronic heart failure. Hemodynamic effects of the substance include an increase in cardiac output and a decrease in the peripheral resistance. Aside from these hemodynamic effects, changes in renal (increased diuresis) and neurohumoral parameters (decreased plasma renin activity, aldosterone, norepinephrine, increased ANF and cGMP) have been found. The renal effects may originate from three independent mechanisms: 1) direct impact of improved hemodynamic parameters on the renal perfusion; 2) the improved cardiac performance results in a reduction of compensatory hormonal adaptations, such as the activation of the renin-angiotensin-aldosterone-axis or the sympathetic system; 3) direct effects on the intrarenal hemodynamic and glomerular/tubular functions induced by stimulation of renal dopaminergic receptors. The continued decrease of the plasma renin activity by 35% results in a reduction of the plasma levels of angiotensin II and aldosterone. Additionally, an increase in plasma atrial natriuretic factor (ANF) and its second messenger cyclic guanosine monophosphate (cGMP) was observed after ibopamine, which could contribute to the diuretic action of the drug. These findings underline the importance of extrarenal effects of a drug in the treatment of heart failure, this may essentially contribute to the improvement of cardiac performance, independent of positive inotropy.

Cardiotonic Agents↗
PubMed1991

[ST-segment depressions correlate in patients with hypertensive heart disease with spontaneous changes in blood pressure].

In 15 patients with essential hypertension, anginal pain, and angiographically excluded coronary artery disease 24-h monitoring of the ST-segment and blood pressure was performed. 26 episodes with ST-segment depressions 0400.1 mV were recorded in 11/15 patients. In 10/26 episodes with ST-segment depressions blood pressure was elevated above 150/95 mm Hg or by more than 20% as compared to three successive measurements before the ST-segment depressions. Heart rate was increased by more than 20% in 20/26 ST-segment depressions. During 9 periods with ST-segment depressions angina pectoris was reported; in addition 27 anginal attacks without ST-segment depressions were observed. A significant, positive correlation between the diastolic (p less than 0.005) and systolic (p less than 0.02) blood pressure and the extent of the ST-segment depression was observed. These correlations imply a patho-physiological meaning of ST-segment depressions in hypertensive patients.

Angina Pectoris↗