Rapid Cardiovascular Action of Aldosterone in Man*

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increase of peripheral vascular resistance and blood pressure and a decrease of cardiac output within 5 min of adminis- tration of aldosterone in man (0.5 mg iv) ...
0021-972X/98/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1998 by The Endocrine Society

Vol. 83, No. 10 Printed in U.S.A.

Rapid Cardiovascular Action of Aldosterone in Man* MARTIN WEHLING, CHRISTOPH H. SPES, NINI WIN, CATHERINE P. JANSON, BERNHARD M. W. SCHMIDT, KARL THEISEN, AND MICHAEL CHRIST Institute of Clinical Pharmacology (M.W., B.M.W.S., M.C.), Faculty of Clinical Medicine Mannheim, University of Heidelberg, 68135 Mannheim, Germany; Medizinische Klinik (C.H.S., N.W., K.T.), Klinikum Innenstadt, University of Munich, 80336 Munich, Germany; and Department of Biostatistics (C.P.J.), Institute of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, 68135 Mannheim, Germany ABSTRACT Rapid nongenomic in vitro effects of aldosterone have been demonstrated recently in cultured vascular smooth muscle and endothelial cells. But there is, as yet, little evidence for corresponding in vivo effects. The present study thus investigates the rapid nongenomic effects of aldosterone on human cardiovascular function. In a doubleblind placebo-controlled randomized parallel trial on 17 patients with suspected coronary heart disease, the effect of 1 mg aldosterone iv on cardiovascular function was assessed during cardiac catheterization. Hemodynamic parameters (such as heart rate, left ventricular and atrial pressures, arterial pressures, vascular resistances, and cardiac

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VER THE past decade, a number of studies have demonstrated rapid in vitro effects of aldosterone on sodium, potassium, and calcium concentrations and cell volume of human mononuclear leukocytes (HML) (1–3) and effects on the activity of the sodium-proton-exchanger of the cell membrane in HML and vascular smooth muscle cells (VSMC) (4 – 6). These effects are not compatible with a genomic action via classical type-I-mineralocorticoid receptors, suggesting the existence of distinct receptors subsequently described in plasma membranes from HML pig kidney and liver (7–9). The phosphoinositide pathway, protein kinase C, and free intracellular calcium are apparently involved in intracellular signaling in HML and VSMC (4, 10 – 12). Intracellular free calcium is consistently increased by aldosterone within 1–2 min. Calcium was shown to be released from perinuclear stores in VSMC, whereas a substantial increase of subplasmalemmal calcium is seen in endothelial cells. Though cortisol was inactive at concentrations up to 0.1 mmol/L, half-maximal effects of aldosterone were found at physiological plasma concentrations of 0.1 nmol/L. Canrenone, the classical mineralocorticoid antagonist, is ineffective in blocking this action of aldosterone (13). In contrast to genomic effects characterized by a substantial delay, nongenomic effects of mineralocorticoids are very Received April 2, 1998. Revision received July 7, 1998. Accepted July 9, 1998. Address all correspondence and requests for reprints to: Martin Wehling, M.D., Curt-Engelhorn-Professor of Medicine, Director of Institute of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 68135 Mannheim, Germany. * This work was supported by the Deutsche Forschungsgemeinschaft (Sc 4/9 – 4) and the Bundesministerium fu¨r Bildung und Forschung (FKZ 01 EC 9407/8).

output) were measured before and 3 and 10 min after administration of aldosterone or placebo. Significant changes were found for systemic vascular resistance, cardiac output, and cardiac index, compared with the placebo group (Wilcoxon test, P , 0.02– 0.05). The effect of aldosterone dissipated within 10 min. The results are in line with the in vitro data cited above and consistent with earlier findings on acute cardiovascular effects of aldosterone, which have now been confirmed and extended by contemporary techniques. The hypotheses of rapid nongenomic in vivo effects of aldosterone are further substantiated by this study. (J Clin Endocrinol Metab 83: 3517–3522, 1998)

rapid. A long series of subcellular processes (including messenger RNA production, messenger RNA modification, translation into proteins, protein translocation, and/or insertion into membranes) may explain the latency of genomic steroid effects. The earliest genomic effects known in the action of mineralocorticoids, the increase of mouse mammary tumor virus long-terminal repeat transcription rate in a feline renal cell line (14, 15), do not start before 30 min after application. Rapid nongenomic aldosterone effects still require further clarification of their physiological and clinical relevance. Their extent is relatively modest, compared with the response to standard stimuli, explaining why they may have been overlooked in related clinical studies. There is little convincing in vivo evidence for rapid aldosterone action, with some studies on rapid cardiovascular effects in man and on baroreceptor neuron discharge frequency in the dog (16, 17). In the latter report, effects of aldosterone on peripheral resistance, cardiac index, and spiking activity of baroreceptor neurones were demonstrated to occur within 5–15 min. Klein and Henk (16) showed an increase of peripheral vascular resistance and blood pressure and a decrease of cardiac output within 5 min of administration of aldosterone in man (0.5 mg iv). At the time of that study, 1964, in vivo assessment of cardiovascular parameters in humans was restricted to noninvasive methods, which were not as sensitive as contemporary methodology. In a recent investigation, rapid effects of aldosterone on the recovery of phosphocreatine were found within 8 min after isometric exercise in calf muscles of healthy volunteers (18). Phosphocreatine concentration was monitored by nuclear magnetic resonance spectroscopy at rest and under stress. One milligram of aldosterone, given iv, significantly facili-

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tated phosphocreatine recovery after isometric contraction, an effect starting within 8 min after administration of steroid. In both studies, the potential physiological relevance of rapid aldosterone effects is underlined by the fact that those effects were detected despite the presence of normal endogenous aldosterone levels. Thus, the rapid effector is still responsive to exogenous steroid and obviously not constantly activated at maximum level. These findings prompted the hypothesis that aldosterone can act as a rapid regulator of cardiovascular parameters in response to variable requirements of the individual, rather than just representing a background activity of so-called housekeeping significance. To assess acute cardiovascular effects of aldosterone in man by invasive techniques, a double-blind placebo-controlled randomized study was performed. Hemodynamic parameters (such as heart rate, ventricular and atrial pressures, pulmonary artery and capillary pressures, arterial pressures, and cardiac output) were determined 3 min and 10 min after administration of aldosterone or placebo. Subjects and Methods Methods The study was designed as a placebo-controlled double-blind randomized parallel trial. It was conducted according to the guidelines for good clinical practice (19) and the declaration of Helsinki (20). The study design was approved by the ethical committee of the University of Munich, Germany.

Patients Seventeen patients were included in the study. Cardiac catheterization was considered clinically necessary for suspicion of coronary artery disease and was independent of the study. Inclusion criterion was suspected coronary artery disease; exclusion criteria were: systolic blood pressure above 190 mm Hg or diastolic blood pressure above 110 mm Hg, age above 75 yr, abnormal electrolyte levels, severe coronary three vessel disease, stenosis of left main coronary artery, unstable angina pectoris, or an estimated left ventricular ejection fraction below 40%. According to patients’ histories, concomitant chronic or acute diseases were exclusion criteria, e.g. hyperthyroidism, collagen disease, malignant tumor, heart failure, renal insufficiency, or primary liver failure.

Study design After informed consent, study patients underwent routine cardiac catheterization. Routine examination included right and left heart catheterization, biplane coronary angiography (7 views of the left, 2 views of the right coronary artery), and levocardiography. The status of the individual patient was then assessed by two independent investigators, with regard to the fulfillment of inclusion and exclusion criteria. At baseline, hemodynamic parameters (heart rate, right and left ventricular and atrial pressures, pulmonary artery pressure, pulmonary capillary wedge pressure, aortic pressure, and cardiac output, measured oxymetrically by the Fick’s principle) were determined. Then 1 mg aldosterone (2 mL) or placebo (2 mL) was injected in the inferior vena cava within 30 sec. The aldosterone solution was prepared according to the original recipe of the formerly registered drug ALDOCORTEN (Ciba-Geigy, Basel, Switzerland) which became clinically unavailable recently. Placebo was isotonic 0.9% NaCl-solution. At 3 and 10 min after injection, assessment of hemodynamic parameters was repeated. In addition, biplane ventriculography was done again after 10 min using the same protocol as during routine investigation to measure left ventricular ejection fraction. Contrast medium (30 mL SOLUTRAST, Byk Gulden, Konstanz, Germany) was injected through a 6 –7 french pigtail catheter. End diastolic and systolic volumes were determined by automated planimetry (Carddas system, Schering, Berlin, Germany).

For safety reasons, the following examinations were done in every potential candidate before the study: physical examination, 12-channel electrocardiography, body weight, and routine laboratory examination (blood smear, electrolytes, aspartate-aminotransferase, urea, and creatinine). Plasma concentrations of aldosterone (baseline and 3 min after injection) were determined by commercially available RIAs (Serono Diagnostika, Freiburg, Germany; ERIA Diagnostics, Pasteur, France) using standard procedures.

Statistical methods The primary effect variable was systemic vascular resistance (SVR); secondary effect variables were heart rate, cardiac output, systolic, diastolic and mean pulmonary and systemic blood pressure, pulmonary capillary wedge pressure, enddiastolic left ventricular pressure, right ventricular pressure, right atrial pressure, pulmonary vascular resistance, and ejection fraction. Descriptive statistics (means 6 sem) were calculated for absolute values. Homogeneity of the two groups was tested by the nonparametric Wilcoxon rank-sum test on baseline data obtained immediately before administration of aldosterone or placebo. Changes in cardiovascular parameters, 3 and 10 min after injection of aldosterone or placebo, were computed as intraindividual differences. Based on those intraindividual differences, the null hypothesis of aldosterone having no effect on cardiovascular parameters was tested by the Wilcoxon test. A P level less than 0.05 was considered statistically significant. Safety parameters were evaluated descriptively. The statistical analysis was performed using the statistical program package SAS (SAS Institute, Inc., Cary, NC).

Results

Important clinical and demographic features and laboratory parameters are given in Table 1. The two groups showed no significant differences in those characteristics. Table 2 provides information on the concomitant medications of the study patients, which were equally distributed in the aldosterone and placebo group. Cardiovascular features, at the time immediately before aldosterone/placebo administration, are shown in Table 3. Despite randomization, differences in probability distribution between the groups were found for mean aortic pressure and systolic left ventricular pressure. Cardiovascular parameters, at 3 and 10 min after administration of aldosterone or placebo, are listed in Tables 4 and 5. Changes (intraindividual differences between time points) of the SVR (P , 0.05), cardiac output (P , 0.05), and cardiac index (P , 0.05) were significantly different for patients in the aldosterone vs. placebo group 3 min after drug injection (Fig. 1). Whereas, in the placebo group, SVR decreased in 6 of 9 patients within 3 min; in aldosterone-treated patients, SVR increased in 5 of 8 cases. The fact that not all patients responded may be attributable to scattering and the small extent of the effect in some individuals. Cardiac output and cardiac index (not shown) changed in opposite directions (Fig. 2). They were significantly interrelated, as shown by linear correlation analysis (Spearman’s rank r 5 20.61, P , 0.01). The overall difference of mean changes in the aldosterone and placebo groups was 225 6 92 dynes (dyn)/sec/ cm5 (mean 6 sem) for SVR, 0.6 6 0.2 (L/min) for cardiac output, and 0.3 6 0.1 (L/min/m) for cardiac index. Changes, from 3–10 min after administration of aldosterone vs. placebo, differed significantly in the variables SVR (P , 0.02) (Fig. 1), mean pulmonary artery pressure (P , 0.05), and cardiac output (P , 0.02) (Fig. 1). The total differences of the mean changes were 244 6 94 (dyn/sec/cm5),

ACUTE ALDOSTERONE ACTION IN MAN TABLE 1. Descriptive statistics of demographic and safety parameters (means 6

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SEM)

Parameter

Aldosterone

Placebo

Age (yr) Height (cm) Body weight (kg) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Male/female (number) Laboratory parameters in serum/blood urea (mmol/L) Creatinine (mmol/L) Sodium (mmol/L) Potassium (mmol/L) Calcium (mmol/L) Plasma protein (g/L) ASAT (nkat/L) Gamma-glutamyl-transferase (nkat/L) Erythrocytes (1012/L) Leukocytes (109/L) Hemoglobin (mmol/L) Thrombocytes (109/L)

59.5 6 3.3 170.5 6 3.1 79.8 6 4.3 147.9 6 11.3 88.1 6 5.6 7/1 6.6 6 0.4 98.2 6 4.2 138.4 6 0.8 3.6 6 0.1 2.2 6 0.03 67.6 6 2.4 158.7 6 26.2 776.6 6 395.5 4.1 6 0.1 5.8 6 0.5 8.0 6 0.3 206.4 6 19.2

58.2 6 2.9 172.8 6 2.6 83.8 6 4.1 139.4 6 5.4 84.4 6 3.2 8/1 5.6 6 0.7 83.2 6 6.2 138.7 6 0.9 3.9 6 0.2 2.2 6 0.04 63.8 6 1.9 196.7 6 29.2 677.4 6 250.0 4.0 6 0.2 6.2 6 0.5 7.8 6 0.4 201.1 6 14.9

ASAT, aspartate amino-transferase. TABLE 2. Concomitant medication of study patients (number of patients) Patients on drug Aldosterone

Placebo

7 4 2 4 5 3

7 3 3 3 6 4

Acetylsalicylic acid Diuretics beta-blockers Calcium channel antagonists ACE-inhibitors Nitrates ACE, angiotensin converting enzyme.

2.5 6 1.1 (mm Hg), and 0.5 6 0.2 (L/min). Repeated-measures ANOVA of the primary effect variable SVR yielded significant interaction of treatment and time (P 5 0.02). The adequacy of this method remains questionable, however, because the requirement for normal distribution cannot be assessed for the small sample size. After 10 min, none of the cardiovascular parameters was significantly different from baseline levels, including left ventricular ejection fraction (66% vs. 69%). Because the initial differences in mean aortic pressure and systolic left ventricular pressure might confound the significance of the above mentioned changes of SVR, cardiac output and cardiac index, correlations between those parameters were assessed by Spearman’s rank correlation coefficient. Analysis of covariance, which would have been a more suitable method to identify confounding variables, was not feasible because a major prerequisite, normal distribution, could not be proven for the small sample size. There was no significant correlation between potential confounding variables and SVR, cardiac index, or cardiac output, thus supporting the conclusion that mean aortic pressure and systolic left ventricular pressure did not confound the changes of SVR, cardiac output, and cardiac index. The median plasma concentrations of aldosterone where 343 pmol/L (quartile range, 70 pmol/L) at baseline and 43,470 pmol/L (quartile range, 13,874 pmol/L) 3 min after injection in the aldosterone group (our normal range is 28 – 443 pmol/L). In the placebo group, the corresponding values

where 258 pmol/L (quartile range, 86 pmol/L) and 259 pmol/L (quartile range, 186 pmol/L). Discussion

In the present study, the acute effects of 1 mg aldosterone on cardiovascular parameters were investigated in a doubleblind, randomized trial in parallel design vs. placebo (isotonic 0.9% NaCl solution). The main result of the study is the demonstration of acute aldosterone effects on the cardiovascular parameters SVR and cardiac output/index in man. At high plasma levels of aldosterone, as produced in this study (;40 nmol/L), a nonspecific membrane effect of aldosterone cannot be excluded with certainty. However, nonspecific effects of steroids on membrane fluidity and physicochemical membrane properties usually occur at much higher concentrations of steroids (.1 mmol/L) (21). Thus, acute aldosterone effects occurring at nanomolar concentrations are still likely to represent specific, nongenomic actions of the steroid. The change of SVR in the placebo group possibly reflects the vasodilatory effect of the contrast media administered during levocardiography shortly before the investigation (22). Apparently, this effect is temporary, because SVR returns to (or even exceeds) basal levels within 10 min. The action of aldosterone also seems to be limited, in that SVR returns to baseline within 10 min. These findings are consistent, not only with data on rapid aldosterone effects in vitro (4, 6, 11–13), but also with those of Klein and Henk (15), who in 1964 demonstrated significant increases of peripheral vascular resistance and decreases of cardiac output as early as 5 min after application of aldosterone by noninvasive techniques. In the meantime, rapid cardiovascular effects in man were demonstrated for other steroids, especially estrogens (23–25). The effects of aldosterone described in cardiovascular effector cells (VSMC and endothelial cells) in vitro (see above) are seen at physiological concentrations [EC50 and dissociation constant (KD) values ; 0.1 nmol/L; free aldosterone concentration in man, 0.1 nmol/L] (26) and thus are likely to contribute to normal physiology. The findings reported here

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TABLE 3. Statistics of cardiovascular parameters at baseline before administration of aldosterone/placebo (means 6

a b

Parameter

Aldosterone

Placebo

Heart rate (bpm) Left ventricular ejection fraction (%) Mean right atrial pressure (mmHg) Systolic right ventricular pressure (mmHg) Enddiastolic right ventricular pressure (mmHg) Mean pulmonary artery pressure (mmHg) Mean pulmonary capillary wedge pressure (mmHg) Mean aortic pressure (mmHg)a Systolic left ventricular pressure (mmHg)b Enddiastolic left ventricular pressure (mmHg) Systemic vascular resistance (dyn/sec/cm5) Pulmonary capillary vascular resistance (dyn/sec/cm5) Cardiac output (L/min) Cardiac index (L/min/m2)

68.5 6 4.3 65.0 6 5.1 3.6 6 0.8 24.0 6 2.2 4.3 6 0.6 13.5 6 1.6 7.0 6 1.3 84.4 6 4.6 125.0 6 5.4 7.1 6 1.6 1420.3 6 111.6 113.5 6 17.5 4.7 6 0.3 2.4 6 0.1

66.8 6 3.6 68.7 6 3.8 4.7 6 1.1 26.3 6 2.8 4.7 6 1.5 15.9 6 2.1 7.2 6 1.8 101.9 6 4.6 150.9 6 5.7 9.7 6 2.1 1760.6 6 107.9 148.6 6 22.4 4.5 6 0.2 2.3 6 0.1

Significant differences of probability distributions, interindividual comparisons, Wilcoxon test, P , 0.05. P , 0.02.

TABLE 4. Cardiovascular parameters 3 min after administration of aldosterone/placebo (means 6

a

SEM)

Parameter

Aldosterone

Placebo

Heart rate (bpm) Mean right atrial pressure (mmHg) Systolic right ventricular pressure (mmHg) Enddiastolic right ventricular pressure (mmHg) Mean pulmonary artery pressure (mmHg) Mean pulmonary capillary wedge pressure (mmHg) Mean aortic pressure (mmHg) Systolic left ventricular pressure (mmHg) Enddiastolic left ventricular pressure (mmHg) Systemic vascular resistance (dyn/sec/cm5)a Pulmonary capillary vascular resistance (dyn/sec/cm5) Cardiac output (L/min)a Cardiac index (L/min/m2)a

65.6 6 4.5 2.9 6 0.9 22.9 6 1.6 3.8 6 0.4 12.0 6 1.3 7.1 6 1.2 82.5 6 3.7 123.3 6 3.3 6.0 6 0.6 1502.9 6 128.1 105.6 6 15.7 4.4 6 0.4 2.3 6 0.2

72.4 6 6.1 3.7 6 1.2 24.9 6 2.8 4.2 6 1.2 16.1 6 2.0 8.3 6 1.8 96.6 6 3.9 109.8 6 30.0 10.3 6 2.9 1618.1 6 101.0 146.1 6 24.6 4.8 6 0.3 2.4 6 0.1

Significant differences of changes 0 3 3 min between groups (comparison of intraindividual changes, Wilcoxon test, P , 0.05).

TABLE 5. Cardiovascular features 10 minutes after administration of aldosterone or placebo (means 6

a b

SEM)

SEM)

Parameter

Aldosterone

Placebo

Heart rate (bpm) Left ventricular ejection fraction (%) Mean right atrial pressure (mmHg) Systolic right ventricular pressure (mmHg) Enddiastolic right ventricular pressure (mmHg) Mean pulmonary artery pressure (mmHg)a Mean pulmonary capillary wedge pressure (mmHg) Mean aortic pressure (mmHg) Systolic left ventricular pressure (mmHg) Enddiastolic left ventricular pressure (mmHg) Systemic vascular resistance (dyn/sec/cm5)b Pulmonary capillary vascular resistance (dyn/sec/cm5) Cardiac output (L/min)b Cardiac index (L/min/m2)

67.6 6 4.1 65.8 6 4.5 2.4 6 0.4 25.3 6 2.4 4.1 6 0.5 13.5 6 1.8 7.8 6 1.3 80.9 6 3.3 121.8 6 4.9 10.0 6 2.6 1396.9 6 102.5 103.0 6 20.3 4.6 6 0.3 2.4 6 0.1

68.4 6 3.2 69.2 6 4.7 4.4 6 1.0 27.5 6 3.2 5.8 6 1.7 15.4 6 2.2 8.9 6 2.1 97.5 6 5.2 118.6 6 14.4 8.5 6 1.8 1774.3 6 127.9 130.6 6 29.7 4.3 6 0.3 2.2 6 0.1

Significant differences of changes 3 3 10 min between groups (comparison of intraindividual changes, Wilcoxon test, P , 0.05. P , 0.02.

support this assumption, though higher aldosterone concentrations were used in the clinical study, and a dose-finding study is needed to define the EC50 of the in vivo effect observed here. It is feasible to assume that the action of aldosterone physiologically varies in response to rapidly changing plasma levels known to occur particularly for this hormone, e.g. after postural changes (27). The aldosteronerelated increase in SVR would then meet the demands of circulatory homeostasis during postural changes and also give sense to the rapid changes of plasma aldosterone levels,

which are difficult to understand if genomic mechanisms were the only effector available. At this point, changes of cardiac output are hard to interpret, but given the in vitro data on aldosterone action in VSMC, SVR would seem to be the primary target of rapid aldosterone action, with counterregulatory effects on cardiac output. The interdependence of both variables is underlined by its significant negative correlation (Fig. 2). In result, blood pressure is not significantly changed, and the exact mechanism of cardiodepression remains to be elucidated. The ex-

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FIG. 2. Intraindividual changes (baseline to 3 min) in SVR and cardiac output in response to aldosterone (E) or placebo (M); each sign represents one patient.

action, is the potential of steroids to freely diffuse in the body, even through lipid barriers. Given this, a hypothetical scenario of rapid cardiovascular aldosterone action might be a general priming of the body, including many (if not all) major vascular beds, for increased sensitivity to other circulating and (possibly more importantly) locally produced mediators such as angiotensin II. By virtue of the rapid effector, this priming is swift, and aldosterone might be regarded as a cardiovascular stress hormone. Because there is no effective antagonist of rapid aldosterone action known to date, future in vitro investigations may identify compounds able to achieve mineralocorticoid membrane blockade. A superspironolactone, blocking both genomic and nongenomic aldosterone actions, would be most desirable for physiological studies and, potentially, for treatment of cardiovascular disease. Acknowledgment We thank K. Sippel for expert technical assistance. FIG. 1. Intraindividual changes of SVR (a), cardiac output (b), and heart rate (c) in response to aldosterone (-E-) or placebo (-M-), means 6 SEM. Significances (Wilcoxon-test) are given for the group differences of intraindividual changes from 0 –3 min and from 3–10 min, respectively. bpm, Beats per minute.

tent of rapid aldosterone effects is small, both in vitro and in vivo effects. On the other hand, scattering is considerable, and the lack of effect in a few patients may simply be caused by this. Where is the evolutionary gain in such a limited effector? Rapid aldosterone action seems to act as a suitable finetuning instrument whereby cardiovascular parameters may be safely modulated up to certain limits (low ceiling effector) and also be sensitized to synergistic stimuli, e.g. catecholamines. An important feature, however, which clearly separates steroid from peptide hormone or catecholamine

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