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Cardiovascular Research 1998 40(1):34-44; doi:10.1016/S0008-6363(98)00147-3
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Copyright © 1998, European Society of Cardiology

Cardiovascular steroid actions: swift swallows or sluggish snails?

Michael Christ and Martin Wehling*

Institut für Klinische Pharmakologie, Klinikum Mannheim, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany

* Corresponding author. Tel.: +49-621-3834058; Fax: +49-621-3832024; E-mail: wehling@medinn.med.uni-muenchen.de

Received 7 January 1998; accepted 12 May 1998


   Abstract
Top
 Abstract
1 Mineralocorticoids
 2 Sex steroids
 3 Glucocorticoids
 4 Conclusions
 References
 
Steroid actions on the vascular wall have been thought to depend on direct, genomic mechanisms being characterized by a considerable delay and on secondary events, including changes of coagulation, plasma lipids, and renal electrolyte and volume regulation. Recently, rapid effects of steroids on the vascular wall have been reported being clearly incompatible with the classical theory of genomic steroid action. As these effects occur in classical target tissues for genomic steroid action, and modulation of intracellular signaling has been shown to influence genomic steroid action, a two-step model of steroid action was developed integrating both genomic and nongenomic aspects and their possible interaction. This review summarizes recent studies on both types of direct, vascular steroid actions, the swift and the sluggish ones, and discusses the role of these actions in regulation of circulatory homeostasis and their potential therapeutic implications.

KEYWORDS Hormones; Receptors; Vasoconstriction/dilation

Over three decades ago, the profound impact of steroids on nuclear transcription and protein synthesis had been recognized. Subsequently, research has primarily focused on analysis of molecular mechanisms for these genomic effects in specific target tissues, including the cloning of the receptors involved. Finally, those receptors transmitting genomic action of various steroids have been defined as the superfamily of intracellular steroid receptors [1].

Demonstration of classical, intracellular receptors for a variety of steroids in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs; [2–5]) has been considered as the molecular correlate of direct vascular steroid actions by genomic mechanisms. Ligand binding to intracellular receptors is followed by binding of the steroid-receptor complex to steroid-specific response elements of the DNA and by related effects on nuclear transcription. These effects are modulated by the action of coactivators, e.g. steroid receptor coactivator-1 protein [6]or cAMP-responsive-binding-protein [7]. They are characterized by a considerable latency of about 4–24 h and their sensitivity to blockers of transcription and protein synthesis, e.g. actinomycin D or cycloheximide.

Another mode of steroid action has been fully recognized only recently, being incompatible with genomic action: for steroids of all classes and in a wide array of tissues and species, very rapid, nongenomic steroid effects have been described (for review, [8]) involving putative membrane receptors with pharmacological properties that are clearly distinct from classical intracellular binding sites. This also applies to the vasculature [9]. However, the significance of these effects for the regulation of vascular tone is still poorly understood. In this review, both aspects of steroid hormone actions in the cardiovascular system are summarized with particular references to those novel nongenomic mechanisms and to the clinical relevance in physiology and therapeutics.


   1 Mineralocorticoids
Top
 Abstract
 1 Mineralocorticoids
2 Sex steroids
 3 Glucocorticoids
 4 Conclusions
 References
 
Effects of aldosterone on systemic circulation are commonly understood as events that are secondary to steroid-induced changes in electrolyte and volume balance, resulting from effects on the distal tubule epithelia of the kidney [10]. As early as 1959, direct actions of mineralocorticoids on systemic circulation have been reported in a study by Langford and Snavely [11], who showed deoxycorticosterone acetate (DOCA)-induced hypertension in bilaterally nephrectomized dogs and rats. These effects are presumably transmitted by classical, intracellular mineralocorticoid receptors that are known to exist in VSMCs ([2, 4]; Table 1). Genomic mechanisms also seem to be involved in aldosterone effects on myocardial fibrosis, which was discussed more recently [12], as classical receptor antagonists for mineralocorticoids efficiently protect the myocardium against pathologic structural remodeling by reactive and reparative fibrosis. This is supported by studies of Brilla et al. [13]who demonstrated aldosterone-induced stimulation of collagen synthesis in cultured adult rat cardiac fibroblasts. However, this study was not confirmed by Fullerton and Funder [14], and there is an ongoing discussion on the origin of aldosterone-dependent myocardial fibrosis, which could also be secondary to the extracardial action of the hormone.


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  		Table 1 Genomic and nongenomic cardiovascular steroid actions with special reference to normal plasma levels

 
Apart from these delayed, presumably genomic mineralocorticoid actions, fast, nongenomic in vitro ([15]; Fig. 1) and in vivo effects of aldosterone have been described. Klein and Henk [16]showed rapid aldosterone effects on systemic vascular resistance in humans occurring within 5 min, which may be explained by mechanisms mediated by direct aldosterone effects on intracellular calcium, as has been shown in single cultured cardiac fibroblasts recently (Fig. 1). Moura and Wourcel [17]demonstrated ouabain- and actinomycin-D-independent sodium efflux in the rat tail artery, which was stimulated as early as 15 min after aldosterone application, indicating a nongenomic response to aldosterone. The same holds true for the suppression of baroreceptor discharge in a canine model, which was obtained within 15 min of aldosterone injection [18], and for the rapid reduction of coronary flow and increases of aortic flow and cardiac output in an isolated rat working heart model [19]. To elucidate further the physiological role of rapid aldosterone action in vivo, a placebo-controlled, randomized study was performed in man, in which a rapid, aldosterone-induced increase of phosphocreatine levels was demonstrated in calf muscle after submaximal exercise [20]. These data point to an involvement of aldosterone in the acute stress adaptation of cellular oxidative metabolism in skeletal muscle.


Figure 1
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  		Fig. 1 Representative tracing of free intracellular calcium measured by Fura2 fluorescence in single cultured cardiac fibroblasts. At the times indicated, aldosterone was added at concentrations given as –lg mol/l. Reprinted from Ref. [15]with permission from Elsevier Science.

 
While reports of rapid in vivo actions of aldosterone are still rare at the moment, more abundant in vitro data have been accumulated to date. Rapid calcium-dependent effects of aldosterone on pH in kidney cells [21]are in line with results demonstrating a stimulation of the sodium–proton exchanger and inositol-1,4,5-trisphosphate production by aldosterone in human mononuclear leukocytes (HMLs) within only 1–2 min [22, 23]. Since these effects were not blocked by the classical mineralocorticoid antagonist, canrenone, a specific membrane receptor for aldosterone has been assumed [24]and, subsequently, demonstrated in membrane preparations of HMLs, porcine kidney and porcine liver [25–27]. Rapid aldosterone effects seem to be mediated by this putative membrane receptor, which is distinct from the classical, intracellular mineralocorticoid receptor [28]with regard to all major pharmacological properties [8, 15]. The EC50 for these effects and the Kd of specific binding to these sites are close to the free plasma aldosterone concentration in man (~0.1 nmol/l; [29]).

A rapid effect of aldosterone on sodium–proton exchanger activity was also found in cultured VSMCs from rat thoracic aortae. A significant, cycloheximide- and actinomycin-D-independent stimulation occurred within 4 min, which was not compatible with an involvement of genomic mechanisms. The apparent EC50 was ~0.2 nmol/l, a concentration that is close to the physiological range of free aldosterone plasma concentrations in rats ([8]; Table 1). The synthetic mineralocorticoid, fludrocortisone, is active at concentrations similar to those of aldosterone, while cortisol is ineffective even at micromolar concentrations. In addition, aldosterone and fludrocortisone significantly stimulate the generation of inositol-1,4,5-trisphosphate (IP3) within 1 min at a subnanomolar EC50. Again, cortisol is active at concentrations >1 µmol/l. Canrenone does not block aldosterone effects at 100-fold excess concentrations [30]. Similarly, diacylglycerol (DAG) production is increased in VSMCs by subnanomolar concentrations of aldosterone, while hydrocortisone is effective in supramicromolar concentrations only [31]. The increases of both IP3 and DAG were short-lived and partially receded within 10 min. As DAG is known to activate protein kinase C (PKC), aldosterone effects on PKC were studied utilizing immunoblotting: Aldosterone stimulates the translocation of PKC from the cytosol to the plasma membrane within 15 min, which is considered to correlate with PKC activation. Stimulation of the sodium–proton exchanger was also visualized by cell imaging using the BCECF method [32]. Aldosterone rapidly induced a decrease in intracellular pH followed by alkalinization of the cell due to a direct activation of the sodium–proton exchanger by aldosterone [30]. As IP3 is known to release calcium from intracellular stores, rapid effects of aldosterone on intracellular [Ca2+]i in VSMCs, porcine endothelial cells (ECs) and cultured myocardial fibroblasts were investigated (Figs. 1 and 2Go): Aldosterone induces an immediate increase in [Ca2+]i, which reaches a plateau within 2–3 min. In VSMCs, half-maximal effects are seen at ~0.1 nmol/l, while glucocorticoids are only active at or above micromolar concentrations [33, 34]. Inhibition of phospholipase C blocked the increase of [Ca2+]i. These findings support the hypothesis of an involvement of phospholipase C and PKC pathways [30, 31]. Due to extremely high unspecific binding of aldosterone in membrane preparations from VSMCs (unpublished results), specific binding of aldosterone could not be extensively studied in VSMCs.


Figure 2
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  		Fig. 2 Representative calcium images of porcine endothelial cells before and 5 min after the addition of 100 nmol/l aldosterone. Free intracellular calcium was measured spectrofluorometrically with the Fura2-method in a microscopic cell imaging system. Modified with permission [33].

 
As a unique feature of rapid aldosterone effects on [Ca2+]i, a relatively small maximum effect of ~30–50 nmol/l is seen consistently, even at high steroid concentrations. In ECs, the rise in free intracellular calcium mainly reflects influx of extracellular calcium (Fig. 2), while in VSMCs, release from intracellular stores is the main source of calcium [33].

In conclusion, mineralocorticoids may affect cardiovascular parameters both by direct and indirect effects. Direct actions of mineralocorticoids on the vascular wall seem to be transmitted both by the genomic and nongenomic actions of mineralocorticoids at physiological plasma concentrations. Both pathways are summarized in the novel, two-step model of mineralocorticoid action (Fig. 3). Greene et al. [35]suggested that aldosterone may contribute to vascular regulation utilizing both pathways synergistically, as the genomic aldosterone antagonist spironolactone does not block all detrimental effects of aldosterone in a remnant kidney model for chronic renal failure. Although unproven at the moment, both pathways of direct aldosterone action may be intertwined and crosstalk possibly occurs.


Figure 3
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  		Fig. 3 Schematic presentation of an integrated model for steroid action comprising genomic and nongenomic actions of steroids exemplified for aldosterone. Steroids act via the classical genomic pathway by binding to intracellular steroid receptors, modulation of protein expression and, thus, cellular function. The rapid nongenomic pathway of steroid action involves membrane receptors, intracellular second messengers and effector systems at the level of the plasma membrane. Changes of the intracellular ion milieu in turn may modulate genomic transcription processes. Abbreviations: intracellular free calcium (Ca2+), diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3), protein kinase C (PKC), intermediary protein–tyrosine kinase (IPYK).

 

   2 Sex steroids
Top
 Abstract
 1 Mineralocorticoids
 2 Sex steroids
3 Glucocorticoids
 4 Conclusions
 References
 
2.1 Estrogens
Coronary artery disease (CAD) is the leading cause of death in both sexes. In women, the cardiovascular risk markedly rises after the loss of ovarian function [36, 37]. Traditionally, the protective cardiovascular action of conventional doses of estrogens in hormone replacement therapy (HRT) is thought to be mediated indirectly by effects on lipoprotein metabolism, coagulation and fibrinolysis [9, 38]. However, epidemiological data suggest that the atheroprotective effects of estrogen may not be explained by those alterations alone, but rather point to an additional, direct effect on the vascular wall [39]. Thus, in recent studies, related explanations for these favourable estrogen effects in vascular cells were tested experimentally.

Demonstration of genomic estrogen receptor expression in VSMCs and ECs [3, 5, 40]pointed to an involvement of classic steroid receptors in antiproliferative, antimigratory and antihyperplastic effects of estrogens [41–43]. Several lines of evidence also support the assumption that vascular tone and reactivity may be modulated by estrogen-induced alterations of metabolizing enzyme or receptor expressions reflecting genomic steroid actions on different signaling pathways [e.g. angiotensin II, endothelin, angiotensin-converting-enzyme, endothelial constitutive nitric oxide (NO)-synthase, prostacyclin synthesis, growth factors; [44, 45]]. Antioxidant actions may be involved in both the antiatherosclerotic and vasomodulatory effects of estrogens, as demonstrated in a model of endothelial cells [46]. Furthermore, the recently discovered estrogen receptor beta [47]has opened the field of previously unrecognized pathways of estrogen signaling and implies the need to re-evaluate cardiovascular estrogen effects, which had been thought to be transmitted via the classical estrogen receptor alpha (for review: [48]). However, most of these genomic actions have been shown at high estrogen concentrations (Table 1), rendering the physiological and/or pharmacological relevance of some proposed mechanisms uncertain. Total 17β-estradiol levels of about 1 nmol/l are achieved in the late follicular phase of the menstrual cycle [49], while during cardioprotective HRT, only levels of ~0.1–0.4 nmol/l estradiol are measured [50, 51]. Considering a plasma protein binding of ~65%, approximately one third of total 17β-estradiol is active in vivo, a fact that is rarely considered in ex vivo or in vitro studies. It should be noted that the interpretation of study results with regard to effective concentrations of estradiol is difficult; discrepancies between in vivo and in vitro dose response relations may be explained to a certain extent by in vivo synergisms of hormones, or unknown factors. How divergent the active concentrations could be on those grounds is speculative, but it is hardly conceivable that estrogen action observed at 1 µmol/l in vitro should occur at 0.1 nmol/l in vivo via the same mechanisms.

Only recently, nongenomic, rapid vasodilatory actions of estrogens have been demonstrated. Oral 17β-estradiol administration was reported to have a beneficial effect on exercise-induced myocardial ischemia in postmenopausal women with angiographically documented CAD within 40 min [52]at total plasma concentrations of ~2.5 nmol/l. Gilligan et al. [53]demonstrated enhancing effects of short term 17β-estradiol infusion on acetylcholine-induced relaxation of coronary arteries in postmenopausal women with and without CAD. Notably, this effect was observed at mid-cycle estradiol concentrations and, thus, may be physiologically relevant (Table 1). Similar results have been obtained in a recent study demonstrating acute improvement of endothelium-dependent forearm blood flow [54].

The existence of direct nongenomic estrogen effects on vascular beds is further supported by in vitro studies using isolated organ and arterial segment preparations: 17β-estradiol causes rapid vasodilation in vasopressin-precontracted rabbit coronary arteries [55]and PGF2{alpha}-precontracted rat thoracic aortic segments [56]. Han et al. [57]demonstrated an instant inhibition of thromboxane-A2-induced Ca2+ influx by 17β-estradiol in porcine coronary arteries, suggesting calcium-dependent mechanisms of estrogen-induced vasodilation. Part of these effects may be explained by estradiol-induced inhibition of L-type and T-type Ca2+ channels [58, 59]. But again, these and other [60]experiments have to be extrapolated to in vivo conditions with restraint, since high doses had to be used (0.03–100 µmol/l). Although the inactive congener of estrogens, estradiol 17{alpha}, has been shown to be without effect in some studies [61], a nonspecific intercalation of steroids in the lipid bilayer of the cell membrane at high concentrations cannot be excluded as an underlying cause for these effects at high steroid concentrations. Changes in membrane fluidity may influence membrane protein function, as has been shown for various steroid hormones, including estrogens [62, 63]; effects at high steroid concentrations may be pseudospecific for certain steroids (e.g. 17β- vs. 17{alpha}-estradiol), mainly reflecting their lipophilicity and polarity. They depend on steroid–membrane interactions altering physicochemical membrane properties such as fluidity and the microenvironment of peptide membrane receptors [64, 65]. This, in turn, may affect receptor activation and signaling and, thus, cell function. For example, progesterone decreases membrane fluidity, leads to aggregation of membrane vesicles, induction of membrane vesicle fusion and also renders them permeable to hydrophilic molecules like carboxyfluorescein, as shown for membrane vesicles prepared from phosphatidylserine [65].

Collins et al. [66]reported a dose-dependent relaxation of rabbit coronary artery rings in response to exogenous 17β-estradiol in estrogen-deprived animals at a concentration as low as ~1 nmol/l 17β-estradiol. The controversy regarding the impact of acute estrogen action in cardioprotection of postmenopausal women is obvious in two studies by Gilligan et al. [51, 54]: Estradiol infusion achieving high physiological levels enhanced acetylcholine-stimulated forearm flow (endothelium-dependent in women without and endothelium-independent in women with cardiovascular risk factors), while HRT for three weeks with transdermal patches did not influence acetylcholine-stimulated responses compared with pretreatment studies. In contrast, studies by Lieberman et al. [67]demonstrated an improvement of endothelium-dependent, flow-mediated vasodilation in postmenopausal women after chronic estrogen replacement therapy. The contradictory results of Lieberman et al. [67]and Gilligan et al. [51]may be possibly explained by the use of different experimental protocols to measure endothelium-dependent vasodilation during chronic estradiol replacement therapy: While Gilligan et al. [51]determined microvascular responses to acetylcholine by assessment of forearm blood flow, Lieberman et al. [67]studied vasodilatory changes during reactive hyperemia in large arteries. These two studies demonstrate the limits of mechanistic interpretations of these results: Acute vascular effects of estrogens are attained in most studies at high doses only, but these concentrations are clearly not achieved during conventional HRT. These data rather question the conclusion that acute estrogen-induced vasodilation could be a major factor contributing to the beneficial effects of HRT, and the mechanisms of cardiovascular benefit by HRT still need further exploration.

With regard to molecular mechanisms involved in rapid estrogen actions [68, 69], steroid-specific, high affinity, low capacity membrane receptors may be involved [8], but, unlike aldosterone membrane binding sites, they have not yet been characterized in cardiovascular tissues: Pietras and Szego [70, 71]reported estrogen-specific binding sites in plasma membranes of myometrium and hepatocytes using a classical ligand–receptor binding assay. Recently, Pappas et al. [72]showed the presence of a membrane estrogen receptor on the surface of GH3/B6 rat pituitary tumor cells, using confocal laser scanning microscopy and immunolabeling (Fig. 4). In conclusion, both genomic estrogen receptor activation and nongenomic membrane effects seem to be involved in the cardiovascular effects of estrogens. An interrelation between these two mechanisms exists, in that genes regulating the production of prostacyclin and NO, potent vasodilators in the vasculature, can be genomically up-regulated by estrogens in a synergistic way, supporting direct nongenomic vasodilatory effects of estrogens. These data probably indicate a convergence of hormonal induction and regulation of endothelial genes and rapid, membrane-initiated events reflecting a ‘cross-talk’ between genomic effects through cytosolic/nuclear steroid receptors and steroid membrane effects [8].


Figure 4
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  		Fig. 4 Serial sections of GH3/B6 cells show that anti-estrogen-receptor antibody localizes with the perimeter of the cell, supporting evidence of a modified, intracellular estrogen receptor at the plasma membrane. A well-attached cell with punctate labeling and peripheral antigen localization is shown using five sections along the z-axis (1–5; A) and with a reconstructed image (B) rotated 30° from horizontal (reprinted with permission from Ref. [72]).

 
However, plasma concentrations of estrogens in studies demonstrating vasodilatory and antiproliferative effects of estrogens are rarely in the physiological range (Table 1) and are considerably higher than those achieved by conventional HRT. Mechanistic explanations of the beneficial effects of sex steroids regarding their ‘swift or sluggish’ ways of actions have, therefore, to be critically evaluated. The clinically more relevant situation is the chronic application of estrogens and, thus, genomic effects in general may be dominant. The contribution of nongenomic mechanisms will become obvious only with antagonists that are selective for either the nongenomic or the genomic effector at hand. With spironolactone, being active on the genomic effector of mineralocorticoid action only, nongenomic and genomic action may be differentiated in vitro and in vivo. However, a comparable selective inhibitor for estrogen action has not yet been identified.

2.2 Gestagens
Comparably little is known about cardiovascular progesterone action: Perrot-Applanat et al. [73]immunohistochemically detected progesterone receptors in the uterine vessel wall of rabbits and humans, and Ford et al. [74]demonstrated a progesterone-induced increase in {alpha}1-adrenoreceptor binding affinity in the uterine artery. Chronic progesterone treatment has also been shown to increase the number and density of Ca2+ channels in rat myometrial cells [75]. While these studies can be explained via genomic mechanisms, nongenomic mechanisms may be involved in dose-dependent reduction of calcium currents in a human intestinal smooth muscle cell line [76]. In addition, nongenomic mechanisms may explain progesterone-induced relaxation of endothelium-denuded rabbit coronary artery rings [77]that were preconstricted with a voltage-gated Ca2+ channel agonist. Again, micromolar concentrations of progesterone had to be used in these assays. Given these sparse data on vascular tissues, it should be mentioned that progesterone rapidly increases intracellular calcium in rat hepatocytes [78], inhibits Ca2+-induced contraction of uterine smooth muscle cells within 3 min of Ca2+ addition [79]and rapidly stimulates Ca2+-influx to human sperms [80]. As for rapid aldosterone effects, classical receptor antagonists are unable to block these rapid progesterone effects. A full-length cDNA sequence of a progesterone membrane binding protein from porcine VSMCs has been cloned recently in our laboratory [81, 82]. Ongoing studies on this first putative steroid membrane receptor, including its functional expression, will be essential to further characterize rapid nongenomic steroid actions in cardiovascular effector cells.

2.3 Androgens
In addition to their effects on plasma lipid levels [83], androgens and anabolic steroids probably exert direct actions on the vascular wall, which may be related to increases in cardiovascular morbidity and mortality during self-administration [84]. Farhat et al. [85]studied the effect of chronic testosterone administration on coronary vascular reactivity in pigs. Testosterone endothelium-dependently increased the maximum response of intact vessels to KCl and prostaglandins [85]. Comparable results were obtained by Ferrer et al. [84], who demonstrated an inhibition of the endothelium-dependent vasodilator response after chronic treatment with nandrolone due to an inhibition or downregulation of guanylyl cyclase. In addition, there are observations of rapid testosterone actions, as demonstrated in studies of Costarella et al. [86]in rat thoracic aortae and of Yue et al. [87]in rabbit coronary arteries and aorta in vitro: for example, testosterone instantly relaxes phenylephrine precontracted aortic rings and attenuated subsequent contractile responses to phenylephrine. However, again at steroid concentrations that high (>10 µmol/l), a nonspecific effect on membrane fluidity cannot be excluded [86], resulting in receptor-independent rapid steroid effects, e.g. on ion transport [64].

The cellular mechanisms underlying androgen effects on the vascular wall remain to be determined. Studies primarily conducted in nonvascular target cells (e.g. osteoblasts; [88]) support the idea that androgens can influence cardiovascular cell function through genomic as well as nongenomic mechanisms of action.


   3 Glucocorticoids
Top
 Abstract
 1 Mineralocorticoids
 2 Sex steroids
 3 Glucocorticoids
4 Conclusions
 References
 
Increased cardiovascular morbidity and mortality in Cushing's syndrome is considered to reflect hypertension, induced by excess levels of circulating glucocorticoids [89]. As early as 1954, changes in electrolyte composition and hormonal milieu were recognized to be involved in abnormalities of vascular reactivity in systemic hypertension [90]. Since glucocorticoids are known to affect plasma electrolyte concentrations and induce volume retention [91], it was thought that glucocorticoid-induced hypertension depends on indirect, renal mechanisms [92]. However, studies by Whitworth et al. [91]demonstrated increases in peripheral vascular resistance by glucocorticoids, while effects on central blood pressure regulation could be excluded. Kornel [2]showed classical intracellular mineralocorticoid and glucocorticoid receptors in VSMCs by binding assays, and increases of intracellular sodium and calcium by dexamethasone were shown at an EC50 similar to the Kd of the binding sites (~2x10–9 mol/l for dexamethasone; [2]).

Glucocorticoids sensitize VSMCs to peptide vasoconstrictors by genomic changes of receptor expression, particularly angiotensin II type 1 (AT) receptors [93, 94]. An increased expression of angiotensin-converting enzyme after glucocorticoid treatment may further contribute to vasoconstriction by angiotensin II [95]. While glucocorticoids increase vasoconstrictive actions of peptide agonists in VSMCs, reduced release of endothelial vasodilating substances, including NO or prostacyclin [96, 97], may be involved in glucocorticoid-induced hypertension. Glucocorticoid actions on the vascular wall seem to be mainly transmitted via genomic mechanisms. However, there is a study demonstrating a rapid glucocorticoid-induced rise in cardiac output and initial vasodilation, which is followed by an increase in peripheral vascular resistance and responsiveness to exogenous norepinephrine in healthy volunteers [98]. Although rapid effects of glucocorticoids in the treatment of acute adrenal insufficiency, anaphylaxis or septic shock are clinically appreciated [99], nongenomic actions of glucocorticoids on vascular reactivity will have to be revisited in this context.

In summary, genomic, ‘sluggish’ effects of glucocorticoids on the vascular wall are well documented by numerous in vivo and in vitro observations [2, 91]at physiological, pathophysiological and pharmacological plasma concentrations. They seem to be involved in glucocorticoid-induced hypertension and, probably, in essential hypertension [92], while reports on rapid glucocorticoid actions in vascular cells are yet rare and need further experimental exploration.


   4 Conclusions
Top
 Abstract
 1 Mineralocorticoids
 2 Sex steroids
 3 Glucocorticoids
 4 Conclusions
References
 
Vascular effects of steroids have been commonly understood to be secondary adaptations to effects on coagulation, vasoactive hormone homeostasis, and renal electrolyte and volume regulation. During recent years, direct steroid hormone actions on vascular cell function have been established, with particular reference to delayed genomic effects. In between, numerous studies have also clearly shown very rapid nongenomic steroid effects on endothelial cell and vascular smooth muscle cell functions, which cannot be explained by these genomic mechanisms. As both pathways are utilized concomitantly, it remains difficult to determine which mode of action is more relevant, the swift or the sluggish one. The theory of steroid action should include the interpretation of both aspects and their potential interaction. Therefore, an integrated two-step model of steroid action (Fig. 3; [8]) was proposed. Though originally developed for mineralocorticoids, it appears applicable to most steroids. This model describes (I) the nongenomic pathway of steroid action, which comprises steroid binding to membrane receptors, resulting in cellular signaling and functional changes, (II) steroid binding to intracellular steroid receptors, modulating nuclear transcription and (III) — as an unproven hypothesis — the interaction of both pathways, as there is increasing evidence for second-messenger-related modulation of steroid-induced transcriptional processes [100].

With regard to the physiological implications of steroid effects on the vascular wall, evidence has been accumulated during recent years describing beneficial (estrogens) or detrimental (glucocorticoids, mineralocorticoids, androgens) aspects of steroid action. Steroids seem to be involved in modulation and fine-tuning of vascular responsiveness to different vasoconstrictors [93, 94]and vasodilators [44, 45]. The importance of steroids in vasoregulation is further supported by a recent study, suggesting an increased glucocorticoid activity in essential hypertension and in men with cardiovascular risk factors [101]. Moreover, ‘escape’ of aldosterone plasma levels in chronic heart failure during therapy with angiotensin converting enzyme (ACE)-inhibitors [102]has been linked to increased cardiovascular risk. Treatment with aldosterone receptor antagonists, in addition to therapy with loop diuretics and ACE-inhibitors, is thought to attenuate symptoms and may reduce mortality in patients with chronic heart failure [103]. These results support the potential clinical relevance of deleterious cardiovascular actions of mineralo- and glucocorticoids, as opposed to beneficial effects of postmenopausal hormone replacement therapy [36, 39].

Although genomic steroid action is likely to represent the dominant pathway, nongenomic action on cardiovascular effector cells, being recognized only recently, deserves increased attention by the scientific community. The beneficial effect of acute 17β-estradiol administration in postmenopausal women with coronary artery disease [53]is an example for the potential clinical implications of acute steroid action and its relevance for cardiovascular diseases. However, the high concentrations of steroids often used in in vivo and in vitro studies have to be kept in mind, which are rarely achieved physiologically or by therapeutic interventions and may only induce nonspecific responses. Since specific nongenomic steroid actions are known for various steroids at concentrations within, or close to, the physiological range of plasma steroid levels, only such effects are likely to be involved in the regulation of physiological and pathophysiological processes. Thus, development of compounds inhibiting rapid steroid actions will not only help to understand the clinical relevance of nongenomic steroid action in vivo, but also introduce the possibility of completely blocking steroid actions, including the rapid ones with potential additional therapeutic benefit. This may e.g. include those spironolactone-insensitive, deleterious actions of aldosterone in a remnant kidney model, as shown by Greene et al. [35].

As steroids may be involved in entities such as hypertension at normal circulating plasma levels, modulation of cardiovascular steroid effects may become important even in diseases that are primarily thought to be unrelated to steroids.

Time for primary review 21 days


   Acknowledgements
 
The authors' studies summarized here have been supported by the Deutsche Forschungsgemeinschaft (We 1184/4-2; We 1184/6-1 and Sc 4/9-4). We thank Dr. Cheryl Watson (Department of Human Biological Chemistry and Genetics, University of Texas, Galveston) for providing us with Fig. 4.


   References
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 Abstract
 1 Mineralocorticoids
 2 Sex steroids
 3 Glucocorticoids
 4 Conclusions
 References
 

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