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Cardiovascular Research 1999 41(1):55-64; doi:10.1016/S0008-6363(98)00230-2
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

The role of corticosteroids in the regulation of vascular tone

Michael E Ullian*

Department of Medicine, Medical University of South Carolina, Clinical Sciences Building 829, 171 Ashley Avenue, Charleston, SC 29425, USA

* Tel.: +843-792-4122; fax: +843-792-8399; e-mail: ullianme@musc.edu

Received 11 February 1998; accepted 30 June 1998


   1 Introduction
Top
 1 Introduction
2 Corticosteroid receptors in...
 3 Potentiation of...
 4 Mechanisms of potentiation...
 5 Potentiation of...
 6 Acute vascular actions...
 7 Vascular hypertrophy
 8 Summary and integrated...
 References
 
Disease states resulting from excesses of circulating (adreno)corticosteroids include primary hyperaldosteronism, renal artery stenosis, ACTH-secreting tumors, and administration of glucocorticoids for treatment of other diseases. Hypertension is commonly associated with these diseases. Although renal sodium retention and intravascular volume overload contribute to the attendant hypertension, especially early in the course of the disease, a non-renal mechanism (increase in peripheral vascular resistance) is involved in the development and maintenance of hypertension. The concept of non-renal actions of corticosteroids in the development of hypertension stems from a seminal report in which Langford and Snavely [1]demonstrated that deoxycorticosterone acetate raised blood pressure in dogs and rats devoid of renal mass. In addition, corticosteroids in lesser amounts are essential for the maintenance of peripheral vascular resistance in healthy persons. This review details the proposed mechanisms by which corticosteroids maintain and, in excess, enhance vascular tone.


   2 Corticosteroid receptors in vascular smooth muscle
Top
 1 Introduction
 2 Corticosteroid receptors in...
3 Potentiation of...
 4 Mechanisms of potentiation...
 5 Potentiation of...
 6 Acute vascular actions...
 7 Vascular hypertrophy
 8 Summary and integrated...
 References
 
If corticosteroids indeed regulate vascular tone, vascular smooth muscle cells (VSMCs), the vasoactive element of the vasculature, should contain specific receptor molecules for corticosteroids. Classically, corticosteroid receptors are considered to be members of the steroid receptor superfamily of ligand-dependent transcription factors [2]. Radioligand binding studies have defined two distinct cytosolic corticosteroid receptors. Type I (mineralocorticoid) receptors bind with greatest affinity to aldosterone, deoxycorticosterone or corticosterone and with less affinity to the synthetic glucocorticoid dexamethasone. In contrast, type II (glucocorticoid) receptors bind with greatest affinity to dexamethasone and with less affinity to aldosterone, deoxycorticosterone or corticosterone. There is significant base sequence homology between these receptors. Corticosteroid receptors possess highly conserved regions that are necessary for ligand binding, receptor dimerization, nuclear translocation, DNA binding and transactivation (recruiting accessory proteins so that transcription will initiate). The genes for the rat [3, 4]and human [5, 6]mineralocorticoid receptor and the human [7]glucocorticoid receptor have been cloned and sequenced.

Ligand binding studies have documented the existence of both mineralocorticoid and glucocorticoid receptors in the cytosol of vascular tissue, both in freshly removed vessels [8]and in cultured VSMCs [9, 10]. In rabbits, receptors for mineralocorticoids were detected in vascular smooth muscle from aorta and pulmonary arteries but not from small vessels by immunohistochemistry [11]. Although membrane binding sites (rather than the classically described cytosolic receptors) for mineralocorticoids in the kidney and for glucocorticoids in the liver and pituitary have been demonstrated recently [12], the existence of membrane binding sites for corticosteroids in vascular tissue has not as yet been reported. In summary, ligand binding assays have demonstrated the presence of both glucocorticoid and mineralocorticoid receptors in the cytosol of vascular tissue. These are necessary findings to support the concept that corticosteroids regulate vascular tone.


   3 Potentiation of vasoconstrictor action by corticosteroids
Top
 1 Introduction
 2 Corticosteroid receptors in...
 3 Potentiation of...
4 Mechanisms of potentiation...
 5 Potentiation of...
 6 Acute vascular actions...
 7 Vascular hypertrophy
 8 Summary and integrated...
 References
 
A recurring theme in the support of vascular tone by corticosteroids has been potentiation of the action of vasoconstrictor hormones. Potent vasoconstrictor hormones that have been investigated include {alpha}-adrenergic agonists (norepinephrine), angiotensin II, arginine vasopressin, endothelin and thromboxanes.

3.1 {alpha}-Adrenergic agonists
In the 1950s, reports on the role of adrenal steroid hormones in supporting the vasoconstrictor actions of catecholamines began to appear. There are more data available on potentiation of catecholamine vasoconstrictors by corticosteroids than for any other vasoconstrictor hormone. In light of vascular collapse resulting from acute adrenal insufficiency, these studies were of extreme clinical interest. Fritz and Levine [13]observed that contractile sensitivity of mesenteric arteries in situ to norepinephrine were greatly reduced in adrenalectomized rats compared to adrenally intact rats and that topical application of a crude adrenal cortical extract restored the contractile sensitivity. A similar result was obtained in dogs, where contractile responses were assessed by increases in systemic blood pressure, and norepinephrine and adrenal extract were administered intravenously [14]. Sensitization to catecholamine-mediated contractions has also been observed after administration of specific glucocorticoids or mineralocorticoids rather than crude adrenal cortical extracts. After hydrocortisone was injected intravenously into dogs and cats, vascular resistance in isolated limb preparations in response to epinephrine was enhanced [15, 16].

Results from other studies have suggested that corticosteroids act directly on blood vessels in potentiating norepinephrine vasoconstrictor actions. Topical application of any of a number of glucocorticoids resulted in increased sensitivity of conjunctival vessels to topical norepinephrine [17, 18]. After hydrocortisone or corticosterone was added to rabbit aortic strips ex vivo (in a tissue bath), contractile responses to norepinephrine were greatly potentiated [19].

Corticosteroids enhance contractile responses to norepinephrine in humans. For example, Kurland and Freedberg [20]administered increasing doses of norepinephrine intravenously to three patients before and 24 h after initiation of glucocorticoid therapy and observed much greater pressor responses in the presence of corticosteroid than in the absence of corticosteroid. Similarly, normal males treated with ACTH or hydrocortisone for five days responded with much greater blood pressure increases to intravenous phenylephrine ({alpha}-adrenergic agonist) than did the same men prior to glucocorticoid stimulation [21]. After seven days of treatment of normal males with either the glucocorticoid dexamethasone or the mineralocorticoid fludrocortisone or neither, forearm vascular resistance to intra-arterial norepinephrine increased at much lower concentrations after the corticosteroid treatment period than after the control period [22].

A number of animal studies are consistent with those in humans. In pigs, increases in total peripheral resistance in response to intravenous norepinephrine after treatment with deoxycorticosterone acetate for seven days were greater than those from the pre-deoxycorticosterone period [23]. In rats, pressor responses to intravenous norepinephrine were potentiated as early as the second day of oral dexamethasone treatment [24]. Webb and collaborators [25–27]have performed a series of studies on rats treated with salt and deoxycorticosterone for four–six weeks, after which, mesenteric arteries were removed and studied in an organ bath; consistently, vessels from treated rats contracted to lower concentrations of norepinephrine than did vessels from untreated animals. Similar results were reported by other investigators treating rats with deoxycorticosterone and salt [28–31].

Studies on the enzyme 11β-hydroxysteroid dehydrogenase in vascular smooth muscle have further emphasized the role of glucocorticoids in enhancing the vasoconstrictor and hypertensinogenic properties of norepinephrine. In the kidney, 11β-hydroxysteroid dehydrogenase catalyzes the conversion of the endogenous glucocorticoid cortisol (corticosterone in rats) to the less active metabolite cortisone (11-dehydrocorticosterone in rats), thus allowing the less abundant aldosterone to gain access to its receptor [32]. 11-Dehydrocorticosterone has been shown to be less active than corticosterone in binding to mineralocorticoid and glucocorticoid receptors [32], to be less active than corticosterone in potentiating angiotensin II action [33]and to be a vasodepressor substance [34]. The presence of 11β-hydroxysteroid dehydrogenase in vascular tissue has been documented [35–37]. It has been suggested that inhibitors of 11β-hydroxysteroid dehydrogenase allow local concentrations of endogenous glucocorticoids to accumulate, which then enhance the vasoconstrictor actions of endogenous catecholamines [38–40]and raise blood pressure [41, 42].

Despite the large number of studies demonstrating enhancement of catecholamine-stimulated vascular contraction by corticosteroids, several studies do not report this enhancement. The concentration of the {alpha}-adrenergic agonist phenylephrine for threshold tension development and the maximal response to phenylephrine in carotid arteries and aortic rings were not different in control and dexamethasone-treated rats [43]. Similarly, contractions to norepinephrine in mesenteric artery segments from rats treated with deoxycorticosterone acetate and salt were not different from those from control animals [44]. Treatment of isolated rabbit ear arteries with dexamethasone caused 50% reductions in contractions to norepinephrine [45].

3.2 Angiotensin II
For the most part, glucocorticoids and mineralocorticoids have been reported to enhance the vasoconstrictor actions of angiotensin II. As with norepinephrine-stimulated responses, angiotensin II-stimulated increases in total peripheral resistance were greater in pigs treated with deoxycorticosterone than in untreated pigs [23]. Blood pressure responses to intravenous angiotensin II were greater in rats treated with deoxycorticosterone and 0.9% saline than in rats treated with saline alone [30]. Contractions of isolated, perfused mesenteric arteries to angiotensin II were significantly greater if harvested from rats treated with deoxycorticosterone and salt than from control animals [29]. In humans, treatment for seven days with dexamethasone or fludrocortisone potentiated forearm vascular resistance to intra-arterial angiotensin II [22]. In contrast, pressor responsiveness to angiotensin II was not altered by five days of treatment with ACTH or hydrocortisone [21].

3.3 Others vasoconstrictors
Although the predominance of the evidence suggests that corticosteroids enhance the vasoconstrictor actions of norepinephrine and angiotensin II, potentiation of the actions of other vasoconstrictors is less clear. Compared to control animals, dexamethasone-treated animals displayed reduced contractions to the thromboxane mimetic U46619 [GenBank] in carotid arteries and aortic segments [43].

The scientific literature is conflicting as to whether or not corticosteroids enhance vascular contractions to vasopressin and thus contribute to hypertension. Several studies demonstrate that corticosteroids do not heighten vasopressin-stimulated vasoconstriction. Contractile sensitivity of mesenteric artery segments to arginine vasopressin was reduced in deoxycorticosterone—salt-treated rats compared with control rats [44], and contractile sensitivity of rat tail arteries was not enhanced by prior treatment with deoxycorticosterone and salt [46]. In contrast, deoxycorticosterone—salt treatment of rats augmented the responses of isolated mesenteric arteries to lysine vasopressin [29], glucocorticoids increased steady state levels of mRNA for vasopressin type-1 receptors in cultured VSMCs [47], and the specific vasopressin type-1 receptor antagonist OPC-21268 reversed deoxycorticosterone—salt hypertension in rats [48]. It is also possible that non-vascular mechanisms, such as the enhancement of sodium reabsorption by vasopressin in the kidney, contribute to corticosteroid-excess hypertension [49].

3.4 Differences in corticosteroid effects in regional vasculature
It is possible that differences in responses to corticosteroids in vascular beds in different parts of the body may explain the above-mentioned discrepancies. In rats treated with deoxycorticosterone acetate and salt for five weeks, the developing hypertension was accompanied by increased pressor responses to intravenously administered angiotensin II and by increased contractile responses of the isolated hindquarter to angiotensin II; in contrast, contractions of the thoracic aorta and the portal vein to angiotensin II were not enhanced by the chronic corticosteroid treatment protocol [30]. In sheep exposed to aldosterone for five days, blood pressure and mesenteric artery resistance became elevated, but renal, coronary and iliac resistances did not become elevated [50]. Deoxycorticosterone–salt therapy supersensitized conductance vessels (carotid) and desensitized resistance vessels (mesenteric) to phenylephrine [51].


   4 Mechanisms of potentiation of vasoconstrictor action by corticosteroids: upregulation of vasoconstrictor receptors in vascular smooth muscle
Top
 1 Introduction
 2 Corticosteroid receptors in...
 3 Potentiation of...
 4 Mechanisms of potentiation...
5 Potentiation of...
 6 Acute vascular actions...
 7 Vascular hypertrophy
 8 Summary and integrated...
 References
 
Despite the existence of a few dissenting studies, most evidence supports the fact that corticosteroids potentiate the vasoconstrictor actions of norepinephrine and angiotensin II. Therefore, more recent studies have been performed to investigate the mechanisms of this potentiation. Because the proximate event in vasoconstrictor action is binding of vasoconstrictor hormones to their specific receptor molecules on the surface of VSMCs, a number of studies have been designed to investigate the possibility that corticosteroids upregulate vasoconstrictor hormone binding. Since corticosteroids are transcription factors, it is possible that they induce synthesis of receptors for vasoconstrictors. Coupling of these new receptors to the signal transduction pathway that mediates cell contraction might be involved in the potentiation of vasoconstrictor action by corticosteroids.

4.1 Corticosteroid effects on receptors for {alpha}-adrenergic agonists
Based upon indirect pharmacological analysis, several early investigations suggested that glucocorticoids act on adrenergic receptors to potentiate the vascular actions of catecholamines [16, 52]. Webb and collaborators [26, 27]suggested that receptor number might be increased and binding affinity unchanged. Radioligand binding and molecular studies were performed more recently in attempts to address this issue more directly. After treatment of rats with deoxycorticosterone and salt for four–six weeks, arteries were removed and subjected to ligand binding studies for the {alpha}-1 adrenergic receptor. Although receptor density in mesenteric arteries was increased by 150% in the corticosteroid-treated animals, binding affinity was reduced by 50% [53]. It is likely that the reduced binding affinity would greatly offset the increase in receptor density. In another study of femoral arteries, receptor density and binding affinity were not increased by deoxycorticosterone–salt treatment [54]. Adrenalectomy decreased {alpha}-1 adrenergic receptor density and increased binding affinity in rat aorta [55]. In uninephrectomized rats treated with aldosterone via osmotic mini-pump for two weeks, neither receptor density nor binding affinity for the {alpha}-1 adrenergic receptor was increased [56]. Treatment of cultured DTT1 MF-2 VSMCs with dexamethasone for 48 h resulted in an increased rate of transcription of the {alpha}1B adrenergic receptor gene and, in consequence, a 2.8-fold increase in steady state mRNA levels [57]. These data are conflicting and do not, in the aggregate, support the concept that upregulated {alpha}-adrenergic receptor binding mediates the potentiation of {alpha}-adrenergic-mediated vasoconstriction by corticosteroids.

4.2 Corticosteroid effects on receptors for angiotensin II
In contrast to {alpha}-adrenergic receptors, angiotensin II receptors appear to be upregulated by corticosteroids. Schiffrin et al. [58, 59]provided the initial reports in this area. After rats were treated with deoxycorticosterone and salt for two weeks, mesenteric arteries were removed for ligand binding with 125I-angiotensin II. Scatchard analysis of binding data revealed a significant increase in receptor density, but no change in binding affinity. Similarly, treatment of rats for six days with aldosterone via osmotic minipump resulted in upregulation of mesenteric artery angiotensin receptor density [60]. In this same study, 18-h exposure of VSMCs cultured from mesenteric arteries to aldosterone also resulted in significant angiotensin II receptor density upregulation.

Ullian et al. [61–63]expanded upon upregulation of angiotensin II receptors by corticosteroids in cultured VSMCs. Any of a number of glucocorticoids and mineralocorticoids elicited concentration- and time-dependent (onset at 4 h, maximum effect at 24 h) increases in angiotensin II radioligand binding that was attributable to receptor density but not binding affinity. Increases in receptor density correlated closely with increases in angiotensin II-stimulated intracellular responses (inositol phosphate formation, diacylglycerol formation, cytosolic calcium mobilization), suggesting that angiotensin II surface receptors are tightly coupled to the intracellular signal transduction pathway that mediates cell contraction. The coupling of angiotensin II receptor density to angiotensin II-stimulated second messenger formation has been corroborated [64]and refuted [65]. The time frame to upregulation (>4 h) is consistent with the classical actions of corticosteroids as transcription factors. Several studies have demonstrated, using non-peptide antagonists, that the vast majority of angiotensin II receptors in cultured VSMCs are angiotensin type 1 (AT1) rather than AT2 receptors and that corticosteroids upregulate AT1 receptors exclusively [62, 66]. Along these lines, dexamethasone increased steady state levels of mRNA for the angiotensin II AT1 receptors by more than two-fold after 30 min and by almost eight-fold after 24 h [66], studies made possible by the prior isolation of a cDNA encoding for this subtype of angiotensin II receptor [67]. The AT1 receptor is the angiotensin II receptor subtype linked via G-protein to the phospholipase C signal transduction pathway. Investigation of the promotor region of the AT1 receptor gene demonstrates three glucocorticoid response elements [68].

Unlike angiotensin receptors, endothelin receptors in mesenteric arteries are downregulated in deoxycorticosterone–salt animals compared to controls [69]. Second messenger responses (inositol phosphate, intracellular calcium concentration, diacylglycerol) to endothelin were depressed in the mineralocorticoid-treated animals, thus correlating the response to exogenous endothelin with the endothelin receptor density [70]. It is possible that enhanced expression of the endothelin-1 gene and resulting increases in endothelin-1 levels by deoxycorticosterone [71]are responsible for the downregulation of endothelin receptors in this experimental setting.


   5 Potentiation of vasoconstrictor action by corticosteroids: non-receptor mechanisms
Top
 1 Introduction
 2 Corticosteroid receptors in...
 3 Potentiation of...
 4 Mechanisms of potentiation...
 5 Potentiation of...
6 Acute vascular actions...
 7 Vascular hypertrophy
 8 Summary and integrated...
 References
 
Although the potentiation of angiotensin II-mediated vasoconstriction correlates with increased angiotensin II receptor density in animals treated with corticosteroids, the same relationship does not hold for {alpha}-adrenergic agonists and their receptors. Therefore, potentiation of catecholamine action by corticosteroids through non-receptor mechanisms was postulated. Corticosteroids may potentiate angiotensin II action not only through its surface receptors but also through non-receptor targets.

5.1 Corticosteroid targets external to the VSMCs
Neither excessive catecholamine stores in nerve terminals nor attenuated uptake of catecholamines back into these terminals was found to be involved in the potentiation of vascular catecholamine action by hydrocortisone [52], findings confirmed more recently by others [28]. Several studies have demonstrated that glucocorticoids increase the formation of angiotensinogen. In an early report, treatment of rats with cortisol resulted in an increase in the rate of angiotensinogen formation, as measured in the perfusate from the liver [72]. More recently, this report has been confirmed by molecular biological techniques [73–75]. Similarly, induction of angiotensin converting enzyme and increased angiotensin converting enzyme activity by glucocorticoids have been reported, both in endothelial cells [76, 77]and VSMCs [77, 78]. By intervening at the level of the precursor molecule or the processing enzyme, glucocorticoids could foster increased formation of angiotensin II, increased occupancy of angiotensin II receptors, and more intense vasoconstriction.

The influence of corticosteroids on the endothelial cell, which is juxtaposed to the VSMCs, may also impact upon vasoreactive responses to constrictors. In rats treated with deoxycorticosterone acetate and salt, endothelium-dependent relaxation of aortic segments to acetylcholine was blunted [79], suggesting that abnormal endothelium-dependent vasodilation contributes to increased peripheral vascular resistance in states of corticosteroid excess. It was unclear from this study if the endothelial abnormality was caused by the excess mineralocorticoid or by the resulting hypertension. Handa et al. [24]reported that oral dexamethasone treatment of rats resulted in heightened pressor responses to norepinephrine, resulting from a reduced synthesis of the vasodilator prostanoid prostaglandin E2 (PGE2). The source of the PGE2 was not elucidated, but the endothelium is most likely. In contrast, other studies have demonstrated that enhanced vasoreactivity of mesenteric vessels to norepinephrine in deoxycorticosterone–salt-treated rats was primarily a VSMC phenomenon and that the endothelium was compensatory in obscuring this effect [80]. Similarly, others have suggested that the corticosteroid-mediated increase in vascular reactivity can only be appreciated when the endothelium is removed [44]. The arterial kallikrein system may be part of this compensatory pathway [81]. White et al. [51]suggest that both of the above-mentioned endothelial mechanisms (enhanced and diminished endothelium-dependent relaxation) are in action simultaneously in mineralocorticoid-treated animals. In conductance vessels, deoxycorticosterone and salt cause hypersensitivity to phenylephrine because of the loss of endothelium-derived, nitric oxide-dependent relaxation, whereas in resistance vessels, deoxycorticosterone and salt cause a reduced sensitivity to phenylephrine through an endothelium-derived, non-nitric oxide-dependent mechanism.

5.2 Corticosteroid targets within VSMCs
The classical vasoconstrictor signal transduction pathway within VSMCs is initiated by binding of hormones to their specific surface receptor molecules. This signal is transduced through G-proteins (Gq), membrane ion channels, phospholipase C, inositol trisphosphate, diacylglyclerol, intracellular calcium concentration, protein kinase C, calmodulin and contractile proteins. The effects of corticosteroids on a number of these sites have been investigated.

Sato et al. [66]determined, by immunoblotting, that the amount of Gq protein (which links vasoconstrictor receptors to phospholipase C) was not altered by dexamethasone treatment of cultured VSMCs. In another study, Gi was decreased and Gs was increased in rat aorta after adrenalectomy, and dexamethasone reversed these effects [82]. These same investigators suggested that glucocorticoids are necessary for the coupling between {alpha}-1 adrenergic receptors and G-proteins [55]. In femoral arteries from deoxycorticosterone–salt-treated rats, inositol phosphate responses to norepinephrine were significantly greater than those from control animals despite the fact that receptor density for norepinephrine ({alpha}1 adrenergic receptors) was not upregulated [54]. These data strongly support the concept that there are post-receptor targets for corticosteroids in potentiating vasoconstrictor action. Contractions of mesenteric artery strips [83]and aortic strips [84]from deoxycorticosterone–salt-treated rats in response to protein kinase C activators (phorbol esters) were greater than contractions in non-corticosteroid-treated (control) animals, suggesting that the corticosteroid target is quite distal in the vasoconstrictor signal transduction pathway.

Exposure of vessels or cultured VSMCs from rat or rabbit to dexamethasone or cortisol resulted in concentration-dependent stimulation of endothelin release [71, 85]. Glucocorticoids could enhance vascular tone by causing the vasculature to release this potent vasoconstrictor in an autacoidal fashion. Vasodilators endogenous to VSMCs may also be inhibited by corticosteroids as a mechanism to enhance vascular tone. In cultured rat VSMCs, interleukin 1β-inducible nitric oxide synthase was inhibited by aldosterone [86]. Similarly, the glucocorticoid dexamethasone has an inhibitory effect on inducible nitric oxide synthase in VSMCs [87, 88].

Corticosteroid effects on ion transport have also been reported. VSMC membrane potential, which is important for the opening of membrane calcium and other ion channels, was not altered by hydrocortisone [52]. Data from studies in rats treated with deoxycorticosterone acetate and salt suggested that increased vascular sensitivity to norepinephrine followed from increased release of calcium from intracellular stores [25, 27]. Consequently, altered calcium handling from aldosterone–salt treatment may enhance potassium efflux associated with hypertension [89]. In a cultured VSMC line, 48 h treatment with dexamethasone resulted in increased calcium uptake and [3H]dihydropyridine binding [90]. It was concluded from this study that glucocorticoids might induce the synthesis of new membrane channels for calcium. Similarly, calcium uptake by aortic segments from rabbits made hypertensive by chronic treatment with dexamethasone was greatly increased [91]. Despite these findings suggesting that corticosteroids alter calcium handling to increase vascular tone, three studies have demonstrated that chronic treatment of animals or isolated vessels with corticosteroids did not enhance contractions to KCl, a contractile agent that functions by depolarizing VSMC membranes and opening calcium channels [43, 44, 63].

A number of studies have reported increased sodium transport in corticosteroid-treated animals. Since vasoconstrictors were not administered to stimulate sodium transport in these studies, direct effects of corticosteroids on sodium transport can be inferred. Even in the prehypertensive phase of deoxycorticosterone–salt treatment (two weeks), increased fluxes of sodium and chloride in intact aorta were observed [92]. Other studies were performed in cultured VSMCs. In a series of studies by Kornel et al. [93, 94], corticosteroid treatment of cultured VSMCs resulted in enhanced sodium influx by a mechanism that required at least 4 h, was inhibited by inhibitors of protein synthesis and involved an increased number of sodium–proton exchangers. These studies support the classical concept of corticosteroid-induced gene induction in enhancing vascular sodium transport. Exposure to aldosterone or dexamethasone for a number of hours resulted in increases in the mRNA levels for the {alpha}1 and β1 isoforms of Na–K-ATPase [95, 96], and dexamethasone increased ouabain-sensitive 86Rb uptake, i.e., Na–K-ATPase activity [97]. It has also been suggested that vascular sodium and chloride accumulation in deoxycorticosterone–salt-treated rats results from enhancement of the Na–K–2Cl co-transporter [98, 99].


   6 Acute vascular actions of corticosteroids
Top
 1 Introduction
 2 Corticosteroid receptors in...
 3 Potentiation of...
 4 Mechanisms of potentiation...
 5 Potentiation of...
 6 Acute vascular actions...
7 Vascular hypertrophy
 8 Summary and integrated...
 References
 
In the studies outlined above, the time course for corticosteroids to potentiate vascular tone or to allow catecholamines to potentiate vascular tone has been in the range of hours to days. This time course is concordant with the classical properties of corticosteroids as transcription factors, i.e., inducers of new protein synthesis. However, closer perusal of the older literature reveals a number of reports of more acute vascular actions of corticosteroids, and a body of exciting newer reports is consistent with this concept.

Ten minutes after intravenous treatment of dogs and cats with hydrocortisone, pressure responses to epinephrine in isolated limbs were enhanced [15, 16]. Moura and Worcel [100]reported that aldosterone stimulated sodium efflux from an intact rat tail vein segment within 5 min. Recently, rapid (less than 5 min) responses to corticosteroids, such as activation of the sodium–proton exchanger [101], stimulation of inositol phosphates [102]and cytosolic calcium mobilization [103], have been documented in cultured VSMCs and other cell types by Wehling and colleagues. These responses were observed at very low concentrations of mineralocorticoids and at much higher concentrations of glucocorticoids, thus demonstrating specificity for mineralocorticoids. Based on these data, the presence of membrane receptors for mineralocorticoids was suggested but has not as yet been documented. If surface receptors for mineralocorticoids do indeed exist, they are a novel subtype, since the classical mineralocorticoid receptor antagonist canrenone did not inhibit these rapid responses to aldosterone.


   7 Vascular hypertrophy
Top
 1 Introduction
 2 Corticosteroid receptors in...
 3 Potentiation of...
 4 Mechanisms of potentiation...
 5 Potentiation of...
 6 Acute vascular actions...
 7 Vascular hypertrophy
8 Summary and integrated...
 References
 
Corticosteroids may increase vascular tone by trophic effects, i.e., hypertrophy or hyperplasia of VSMCs. More VSMCs or larger VSMCs in a given vessel may allow enhanced contractile responses to angiotensin II or norepinephrine. Schiffrin et al. [71]have hypothesized that the enhanced expression of the endothelin-1 gene by mineralocorticoids mediates the vascular hypertrophy observed in rats treated with deoxycorticosterone and salt [104, 105]. However, vascular hypertrophy is not the sole mechanism of enhanced vascular tone by corticosteroids. Several studies [15, 16, 19, 63]have demonstrated that exposure of animals or isolated vessels to corticosteroids for 24 h or less, a time frame that is insufficient for vascular hypertrophy, results in enhanced vasoconstrictor responses to {alpha}-adrenergic agonists or angiotensin II.

The results of a number of studies have been used to argue against the concept that corticosteroids foster vascular hypertrophy. Consistently, glucocorticoids inhibit growth of VSMCs in culture [106–108]. In a more physiological setting, topically applied dexamethasone suppressed the neointimal hyperplasia resulting from balloon injury in carotid arteries of the rat [109]. Despite the direct effects of glucocorticoids to suppress the growth of VSMCs, corticosteroids may enhance growth through potentiation of the action of other hormones. For example, in cultured VSMCs, angiotensin II-mediated protein synthesis was enhanced by prior incubation with aldosterone, most likely due to increased signal transduction coupled to an increased number of angiotensin II surface receptors [110]. Along the same lines, blood vessels themselves have been reported to synthesize aldosterone [111], and angiotensin II-stimulated hypertrophy of VSMCs was attenuated by a mineralocorticoid receptor antagonist [112]. Similarly, exposure of cultured fibroblasts to dexamethasone resulted in potentiation of epidermal growth factor-induced growth and an increased number of binding sites for epidermal growth factor [113].


   8 Summary and integrated approach to the problem
Top
 1 Introduction
 2 Corticosteroid receptors in...
 3 Potentiation of...
 4 Mechanisms of potentiation...
 5 Potentiation of...
 6 Acute vascular actions...
 7 Vascular hypertrophy
 8 Summary and integrated...
References
 
From the above review, one can see that corticosteroids foster hypertension not only by enhancing renal sodium reabsorption but also by augmenting vascular tone. Corticosteroids augment vascular tone by potentiating the actions of vasoconstrictor hormones and by direct actions on VSMCs that are independent of vasoconstrictor hormones. In Table 1, potential sites at which corticosteroids might interact with the vasculature to augment vascular tone are listed and scored for relative importance. So many individual sites of action and mechanisms of action have been postulated that creating an integrated picture of such mechanisms is difficult. Future studies on two important issues (acute versus chronic effects of corticosteroids, glucocorticoid versus mineralocorticoid effects) may ameliorat this lack on integration. These issues are touched upon here.


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  		Table 1 Potential biochemical sites and processes by which corticosteroids might enhance vascular tone

 
The observation of rapid responses (seconds) to mineralocorticoids upon binding to membrane receptors on VSMCs has given rise to a new concept in mineralocorticoid biology [103]. By such a mechanism, mineralocorticoids mimic peptide hormones. If and how this acute action at the plasma membrane interacts with or modulates the more classical action of corticosteroids as transcription factors over a longer time frame (hours) is totally unknown. It is certainly possible that the acute actions of mineralocorticoids may potentiate the later, genomic actions of mineralocorticoids and glucocorticoids. Although the classical actions of corticosteroids have been characterized in details over the past four decades and the acute membrane actions of mineralocorticoids are being characterized at present, the nature of their interaction is unclear but of significant interest. It is intriguing that acute membrane responses to corticosteroids are specific for mineralocorticoids rather than glucocorticoids, whereas cytosolic effects of corticosteroids appear to be mediated through glucocorticoid receptors rather than mineralocorticoid receptors (see below).

A second complex issue is distinguishing between glucocorticoids and mineralocorticoids in enhancing vascular tone by the classical steroid hormone motif. The predominance of the evidence suggests that glucocorticoids and glucocorticoid receptors are more important than mineralocorticoids and their receptors in enhancing vascular tone. Yagil and Krakoff [114]demonstrated that, in adrenalectomized rats, replacement with dexamethasone restored pressor responses to angiotensin II to normal, whereas replacement with aldosterone did not. Despite the fact that mineralocorticoids can bind to both mineralocorticoid receptors and glucocorticoid receptors and that glucocorticoids can bind to both glucocorticoid receptors and mineralocorticoid receptors [2], the receptor density of glucocorticoid receptors appears to be 20–30-fold greater than that of mineralocorticoid receptors in vascular tissue [10]. Also, Provencher et al. [115]observed that the specific glucocorticoid receptor antagonist RU38486 prevented either aldosterone or dexamethasone from upregulating angiotensin II receptor density.

Time for primary review 31 days.


   References
Top
 1 Introduction
 2 Corticosteroid receptors in...
 3 Potentiation of...
 4 Mechanisms of potentiation...
 5 Potentiation of...
 6 Acute vascular actions...
 7 Vascular hypertrophy
 8 Summary and integrated...
 References
 

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