Mineralocorticoid Receptors in Myocardial Infarction
In this issue of Hypertension, Mihailidou et al1 provide important new information regarding the role of corticosteroids in myocardial infarction (MI). These findings are timely and of particular relevance because mineralocorticoid receptor (MR) antagonists are now thought to be among the first drugs used for treatment after MI along with angiotensin-converting enzyme inhibitors, β-blockers, and aspirin. The authors found in an ex vivo model of regional myocardial ischemia (30 minutes) followed by reperfusion with Krebs-Henseleit buffer (2.5 hours) that aldosterone or cortisol infusion could increase infarct size. These effects were blocked by spironolactone, suggesting that both of these corticosteroids act to promote damage through MR stimulation. Dexamethasone and mifepristone (RU486), a glucocorticoid receptor (GR)/progesterone receptor antagonist, also increased infarct size, and, surprisingly, both of these effects were reversed by spironolactone as well. However, spironolactone alone had a protective effect against reperfusion injury in the absence of aldosterone or cortisol infusion suggestive of a direct, inverse agonist action. The ability of spironolactone to decrease baseline infarct size was maintained in hearts from animals that were adrenalectomized 2 to 5 days earlier and provides strong evidence that the mechanism of the protective effect of spironolactone is not dependent on the presence of endogenous corticosteroids. These studies expand our view on the role of corticosteroids in end-organ damage and how MR antagonists may work to provide cardiac protection.
The present study is consistent with the observations of Dorrance et al,2 who found that spironolactone treatment reduced the size of cerebral infarcts in stroke-prone spontaneously hypertensive rats subjected to permanent middle cerebral artery occlusion. Triphenyl-tetrazolium chloride staining was used to assess viable tissue in both of these studies. Several studies have described the ability of chronic in vivo treatment with spironolactone to diminish myocardial fibrosis in response to MI.3,4 However, the results of the present study indicate comparatively early ex vivo effects of corticosteroids to enhance tissue injury and apoptosis in response to myocardial ischemia and the ability of spironolactone to oppose these effects and maintain tissue viability. In addition, these results support direct effects on cardiac tissue.
In general, acute MI is thought to be a proinflammatory state, and aldosterone has been shown to have proinflammatory activity. Studies by Rebsamen et al4 have shown that aldosterone applied to cultured cardiac myocytes can provoke increases in inflammatory cytokines and that this action could be blocked by spironolactone but not RU486. However, the present studies were conducted in isolated hearts perfused with cell-free medium, thus minimizing any participation of an immune-cell response. Indeed, the authors also demonstrated that Tempol has direct cardioprotective effects, implicating the importance of limiting free radical formation to the beneficial effects observed in their studies.
Inverse Agonist Activity
To explain the beneficial effects of spironolactone in the absence of corticosteroid infusion in their study, the authors suggested that spironolactone may also function as an inverse agonist at the MR. Agents such as olmesartan and β-carbolines have been described previously as inverse agonists at the angiotensin II type 1 receptor and the benzodiazepine receptor, respectively. An inverse agonist, or negative antagonist, is a compound that binds to a receptor and produces changes opposite to those produced by other agonists.5 Implicit in this definition is that the receptor is constitutively active in the absence of the agonist. The conditions under which an inverse agonist can best be characterized are in vitro, where responses independent of the presence of any agonist can be obtained. Such data are available for spironolactone. Chun et al6 found that spironolactone induced integrin-β protein expression in cultured rat cardiomyocytes and A6 cells, whereas aldosterone diminished integrin-β protein expression in both of these cell types. These results indicate a direct inductive response to spironolactone opposite to that of aldosterone and, thus, are consistent with an inverse agonist effect of spironolactone. The findings of Mihailidou et al1 would suggest that this effect of spironolactone may be extended to the whole-organ situation. It is tempting to speculate that, under conditions of increased free radical formation, as occurs during ischemia reperfusion injury, there may not only be increased transactivation of the MR but also increased constitutive activity of the MR. As inverse agonist activity appears to be a unique feature of drugs, even within a drug class, it will be of great interest to determine whether eplerenone or other MR antagonists share this pharmacological property with spironolactone.
Adverse Glucocorticoid Effects
Another finding made in this study is that glucocorticoids may have adverse effects on reperfusion injury not only at the level of the MR but also at the level of the GR. Thus, it was not only found that cortisol administration worsens reperfusion injury and that this effect could be blocked by spironolactone but that dexamethasone could also aggravate ischemia reperfusion injury and that this effect could be blocked by spironolactone. The interpretation of the latter finding is complex. However, in view of the low affinity of dexamethasone for the MR, one interpretation might be that the ability of spironolactone to antagonize the effect of dexamethasone reflects an inverse agonist effect of spironolactone at the MR superimposed on an agonist effect of dexamethasone at the GR. The adverse response to RU486 remains an enigma but perhaps is attributable to an inverse agonist effect at the GR or somehow relates to effects at the progesterone receptor. The possibility that glucocorticoids may accelerate the progression of chronic renal disease led Quan et al7 to investigate the effects of adrenalectomy on renal ablation nephropathy in the rat. They found that renal histopathologic damage was markedly improved when the adrenal glands were absent but that this beneficial effect could not be reversed by replacement with either low or high doses of corticosterone. These findings suggested that some substance produced by the adrenal glands, other than corticosterone, was responsible for renal ablative nephropathy. Unfortunately, aldosterone replacement was not examined.
In general, glucocorticoids have anti-inflammatory activity and have been used therapeutically in patients with brain injury to reduce cerebral edema. Indeed, glucocorticoids decrease renal injury and are widely used to treat various forms of glomerular disease in humans. Kawamura et al8 studied the effects of methylprednisone on the renal injury in response to intrarenal arterial infusion of H2O2 or puromycin aminonucleoside injection. They found a therapeutic effect of glucocorticoid administration that was largely attributed to enhancement of glomerular antioxidant enzyme activities, which attenuates lipid peroxidation of glomerular tissue. Interestingly, despite the proinflammatory effects of aldosterone and the anti-inflammatory effects of glucocorticoids, both of these corticosteroids administered in vivo can produce hypertension, indicating that their effects are not always opposite. Thus, the finding in this study that glucocorticoids can increase cardiac damage through a GR mechanism during ischemia reperfusion is not entirely unexpected and may in part reflect the experimental conditions, which include the absence of inflammatory cells.
Aldosterone Synthase Inhibition: The Importance of Aldosterone
The studies described put great emphasis on MR stimulation in transducing end-organ damage and shed new light on how spironolactone may antagonize this effect. However, the importance of aldosterone, per se, must not be overlooked. Numerous studies using a variety of experimental pathological conditions point to remarkable target-organ protection as a consequence of adrenalectomy.9 Unlike spironolactone, however, such dramatic end-organ protection with adrenalectomy cannot be ascribed to an inverse antagonist effect. In addition, adrenalectomy studies typically use glucocorticoid replacement and, as referred to above,6 with little impact on the recreation of target-organ damage. In contrast, aldosterone replacement in the face of adrenalectomy typically results in recapitulation of target-organ damage to, or even worse than, the sham-operated control condition. Although previous reports indicate significant myocardial production of aldosterone,3 more recent studies indicate that the majority of aldosterone found in cardiac tissue is derived from the circulation10 and is consistent with the ability of adrenalectomy to produce impressive end-organ protective effects. Studies with aldosterone synthase inhibitors further support the importance of aldosterone in target-organ damage.11 These agents inhibit the formation of aldosterone but do not block the synthesis of glucocorticoids and, thus, leave the latter available for interaction with the MR and yet can provide substantial target-organ protection. Thus, in vivo, the importance of aldosterone is not overshadowed by glucocorticoids, as evidenced by the ability of aldosterone synthase inhibitors, which decrease aldosterone levels but not corticosterone/cortisol levels, to provide target-organ protection. This is not to say that glucocorticoids can never elicit adverse effects through the MR or GR, because this is clearly demonstrated in the present study. However, the relative importance of the mechanisms described in eliciting these effects may vary in different tissue types and pathological conditions and will require further elucidation.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Mihailidou AS, Le TYL, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension. 2009; 54: 1306–1312.
Dorrance AM, Osborn HL, Grekin R, Webb RC. Spironolactone reduces cerebral infarct size and EGF-receptor mRNA in stroke-prone rats. Am J Physiol Regulatory Integrative Comp Physiol. 2001; 281: R944–R950.
Ross EM. Pharmacodynamics: mechanisms of drug action and the relationship between drug concentraton and effect. In: Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw Hill; 2008: 20–41.
Chander PN, Rocha R, Ranaudo J, Singh G, Zuckerman A, Stier CT. Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP. J Am Soc Nephrol. 2003; 14: 1990–1997.
Fiebeler A, Nussberger J, Shagdarsuren E, Rong S, Hilfenhaus G, Al-Saadi N, Dechend R, Wellner M, Meiners S, Maser-Gluth C, Jeng AY, Webb RL, Luft FC, Muller DN. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation. 2005; 111: 3087–3094.