Corticosteroid-dependent, aldosterone-independent mineralocorticoid-receptor activation in the heart

Mineralocorticoid receptors are present in a variety of tissues including cardiomyocytes and vascular smooth muscle cells [1]. As the free cortisol concentration is two to three orders of magnitude higher than the aldosterone concentration and cortisol's affinity for the mineralocorticoid receptor equals that of aldosterone, mineralocorticoid receptors are predominantly occupied by cortisol [2]. The cytosolic enzyme 11-β-hydroxysteroid-dehydrogenase type 2 (11βHSD2) reduces cortisol to cortisone, but does not affect aldosterone. Unlike cortisol, cortisone has no affinity for the mineralocorticoid receptor. As a consequence, in cells where this enzyme is active, like the cortical distal tubular cells of the kidney, the occupation of the mineralocorticoid receptor is in favor of aldosterone. However, it should be realized that also in cells where 11βHSD2 is present, still about 90% of mineralocorticoid receptors are occupied by cortisol [2]. In cells lacking 11βHSD2 (e.g. in cardiomyocytes), the occupation of mineralocorticoid receptors by cortisol is close to 100%. When aldosterone binds to the cytosolic mineralocorticoid receptor, the aldosterone–mineralocorticoid receptor complex translocates from the cytoplasm to the nucleus to regulate its various target genes, which, in the kidney, eventually results in sodium and water retention and potassium excretion. The situation is different for the cortisol–mineralocorticoid receptor complex. Under physiological conditions, this complex is inactive but, under pathophysiological conditions, it may become active and function like the aldosterone–mineralocorticoid receptor complex [3]. For example, mineralocorticoid receptor activation despite suppressed aldosterone because of salt loading has been reported in the kidney of obese spontaneously hypertensive rats and in the heart of Dahl salt-sensitive rats [4,5]. Of interest, renal mineralocorticoid receptor activation could be antagonized not only by the mineralocorticoid receptor antagonist eplerenone, but also by tempol, a membrane-soluble, superoxide-dismutase that exerts antioxidative activity [4]. In the present issue of the Journal of Hypertension, Wang and colleagues, as an extension of their previous work in this field, provide evidence that glucocorticoid-dependent, aldosterone-independent mineralocorticoid receptor activation under conditions of salt loading contributes to the development of left ventricular diastolic dysfunction in rats exposed to angiotensin II (Ang II) [4,6]. In their elaborate experiments, Sprague–Dawley rats were subjected to either a low- (0.05% NaCl) or high-salt (8% NaCl) diet for 6 weeks. About 50% of the rats in the low-salt and high-salt diet groups were concomitantly exposed to Ang II (100 ng/kg/min, for 6 weeks) to increase myocardial oxidative stress by activation of NAD(P)H-oxidase [7]. Although no data are provided, it is stated that, with this infusion rate, Ang II plasma concentration increased three-fold, which is well within the pathophysiological range. Information about cardiac diastolic function was obtained by standard echo Doppler techniques as well as by direct monitoring of left ventricular pressure. The expression of the Na+–H+ exchanger isoform 1 (NHE-1) in left ventricular tissue as assessed by real-time PCR was used as one of the indicators of mineralocorticoid receptor activation at the level of gene transcription [8]. As anticipated, serum aldosterone concentration was markedly suppressed in the high-salt group compared with the low-salt group, irrespective of Ang II infusion. Serum corticosterone, the active glucocorticoid of rodents, did not differ among the four groups. Left ventricular NADPH-oxidase activity was increased in the Ang II/high-salt group but not in the Ang II/low-salt group, as was left ventricular NHE-1 expression. Blood pressure did not differ between the low-salt and high-salt group, but was increased in the groups exposed to Ang II. Left ventricular function was impaired in the Ang II/high-salt group as compared with the other groups. Treatment of the Ang II/high-salt group with the highly selective mineralocorticoid receptor antagonist eplerenone and with tempol reduced left ventricular NHE-1 expression and prevented the development of diastolic dysfunction. Can the findings of this study be taken as a proof for corticosteroid-dependent, aldosterone-independent activation of the mineralocorticoid receptor? An important point of concern is that the rise in blood pressure was most pronounced in the Ang II/high-salt group. Compared with baseline values, systolic blood pressure in this group, as measured by the tail-cuff method, had increased by 22 mmHg in the Ang II/high-salt group compared with 14 mmHg in the low-salt/Ang II group. Although apparently not significantly different, the diastolic dysfunction observed in the high-salt/Ang II group might be a consequence of the higher blood pressure and had no relation at all with corticosteroid-dependent mineralocorticoid receptor activation. However, as rightly argued by the authors, treatment with the mineralocorticoid receptor antagonist eplerenone or with tempol did prevent the development of diastolic dysfunction without affecting blood pressure, supporting the contention that the adverse effect of high salt and Ang II on cardiac function was unrelated to blood pressure. To be more certain about this point, direct blood pressure measurement for prolonged periods, preferably by telemonitoring, is recommended. The key question of course is whether the findings reported by Wang et al.[6] have their counterpart in clinical medicine. There is no doubt that glucocorticoid-dependent mineralocorticoid receptor activation can occur in humans. The most straightforward example is deficiency of the enzyme 11βHSD2, either because of a genetic defect or excessive liquorice ingestion [9]. Although renin and aldosterone are suppressed in persons with genetic or acquired 11βHSD2 deficiency, blood pressure is increased due to cortisol-dependent mineralocorticoid receptor activation in the renal cortical collecting duct cells. Given that, in these cells, 90% of mineralocorticoid receptors are normally occupied by cortisol, it remains puzzling that this cortisol-mediated mineralocorticoid receptor activation is switched on only under circumstances of low or absent activity of the enzyme 11βHSD2 [10]. In other conditions, evidence for cortisol-dependent, aldosterone-independent mineralocorticoid receptor activation in humans is indirect and mainly based on the interpretation of the findings of two outcome trials with mineralocorticoid receptor antagonists performed in patients with overt heart failure or cardiac dysfunction [11,12]. These studies showed impressive reduction in cardiac morbidity and mortality, including hospitalization for heart failure, when mineralocorticoid receptor blockade with either spironolactone or eplerenone was added to standard treatment including angiotensin-converting enzyme inhibition. Although the outcome of these studies can be interpreted as compelling evidence that the beneficial effects observed were caused by blockade of glucocorticoid-dependent mineralocorticoid receptor activation, especially within the heart, alternative possibilities, such as a rise in serum potassium concentration, a more optimal volume status and/or blood pressure reduction, cannot be ruled out. Thus, at best, the evidence in these outcome studies for the existence of glucocorticoid-dependent mineralocorticoid receptor activation that can be blocked by mineralocorticoid receptor antagonists remains circumstantial. If oxidative stress is instrumental for glucorticoid-dependent mineralocorticoid receptor activation and its adverse cardiovascular sequelae in clinical medicine, what about antioxidative therapy? Epidemiological studies indicate an inverse association between cardiovascular risk and intake from dietary sources and/or supplements of the antioxidant vitamin E but, in the prospective, placebo-controlled Heart Outcomes Prevention Evaluation (HOPE) trial, vitamin E supplementation to patients with a high cardiovascular risk had no apparent effect on cardiovascular outcome [13,14]. This was confirmed in the HOPE-TOO trial [15]. Unexpectedly and unexplained, these trials, if anything, demonstrated an enhanced risk of heart failure associated with the use of vitamin E of 13% in the HOPE trial and 19% in the HOPE-TOO trial. Furthermore, another approach to reduce oxidative stress by inhibition of xanthine-oxidase with allopurinol or oxypurinol in patients with heart failure was also without any beneficial effects on cardiac outcome [16,17]. Taken together, although the findings of Wang et al.[6] are appealing and supportive for glucocorticoid-dependent, aldosterone-independent mineralocorticoid receptor activation in the rodent heart under conditions of excessive salt and high Ang II, it remains a ‘tour de force’ for researchers to demonstrate unequivocally the existence of such a mechanism in human hearts when conditions are less extreme. If successful, these studies would provide a solid scientific basis to explain the beneficial effects of mineralocorticoid receptor blockade reported in patients with cardiac dysfunction or heart failure.