Corticosteroids and Redox Potential Modulate Spontaneous Contractions in Isolated Rat Ventricular Cardiomyocytes

Abstract

Abstract-The mineralocorticoid receptor has been implicated in the development of several cardiac pathologies and could participate in the high incidence of lethal ventricular arrhythmias associated with hyperaldosteronism. We have observed previously that aldosterone markedly increases in vitro the rate of spontaneous contractions of isolated neonate rat ventricular myocytes, a putative proarrhythmogenic condition if occurring in vivo. In the present study, we investigated the effect of glucocorticoids, the involvement of the glucocorticoid receptor, and the modulation of their action by redox agents. Aldosterone and glucocorticoids exerted in vitro a similar, concentration-dependent chronotropic action on cardiomyocytes, which was mediated by both the mineralocorticoid and glucocorticoid receptors. However, the relative contribution of each receptor was different for each agonist, at each concentration. Angiotensin II induced a similar response that was entirely dependent on the activity of the glucocorticoid receptor. Corticosteroid action was modulated by the redox state of the cells, with oxidation increasing the response while reducing conditions partially preventing it. When only the mineralocorticoid receptor was functionally present in the cells, oxidation was necessary to reveal glucocorticoid action, but no obvious competition with mineralocorticoids was observed when both agonists where simultaneously present. In conclusion, corticosteroids exert a strong chronotropic action in ventricular cardiomyocytes, mediated by both the mineralocorticoid and glucocorticoid receptors and modulated by the redox state of the cell. This phenomenon is believed to be because of cell electric remodeling and could contribute in vivo to the deleterious consequence of inappropriate receptor activation, leading to increased susceptibility of patients to arrhythmias.

Excess of glucocorticoid induces myocardial remodeling and alteration of calcium signaling in cardiomyocytes

“…In contrast to reduced spontaneous Ca 2C oscillations in the present study, it is reported earlier that beating frequency of cardiomyocytes is increased by DEX treatment (Rossier et al 2008). The exact reason for such difference is unclear, yet it is likely to be due to the difference in the method of assessment of spontaneous Ca 2C oscillations in two studies.…”

“…The exact reason for such difference is unclear, yet it is likely to be due to the difference in the method of assessment of spontaneous Ca 2C oscillations in two studies. The contractile activity of whole cardiomyocyte cluster as measured by Rossier et al (2008) may not be directly compared with the change of fluorescence intensity of Fluo-3 within the isolated cardiomyocytes in the present study.…”

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

“…2D). It has been reported that GR is activated by aldosterone in cardiomyocytes, but at a relatively high dose (over 10 K8 M) for long-term stimulation, compared with that observed in the current study (Rossier et al 2008). It is more likely that rapid MR-independent actions are mediated via GPER signaling (Deschamps & Murphy 2009, Krug et al 2011, although the aldosterone-GPER pathway may be activated in a cell-type-specific manner (vascular cells rather than cardiomyocytes) (Gros et al 2011(Gros et al , 2013.…”

“…2C). Notably the administration of eplerenone, a selective MR antagonist, during aldosterone preconditioning did not abrogate these beneficial effects ( Fig MR-independent cascade, the effects of aldosterone in improving the cardiac functional recovery may be mediated via GR-dependent (Rossier et al 2008) or GPER-dependent (Krug et al 2011) actions. However, neither RU486 (GR inhibitor) nor G15 (GPER inhibitor) affected the cardiac function at baseline or in terms of LVDP recovery after IRI (Fig.…”

Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor–dependent pathway

“…Another hypothesis explaining the discrepancy is that glucocorticoid might act as a ligand for MR. Endogenous glucocorticoids, cortisol in humans and corticosterone in rodents, manifest a similar affinity for MR as aldosterone. The agonistic activity of glucocorticoids is considered to be negligible in physiological milieu; however, they can act as agonists in some pathological conditions (18,52,53). Although we acknowledge that glucocorticoids can activate MR, especially in tissue damage in heart failure (52, 54), corticosterone may not potentiate the development of salt-sensitive hypertension in our study, considering that aldosterone supplementation fully nullified the protective effects of adrenalectomy.…”