Objective: Glucocorticoids as well as mineralocorticoids have been shown to increase the cardiac L-type Ca²⁺ current (I_CaL) in vitro by activation of the mineralocorticoid receptor (MR). The mechanisms of activation and signal transduction of the MR, however, remain elusive. Here we demonstrate that the upregulation of I_CaL is dependent on the presence of insulin or IGF-1. Methods: Single cardiac myocytes were isolated from the left ventricular free wall of female Wistar rats and investigated using the whole-cell configuration of the patch-clamp technique after 24h incubation with corticosteroids alone or in combination with insulin or IGF-1. Results: In the presence of 100nM insulin, the glucocorticoid dexamethasone (dexa, 1M) increased I_CaL (at 0mV) by 49% (p<0.001), while dexa alone had no effect. 10nM IGF-1 mimicked the effect of insulin: co-incubation with 1M dexa increased I_CaL by 42% (p<0.01). Again, dexa alone did not exert an effect. Insulin or IGF-1 did not have an effect on I_CaL after 24h incubation in the absence of corticosteroids. Concentration-response curves revealed an EC₅₀ of 0.43nM and 4.7nM for IGF-1 and insulin respectively. Similar to the situation for glucocorticoids, incubation with the mineralocorticoid aldosterone increased I_CaL in the presence of insulin only. Preliminary results indicate that the observed effect is sensitive to the PI3-kinase inhibitor LY294002 (50mM) but not to the Akt/SGK inhibitor indirubin-monoxime (10mM). Conclusion: Incubation with corticosteroids or insulin/IGF-1 alone is not sufficient to regulate I_CaL in vitro after 24h. Instead, corticosteroids and insulin/IGF-1 synergistically induce the increase in I_CaL. Therefore, insulin and IGF-1 may constitute important cofactors in the regulation of cardiac function by corticosteroids under physiological and pathophysiological conditions.