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Calcitriol, the bioactive metabolite of vitamin D, interacts with the ubiquitously expressed nuclear vitamin D receptor (VDR) to induce genomic effects, but it can also elicit rapid responses via membrane-associated VDR through mechanisms that are poorly understood. The down-regulation of K+ currents is the main origin of electrophysiological remodeling in pathological hypertrophy and heart failure (HF), which can contribute to action potential prolongation and subsequently increase the risk of triggered arrhythmias. Adult mouse ventricular myocytes were isolated and treated with 10 nM calcitriol or vehicle for 15–30 min. In some experiments, cardiomyocytes were pretreated with the Akt inhibitor triciribine. In the adult mouse ventricle, outward K+ currents involved in cardiac repolarization are comprised of three components: the fast transient outward current (Itof), the ultrarapid delayed rectifier K+ current (Ikur), and the non-inactivating steady-state outward current (Iss). K+ currents were investigated using the whole-cell or the perforated patch-clamp technique and normalized to cell capacitance to obtain current densities. Calcitriol treatment of cardiomyocytes induced an increase in the density of Itof and Ikur, which was lost in myocytes isolated from VDR-knockout mice. In addition, calcitriol activated Akt in cardiomyocytes and pretreatment with triciribine prevented the calcitriol-induced increase of outward K+ currents. In conclusion, we demonstrate that calcitriol via VDR and Akt increases both Itof and Ikur densities in mouse ventricular cardiomyocytes. Our findings may provide new mechanistics clues for the cardioprotective role of this hormone in the heart.

Calcitriol, the bioactive metabolite of vitamin D, interacts with the ubiquitously expressed nuclear vitamin D receptor (VDR) to induce genomic effects, but it can also elicit rapid responses via membrane-associated VDR through mechanisms that are poorly understood. The down-regulation of K+ currents is the main origin of electrophysiological remodeling in pathological hypertrophy and heart failure (HF), which can contribute to action potential prolongation and subsequently increase the risk of triggered arrhythmias. Adult mouse ventricular myocytes were isolated and treated with 10 nM calcitriol or vehicle for 15–30 min. In some experiments, cardiomyocytes were pretreated with the Akt inhibitor triciribine. In the adult mouse ventricle, outward K+ currents involved in cardiac repolarization are comprised of three components: the fast transient outward current (Itof), the ultrarapid delayed rectifier K+ current (Ikur), and the non-inactivating steady-state outward current (Iss). K+ currents were investigated using the whole-cell or the perforated patch-clamp technique and normalized to cell capacitance to obtain current densities. Calcitriol treatment of cardiomyocytes induced an increase in the density of Itof and Ikur, which was lost in myocytes isolated from VDR-knockout mice. In addition, calcitriol activated Akt in cardiomyocytes and pretreatment with triciribine prevented the calcitriol-induced increase of outward K+ currents. In conclusion, we demonstrate that calcitriol via VDR and Akt increases both Itof and Ikur densities in mouse ventricular cardiomyocytes. Our findings may provide new mechanistics clues for the cardioprotective role of this hormone in the heart. [ABSTRACT FROM AUTHOR]

Circulating leptin levels are elevated in obesity and hyperleptinaemia has been postulated to be an independent risk factor for the development of cardiovascular diseases. Although many studies have been published on the mechanisms involved in the effects of leptin on cardiac function and pathological remodeling, scarce information is currently available analyzing the influence of prolonged leptin treatment on ionic cardiac channels remodeling in adult ventricular myocytes. Enzymatically isolated adult rat ventricular myocytes were treated with leptin or vehicle for 48h. Real-Time RT-PCR were used to analyze mRNA expression of Kir2.1, Cav1.2, Cav 3.1, Kv4.2 and Kv4.3 α-subunits and KChIP2 auxiliary subunit. The fast transient outward potassium channels (I) α-subunits Kv4.2, Kv4.3 and KChIP2 were analyzed by Western-blot. The fast transient outward potassium current and the action potentials were recorded in isolated myocytes by the whole-cell patch-clamp technique. Leptin treatment induced an up-regulation of Kv4.2, Kv4.3 and KChIP2 subunits mRNA expression. However, transcriptional levels of Kir2.1, Cav1.2, or Cav3.1 α-subunit channels were unmodified by leptin. Protein expression levels of Kv4.2, Kv4.3 and KChIP2 subunits were also increased by leptin. The electrophysiological study showed that leptin increases the fast transient outward potassium current amplitudes and densities shortening action potential duration. In addition, leptin activated Akt signaling in cardiomyocytes and this mechanism was involved in the effect of leptin on I channels. In conclusión, leptin increases both the expression and function of channels in adult ventricular myocytes and this mechanism involves Akt signaling. Altogether these data suggest that leptin could exert beneficial or detrimental effects depending on the initial ventricular myocyte repolarizing reserve. [ABSTRACT FROM AUTHOR]

Calcitriol, the bioactive metabolite of vitamin D, interacts with the ubiquitously expressed nuclear vitamin D receptor (VDR) to induce genomic effects, but it can also elicit rapid responses via membrane-associated VDR through mechanisms that are poorly understood. The down-regulation of K + currents is the main origin of electrophysiological remodeling in pathological hypertrophy and heart failure (HF), which can contribute to action potential prolongation and subsequently increase the risk of triggered arrhythmias. Adult mouse ventricular myocytes were isolated and treated with 10 nM calcitriol or vehicle for 15-30 min. In some experiments, cardiomyocytes were pretreated with the Akt inhibitor triciribine. In the adult mouse ventricle, outward K + currents involved in cardiac repolarization are comprised of three components: the fast transient outward current (I tof ), the ultrarapid delayed rectifier K + current (I kur ), and the non-inactivating steady-state outward current (I ss ). K + currents were investigated using the whole-cell or the perforated patch-clamp technique and normalized to cell capacitance to obtain current densities. Calcitriol treatment of cardiomyocytes induced an increase in the density of I tof and I kur , which was lost in myocytes isolated from VDR-knockout mice. In addition, calcitriol activated Akt in cardiomyocytes and pretreatment with triciribine prevented the calcitriol-induced increase of outward K + currents. In conclusion, we demonstrate that calcitriol via VDR and Akt increases both I tof and I kur densities in mouse ventricular cardiomyocytes. Our findings may provide new mechanistics clues for the cardioprotective role of this hormone in the heart.