Rationale: Fast-transient outward K + ( I to,f ) and ultrarapid delayed rectifier K + currents ( I K,slow , also known as I Kur ) contribute to mouse cardiac repolarization. Gender studies on these currents have reported conflicting results. Objective: Key missing information in these studies is the estral stage of the animals. We revisited gender-related differences in K + currents, taking into consideration the females’ estral stage. We hypothesized that changes in estrogen levels during the estral cycle could play a role in determining the densities of K + currents underlying ventricular repolarization. Methods and Results: Peak total K + current ( I K,total ) densities (pA/pF, at +40 mV) were much higher in males (48.6±3.0) versus females at estrus (27.2±2.3) but not at diestrus-2 (39.1±3.4). Underlying this change, I to,f and I K,slow were lower in females at estrus versus males and diestrus-2 ( I K,slow : male 21.9±1.8, estrus 14.6±0.6, diestrus-2 20.3±1.4; I to,f : male 26.8±1.9, estrus 14.9±1.6, diestrus-2 22.1±2.1). Lower I K,slow in estrus was attributable to only I K,slow 1 reduction, without changes in I K,slow 2 . Estrogen treatment of ovariectomized mice decreased I K,total (46.4±3.0 to 28.4±1.6), I to,f (26.6±1.6 to 12.8±1.0) and I K,slow (22.2±1.6 to 17.2±1.4). Transcript levels of Kv4.3 and Kv1.5 (underlying I to,f and I K,slow , respectively) were lower in estrus versus diestrus-2 and male. In ovariectomized mice, estrogen treatment resulted in downregulation of Kv4.3 and Kv1.5 but not Kv4.2, KChIP2, or Kv2.1 transcripts. K + current reduction in high estrogenic conditions were associated with prolongation of the action potential duration and corrected QT interval. Conclusion: Downregulation of Kv4.3 and Kv1.5 transcripts by estrogen are one mechanism defining gender-related differences in mouse ventricular repolarization.

Estrogen Contributes to Gender Differences in Mouse Ventricular Repolarization

Aims The omega-3 (n-3) polyunsaturated fatty acids (omega-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil were recently reported to have an anti-atrial fibrillation effect in humans; however, the ionic mechanisms of this effect are not fully understood. The present study was designed to determine the effects of EPA and DHA on transient outward and ultra-rapid delayed rectifier potassium currents ( I to and I Kur) and the voltage-gated sodium current ( I Na) in human atrial myocytes.

Methods and results A whole-cell patch voltage clamp technique was employed to record I to and I Kur, and I Na in human atrial myocytes. It was found that EPA and DHA inhibited I to in a concentration-dependent manner (IC50: 6.2 µM for EPA; 4.1 µM for DHA) and positively shifted voltage-dependent activation of the current. In addition, I Kur was suppressed by 1–50 µM EPA (IC50: 17.5 µM) and DHA (IC50: 4.3 µM). Moreover, EPA and DHA reduced I Na in human atrial myocytes in a concentration-dependent manner (IC50: 10.8 µM for EPA; 41.2 µM for DHA) and negatively shifted the potential of INa availability. The I Na block by EPA or DHA was use-independent.

Conclusion The present study demonstrates for the first time that EPA and DHA inhibit human atrial I to, I Kur, and I Na in a concentration-dependent manner; these effects may contribute, at least in part, to the anti-atrial fibrillation of omega-3 PUFAs in humans.

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Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes

Clotrimazole is a broad-spectrum antimycotic drug mainly used for the treatment of Candida albicans and other fungal infections. A synthetic, azole antimycotic, clotrimazole is widely used as a topical treatment for tinea pedis (athlete's foot), as well as vulvovaginal and oropharyngeal candidiasis. It displays fungistatic antimycotic activity by targeting the biosynthesis of ergosterol, thereby inhibiting fungal growth. As well as its antimycotic activity, clotrimazole has become a drug of interest against several other diseases such as sickle cell disease, malaria and some cancers. It has also been combined with other molecules, such as the metals, to produce clotrimazole complexes that show improved pharmacological efficacy. Moreover, several new, modified-release pharmaceutical formulations are also undergoing development. Clotrimazole is a very well-tolerated product with few side effects, although there is some drug resistance appearing among immunocompromised patients. Here, we review the pharmaceutical chemistry, application and pharmacology of clotrimazole and discuss future prospects for its further development as a chemotherapeutic agent.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jam.12554

Clotrimazole as a pharmaceutical: past, present and future.

The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug–hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC50) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC50 values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC50 data available in accessible scientific literature to provide a high-quality data set for further studies. Copyright © 2008 John Wiley & Sons, Ltd.

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Sex differences in cardiovascular diseases can be classified as those which are specific to one sex and those that differ in incidence, prevalence, etiology, symptomatology, response to treatment, morbidity, and mortality in one sex compared to the other All sex differences in cardiovascular conditions have their basis in the combined expression of genetic and hormonal differences between women and men This chapter addresses how understanding basic mechanisms of hormone responses, imaging diagnostics, and integration of genomics and proteomics has advanced diagnosis and improved outcomes for cardiovascular conditions, apart from those related to pregnancy that are more prevalent in women These conditions include obstructive coronary artery disease, coronary microvascular dysfunction, spontaneous coronary artery dissection, diseases of the cardiac muscle including heart failure and takotsubo cardiomyopathy, and conditions related to neurovascular dysregulation including hot flashes and night sweats associated with menopause and effects of exogenous hormones on vascular function Improvement in technologies allowing for noninvasive assessment of neuronally mediated vascular reactivity will further improve our understanding of the basic etiology of the neurovascular disorders Consideration of sex, hormonal status, and pregnancy history in diagnosis and treatment protocols will improve prevention and outcomes of cardiovascular disease in women as they age

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Sex-Specific Physiology and Cardiovascular Disease.

The antifungal antibiotic clotrimazole (CLT) shows therapeutic effects on cancer, sickle cell disease, malaria, etc. by inhibiting membrane intermediate-conductance Ca2+ -activated K+ channels (IKCa). However, it is unclear whether this drug would affect human cardiac K+ currents. The present study was therefore designed to investigate the effects of CLT on transient outward K+ current (Ito1), and ultra-rapid delayed rectifier K+ current (IKur) in isolated human atrial myocytes, and cloned hERG channel current (IhERG) and recombinant human cardiac KCNQ1/KCNE1 channel current (IKs) expressed in HEK 293 cells. It was found that CLT inhibited Ito1 with an IC50 of 29.5 microM, accelerated Ito1 inactivation, and decreased recovery of Ito1 from inactivation. In addition, CLT inhibited human atrial I(Kur) in a concentration-dependent manner (IC50 = 7.6 microM). CLT substantially suppressed IhERG (IC50 = 3.6 microM), and negatively shifted the activation conductance of IhERG. Moreover, CLT inhibited IKs (IC50 = 15.1 microM), and positively shifted the activation conductance of the current. These results indicate that the antifungal antibiotic CLT substantially inhibits human cardiac repolarization K+ currents including Ito1, IKur, IhERG, and IKs. However, caution is recommended when correlating the observed in vitro effects on cardiac ion currents to the clinical relevance.

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Shui-Wha Chiu

Papers

Effects of the antifungal antibiotic clotrimazole on human cardiac repolarization potassium currents

Raloxifene inhibits transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes.