Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity.

Iron deficiency is present in ~50% of heart failure (HF) patients. Large multicenter trials have shown that treatment of iron deficiency with i.v. iron benefits HF patients, but the underlying mechanisms are not known. To investigate the actions of iron deficiency on the heart, mice were fed an iron-depleted diet, and some received i.v. ferric carboxymaltose (FCM), an iron supplementation used clinically. Iron-deficient animals became anemic and had reduced ventricular ejection fraction measured by magnetic resonance imaging. Ca2+ signaling, a pathway linked to the contractile deficit in failing hearts, was also significantly affected. Ventricular myocytes isolated from iron-deficient animals produced smaller Ca2+ transients from an elevated diastolic baseline but had unchanged sarcoplasmic reticulum (SR) Ca2+ load, trigger L-type Ca2+ current, or cytoplasmic Ca2+ buffering. Reduced fractional release from the SR was due to downregulated RyR2 channels, detected at protein and message levels. The constancy of diastolic SR Ca2+ load is explained by reduced RyR2 permeability in combination with right-shifted SERCA activity due to dephosphorylation of its regulator phospholamban. Supplementing iron levels with FCM restored normal Ca2+ signaling and ejection fraction. Thus, 2 Ca2+-handling proteins previously implicated in HF become functionally impaired in iron-deficiency anemia, but their activity is rescued by i.v. iron supplementation.

Wenxin Keli diminishes Ca2+ overload induced by hypoxia/reoxygenation in cardiomyocytes through inhibiting INaL and ICaL.

BACKGROUND: An increase in the late sodium current (INaL ) causes intracellular Na+ overload and subsequently intracellular Ca2+ ([Ca2+ ]i ) overload via the stimulated reverse Na+ -Ca2+ exchange (NCX). Wenxin Keli (WXKL) is an effective antiarrhythmic Chinese herb extract, but the underlying mechanisms are unclear. METHODS AND RESULTS: The INaL , NCX current (INCX ), L-type Ca2+ current (ICaL ), and action potentials were recorded using the whole-cell patch-clamp technique in rabbit ventricular myocytes. Myocyte [Ca2+ ]i transients were measured using a dual excitation fluorescence photomultiplier system. WXKL decreased the enhanced INaL , reverse INCX , diastolic [Ca2+ ]i , and the amplitude of Ca2+ transients induced by sea anemone toxin II (ATX II, a specific INaL channel opener) in a concentration-dependent manner. Hypoxia increased INaL , INCX , and diastolic [Ca2+ ]i , and decreased amplitude of [Ca2+ ]i transients. Hypoxia-reoxygenation aggravated these changes and induced spontaneous [Ca2+ ]i transients and hypercontraction in 86% cells (6/7). The application of WXKL during hypoxia or reoxygenation periods decreased the increased INaL , INCX , and diastolic [Ca2+ ]i , and prevented those events in 82% cells (9/11) under hypoxia-reoxygenation conditions. WXKL also inhibited the ICaL in a dose-dependent manner. Furthermore, WXKL shortened the action potential duration and completely abolished ATX II-induced early afterdepolarizations from 9/9 to /9. In isolated heart electrocardiogram recordings, WXKL inhibited ischemia-reperfusion induced ventricular premature beats and tachycardia. CONCLUSIONS: WXKL attenuated [Ca2+ ]i overload induced by hypoxia-reoxygenation in ventricular myocytes through inhibiting INaL and ICaL and prevents arrhythmias. This could, at least partly, contribute to the antiarrhythmic effects of WXKL.

The effect of ligustrazine on L-type calcium current, calcium transient and contractility in rabbit ventricular myocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Ligustrazine, the biologically active ingredient isolated from a popular Chinese medicinal plant, Ligusticum chuanxiong Hort. (Umbelliferae), has been used effectively to treat ischemic heart diseases, cerebrovascular and thrombotic vascular diseases since the 1970s. MATERIALS AND METHODS: At present, the effect of ligustrazine on L-type calcium current (I(Ca-L)) of ventricular myocytes remains controversial. In this study, we use the whole-cell patch-clamp techniques and video-based edge detection and dual excitation fluorescence photomultiplier systems to study the effects of ligustrazine on I(Ca-L), and calcium transient and contractility in rabbit ventricular myocytes in the absence and presence of isoprenaline (ISO). RESULTS: Ligustrazine (5 µM) in low concentration did not affect I(Ca-L) (P>0.05), higher concentrations of this drug (10, 20, 40, 80 µM) inhibited I(Ca-L) in a concentration-dependent manner and reduced I(Ca-L) by 9.6 ± 2.9%, 21.0 ± 4.3%, 33.9 ± 4.3%, and 51.6 ± 7.3%, respectively. Under normal conditions, ligustrazine (40 µΜ) reduced baseline of fura-2 fluorescence intensities (FFI, 340/380 ratio), namely diastolic calcium concentration, changes in FFI (ΔFFI, 340/380 ratio) and maximal velocity of Ca(2+) rise and decay (340/380 ratio/ms) by 6.3%, 26.1%, 25.2%, and 26.5%, and decreased sarcomere peak shorting (PS) and maximal velocity of shorting and relengthening by 36.4%, 31.9%, and 25.0%, respectively. Similarly, ligustrazine (40 µM) reduced baseline FFI, ΔFFI, and maximal velocity of Ca(2+) rise and decay by 14.1%, 51.1%, 35.2%, and 41.1%, and reduced sarcomere PS and maximal velocity of shorting and relengthening by 38.6%, 50.0% and 39.1%, respectively, in the presence of ISO. CONCLUSIONS: Ligustrazine not only significantly inhibits I(Ca-L) in a concentration-dependent manner but also suppressed calcium transient and contraction in the absence and presence of ISO.