Adrenergic inhibition facilitates normalization of extracellular potassium after cortical spreading depolarization

Cortical spreading depolarization (CSD) is a propagating wave of tissue depolarization characterized by a large increase of extracellular potassium concentration and prolonged subsequent electrical silencing of neurons. Waves of CSD arise spontaneously in various acute neurological settings, including migraine aura and ischemic stroke. Recently, we have reported that pan-inhibition of adrenergic receptors (AdRs) facilitates the normalization of extracellular potassium after acute photothrombotic stroke in mice. Here, we have extended that mechanistic study to ask whether AdR antagonists also modify the dynamics of KCl-induced CSD and post-CSD recovery in vivo. Spontaneous neural activity and KCl-induced CSD were visualized by cortex-wide transcranial Ca2+ imaging in G-CaMP7 transgenic mice. AdR antagonism decreased the recurrence of CSD waves and accelerated the post-CSD recovery of neural activity. Two-photon imaging revealed that astrocytes exhibited aberrant Ca2+ signaling after passage of the CSD wave. This astrocytic Ca2+ activity was diminished by the AdR antagonists. Furthermore, AdR pan-antagonism facilitated the normalization of the extracellular potassium level after CSD, which paralleled the recovery of neural activity. These observations add support to the proposal that neuroprotective effects of AdR pan-antagonism arise from accelerated normalization of extracellular K+ levels in the setting of acute brain injury.

Effects of Increased Extracellular Potassium Concentration Induced by Ischemia on the Vulnerability of Ventricular Arrhythmias and the Regularity of Related Ventricular Tachycardia

Myocardial ischemia could induce arrhythmias such as ventricular tachycardia and ventricular fibrillation, leading to sudden death and other serious consequences. This manuscript adopted the cardiac modeling and simulation method to study the activity pattern of myocardial ischemia-related ventricular tachycardia and the effect of increased extracellular potassium concentration on arrhythmia vulnerability. A whole ventricular electrophysiological model of endocardial ischemia caused by distal occlusion of left anterior descending coronary artery was established. The simulation results suggested that the relationship between the vulnerability of ventricular arrhythmias and extracellular potassium concentration was bell shaped with a peak in susceptibility at 12 mM. This result was caused by the effect of extracellular potassium concentration on the dispersion of repolarization and the effective refractory period of cardiomyocytes. The extension of the effective refractory period was due to the electrical remodeling of the ventricle. Specifically, it was because of the delayed recovery of the INa current. In addition, the regularity of endocardial/epicardial reentrant pattern during non-transmural ischemia was also analyzed. The endocardium formed micro-reentrant, while the epicardium established macro-reentrant rotating around the ischemic regions provided a new idea for the determination of clinical ablation targets.

Kidney Is Essential for Blood Pressure Modulation by Dietary Potassium

Eating more potassium may reduce blood pressure and the occurrence of other cardiovascular diseases by actions on various systems, including the vasculature, the sympathetic nervous system, systemic metabolism, and body fluid volume. Among these, the kidney plays a major role in the potassium-rich diet–mediated blood pressure reduction. Purpose of Review To provide an overview of recent discoveries about the mechanisms by which a potassium-rich diet leads to natriuresis. Recent Findings Although the distal convoluted tubule (DCT) is a short part of the nephron that reabsorbs salt, via the sodium-chloride cotransporter (NCC), it is highly sensitive to changes in plasma potassium concentration. Activation or inhibition of NCC raises or lowers blood pressure. Recent work suggests that extracellular potassium concentration is sensed by the DCT via intracellular chloride concentration which regulates WNK kinases in the DCT. Summary High-potassium diet targets NCC in the DCT, resulting in natriuresis and fluid volume reduction, which are protective from hypertension and other cardiovascular problems.

Punicalagin Damages the Membrane of Salmonella Typhimurium

ABSTRACT Salmonella, a bacterial foodborne pathogen, can contaminate meat, milk, and vegetables. While appropriate measures are available to control Salmonella, the inhibitory phytochemicals from plants are gaining increased attention. Punicalagin, a natural antimicrobial, is one of the main active tannins isolated from Punica granatum L. To obtain a broader understanding of the effect of punicalagin on the cell membranes of Salmonella Typhimurium, the growth curves, extracellular potassium concentration, release of cell constituents, intracellular pH, membrane potential, and morphological features were characterized to elucidate the mechanisms of action. Treatment with punicalagin induced an increase in the extracellular concentrations of potassium and a release of cell constituents. A higher pH gradient, an increase in the intracellular pH, and cell membrane depolarization were observed after punicalagin treatment. Electron microscopy observations showed that the cell membrane structures of Salmonella Typhimurium were damaged by punicalagin. It is concluded that punicalagin inhibits the proliferation of Salmonella Typhimurium and destroys the integrity of the cell membrane, leading to a loss of cell homeostasis. These findings indicate that punicalagin has the potential to be developed as a future alternative to control Salmonella Typhimurium contamination in foods and reduce the risk of salmonellosis.

Astrocyte-Selective Volume Increase in Elevated Extracellular Potassium Conditions Is Mediated by the Na+/K+ ATPase and Occurs Independently of Aquaporin 4

Astrocytes and neurons have been shown to swell across a variety of different conditions, including increases in extracellular potassium concentration (^[K+]o). The mechanisms involved in the coupling of K+ influx to water movement into cells leading to cell swelling are not well understood and remain controversial. Here, we set out to determine the effects of ^[K+]o on rapid volume responses of hippocampal CA1 pyramidal neurons and stratum radiatum astrocytes using real-time confocal volume imaging. First, we found that elevating [K+]o within a physiological range (to 6.5 mM and 10.5 mM from a baseline of 2.5 mM), and even up to pathological levels (26 mM), produced dose-dependent increases in astrocyte volume, with absolutely no effect on neuronal volume. In the absence of compensating for addition of KCl by removal of an equal amount of NaCl, neurons actually shrank in ^[K+]o, while astrocytes continued to exhibit rapid volume increases. Astrocyte swelling in ^[K+]o was not dependent on neuronal firing, aquaporin 4, the inwardly rectifying potassium channel Kir 4.1, the sodium bicarbonate cotransporter NBCe1, , or the electroneutral cotransporter, sodium-potassium-chloride cotransporter type 1 (NKCC1), but was significantly attenuated in 1 mM barium chloride (BaCl2) and by the Na+/K+ ATPase inhibitor ouabain. Effects of 1 mM BaCl2 and ouabain applied together were not additive and, together with reports that BaCl2 can inhibit the NKA at high concentrations, suggests a prominent role for the astrocyte NKA in rapid astrocyte volume increases occurring in ^[K+]o. These findings carry important implications for understanding mechanisms of cellular edema, regulation of the brain extracellular space, and brain tissue excitability.

Cardiac Targeting Peptide, a Novel Cardiac Vector: Studies in Bio-Distribution, Imaging Application, and Mechanism of Transduction

Our previous work identified a 12-amino acid peptide that targets the heart, termed cardiac targeting peptide (CTP). We now quantitatively assess the bio-distribution of CTP, show a clinical application with the imaging of the murine heart, and study its mechanisms of transduction. Bio-distribution studies of cyanine5.5-N-Hydroxysuccinimide (Cy5.5) labeled CTP were undertaken in wild-type mice. Cardiac targeting peptide was labeled with Technetium 99m (99mTc) using the chelator hydrazino-nicotinamide (HYNIC), and imaging performed using micro-single photon emission computerized tomography/computerized tomography (SPECT/CT). Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMCs) were incubated with dual-labeled CTP, and imaged using confocal microscopy. TriCEPs technology was utilized to study the mechanism of transduction. Bio-distribution studies showed peak uptake of CTP at 15 min. 99mTc-HYNIC-CTP showed heart-specific uptake. Robust transduction of beating human iPSC-derived CMCs was seen. TriCEPs experiments revealed five candidate binding partners for CTP, with Kcnh5 being felt to be the most likely candidate as it showed a trend towards being competed out by siRNA knockdown. Transduction efficiency was enhanced by increasing extracellular potassium concentration, and with Quinidine, a Kcnh5 inhibitor, that blocks the channel in an open position. We demonstrate that CTP transduces the normal heart as early as 15 min. 99mTc-HYNIC-CTP targets the normal murine heart with substantially improved targeting compared with 99mTc Sestamibi. Cardiac targeting peptide’s transduction ability is not species limited and has human applicability. Cardiac targeting peptide appears to utilize Kcnh5 to gain cell entry, a phenomenon that is affected by pre-treatment with Quinidine and changes in potassium levels.