Potassium Channels in Cardiovascular Biology

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1 Introduction

Start here. The gravity of severe hyperkalemia lies in the dire consequences of its ramification on the action potential, resulting in dysrhythmias and cardiac arrest. Controlling the functionality of the sodium potassium pump could rewrite the guidelines for cardiopulmonary resuscitation CPR and cardiac arrest management.

Potassium is a soft, silvery-white highly reactive cation belonging to the alkali metal group family in the periodic table. It is the most abundant cation in the human body as a whole, and the most widespread ion in its intracellular compartments. Stimulation of the alpha receptors impairs potassium entry into the cells, and stimulation of the beta receptors promotes it by activating the sodium potassium ATPase pump. The sodium-potassium ATPase pump is the gate-keeper enzyme located in the sarcolemma.

This ensures the preservation of the vital potential difference across the cell membranes needed for proper cell function, especially the excitable cells such as nerve cells and the cardiac muscle cells. After its rapid absorption, potassium helps orchestrate its own body levels through the release of insulin and aldosterone. Other inherent body stimuli also found to control potassium body levels include beta-2 adrenergic receptors, alkaline blood PH, and cellular anabolism.

Release of Insulin and Aldosterone : Ingested potassium rapidly enters circulation. On reaching the portal circulation, it stimulates the pancreas to release insulin. Concurrently, the circulating potassium reaching the juxtaglomerular cells results in the release of renin. Renin, on reaching the liver, is converted to angiotensin I. Angiotensin I travels to the lungs where it is converted into angiotensin II. Angiotensin II then completes its journey back to the kidneys through the circulating blood to stimulate the zona glomerulosa to secrete aldosterone.

Internal Potassium Balance : The insulin released post-prandially acts primarily on the skeletal muscles, activating two pathways, the AKT-dependent pathway responsible for the insertion of the glucose transporter GLUT4 and the APK pathway activating the cellular sodium potassium ATPase to shift the potassium into the intracellular space.

Figure 1. Action of insulin on a skeletal muscle cell. Insulin released post-prandially activates two pathways in skeletal muscles, the AKT-dependent pathway responsible for the insertion of the glucose transporter GLUT4 and the APK pathway activating the cellular sodium potassium ATPase to shift the potassium into the intracellular space. At the beginning of the distal convoluted tubule, secretion of excess potassium commences and increases progressively as it advances further towards the distal nephron and into the collecting duct.

Lily Jan (UCSF / HHMI) 1: Introduction to Ion Channels: The role and function of potassium channels

This is mediated by the upregulation of hydrogen potassium ATPase on the alpha-intercalated cells [5]. The presence of higher potassium levels in the peritubular cells of the kidneys activates the RAAS system to release aldosterone, which activates the sodium potassium ATPase in the basolateral membrane, resulting in a decrease in the intracellular sodium which leads to the increased electrogenic transport of potassium uptake by hyperpolarizing the membrane voltage and allowing its excretion into urine [2].

To comprehend the mechanism of imminent danger from hyperkalemia and its management, one must understand the physiology of the action potential and the innards of the sodium potassium ATPase enzyme. Electrophysiology of the action potential, i. There are five phases to an action potential, which begin and end at phase 4. The pumps involved in this process include the sarcolemma sodium calcium exchanger, calcium ATPase and, ultimately, the sodium potassium ATPase.

First in a series on hyperkalemia: hyperkalemia, the sodium potassium pump and t

The cardiac pacemaker cells have an innate automaticity, allowing their depolarization in rhythmic cycles. The membrane potentials of pacemaker cells are unstable and their action potentials have no clear-cut phases. They have fewer inward rectifier potassium channels and their TMP never drops to below mV, eliminating the role of the fast sodium channels that require a TMP of mV resulting in the absence of the rapid depolarization phase.

All the cardiomyocytes are electrically coupled through the gap junction, including the pacemaker cell. This facilitates the widespread depolarization of all neighboring cells, turning the heart into one functional unit in which the cell with the highest inherent rate becomes the "pacemaker".


The longer refractory period during the long plateau in phase 2 due to the slow calcium channels provides the time needed for the complete emptying of the ventricles before the next contraction. In an ARP, the cell is absolutely unexcitable. A stimulus at this point could minimally depolarize the cell, but the level of depolarization is weaker than propagating an action potential to the neighboring cells. RRP is brought about by an above normal stimulus, leading to the depolarization of the cell and the production of an action potential.

Figure 2. Refractory Periods. Hyperkalemia is classified as mild when levels are in the range of 5. Hyperkalemia occurs when compensatory mechanisms are no longer able to cope with the imbalance, which is why it is usually multifactorial. Mild hyperkalemia is often asymptomatic, detected accidentally by laboratory tests, due to its vague symptoms such as malaise, muscle weakness and paraesthesia. Severe hyperkalemia will affect the neuromuscular function in the form of skeletal muscle weakness and paralysis; however, this is not a frequent presentation as the cardiac toxicity dominates the picture and is the preliminary presentation.

Cardiac toxicity will usually present on the ECG in the following step-up escalating manner, although not necessarily so, depending on the etiology:. Hyperkalemia leads to hyperchloremic metabolic acidosis as the hyperkalemia promotes the intracellular uptake of potassium in exchange for hydrogen ions. This creates intracellular alkalosis, suppressing kidney ammonia production in the proximal tubules, leading to a decrease in urinary ammonium and acid excretion and a type IV renal tubular acidosis [8].

Heme regulation of signalling at potassium channels in the cardiovascular system

The sodium potassium ATPase was discovered in by Skou, who was later awarded a share of the Nobel Prize in Chemistry for his discovery. Skou was the first to discover the sodium potassium ATPase in the sarcolemma of the cardiac muscles' cell surface. Its presence was later detected in every eukaryotic single and multicellular organism. The sodium potassium pump functions by linking the hydrolysis of ATP to the cellular export of three sodium ions in exchange for two potassium ions against their electrochemical gradients.

It is the molecular target for digitalis and digoxin, which have been in use since the 18th century as foxglove extracts.

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  6. Potassium channels in the heart: structure, function and regulation.!

The action of the sodium potassium pump is regulated by a phosphoprotein phospholemman, whose unphosphorylation leads to the inhibition of the pump and whose phosphorylation leads to an increase in the pump activity. It has three phosphorylation sites, two palmitoylation sites and one glutathionylation site, which explains the multitude of signals capable of stimulating and inhibiting the pump.

The sodium potassium pump itself is an enzyme composed of multiple subunits with multiple isoforms. The presence of the alpha and beta subunits mainly B1 in the heart is essential for its function. Recently, a third protein gamma subunit has been identified in the kidneys, but to date its function remains unknown. The alpha subunit is the catalytic core of the sodium potassium pump enzyme.

It is approximately kDa and contains the binding sites for sodium, potassium, ATP, and cardiotonic steroids such as ouabain. Only alpha 1 and alpha 2 display a significant presence in a normal cardiac myocyte and are functionally linked to the sodium calcium exchanger NCX. Alpha 3 has been reported to replace alpha 2 in experimental heart failure models [2].

Data from recent experiments favor the involvement of both alpha 1 alpha 2 subunits of the pump in the regulation of the excitation-contraction E-C coupling. The alpha 1, which was found to be more evenly distributed across the sarcolemma, is thought to play more of a "housekeeping" role, controlling both contractility and the bulk intracellular sodium, while the alpha 2 whose expression is concentrated in the T-tubules along with other key components of E-C coupling is thought to focus mainly on contractility [2,9].

Its end result is life-threatening. As all of the cells in the body are ultimately affected by the sodium potassium pump, and ischemic cardiac muscles are known to extrude their potassium extracellularly leading to a reduction in the arrhythmia threshold with the possibility of ventricular arrhythmias that aggravate the hypopolarization and lower the threshold even more, more studies need to be focused on the manipulation of the sodium potassium enzyme, as its control could favorably alter the outcomes of cardiac arrests and rewrite the current CPR guidelines.

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Sign in to My ESC. ESC sub specialties communities. Javascript is currently disabled in your browser. Several features of this site will not function whilst javascript is disabled. Received 1 July Published 7 November Volume Pages — Review by Single-blind. Editor who approved publication: Professor Shu-Feng Zhou. Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking.

Using the double-electrode voltage clamp technique, we studied pharmacological effects of midazolam on heterologously expressed Kv1. Midazolam dose-dependently inhibited Kv1. We further showed that midazolam did not affect the half-maximal activation voltage of Kv1. However, a small negative shift of the inactivation curve could be observed. Midazolam acted as a typical open-channel inhibitor with rapid onset of block and without frequency dependence of block. Taken together, midazolam is an open channel inhibitor of cardiac Kv1.

Cardiac Potassium Channel Disorders, An Issue of Cardiac Electrophysiology Clinics, Volume 8-2

These data add to the current understanding of the pharmacological profile of midazolam. Keywords: anesthetics, potassium channels, pharmacology. Midazolam is a short-acting imidazobenzodiazepine that is widely used in anesthesia. However, it is well recognized that midazolam application might influence cardiac repolarization, thereby prolonging the QT interval. As a consequence, pharmacological inhibition of Kv channels represents a cornerstone of antiarrhythmic drug therapy. Among the family of Kv channels, Kv1.

When heterologously expressed, Kv1. Pharmacological inhibition of cardiac ion channels is a well-recognized side effect that has been reported for a number of clinically established anesthetics. So far, inhibitory effects of midazolam on the calcium-independent transient outward current I to , the inward rectifier potassium current I K1 , and a neural delayed rectifier current I K DR have been described. These data might, on the one hand, provide better insights into the pharmacological profile of midazolam and, on the other hand, help identify new lead compounds for the development of Kv1.

Midazolam Hoffman-La Roche Ltd. On the day of the experiment, the stock solution was further diluted to the desired concentration with external solution. Double-electrode voltage-clamp experiments were carried out using a standard external solution containing 5 mM KCl, mM NaCl, 1. Electrodes were back-filled with 3 M KCl solution. As soon as a control measurement had been performed, electrodes were removed from the oocytes and cells were placed in small 10 mL dishes for drug incubation 30 minutes. After incubation, cells were again placed in the recording chamber and the experiment was repeated.

For the analysis of frequency dependence, cells were kept in the recording chamber after the control measurement without pulsing at the holding potential. Midazolam was washed-in over a period of 15 minutes, and the measurements were repeated. The Kv1. Out of the pSP64 plasmid, complementary Kv1.

Frogs were anesthetized with a solution containing 0. As soon as to oocytes had been carefully removed, the muscle layer and skin were sutured and the animal was revitalized. The volume of injected complementary RNA cRNA solution was 46 nL per oocyte, and measurements were carried out 1 to 3 days after injection. Human embryonic kidney HEK cells stably expressing Kv1. Data were low-pass-filtered at 1 to 2 kHz -3 dB, four-pole Bessel filter before digitalization at 5 to 10 kHz.

For patch-clamp experiments, cells were transferred from the incubator into a recording chamber which was continuously rinsed with bath solution. For measurements, single cells were selected. Dose-response curves were fitted to the Hill function:.

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  • First in a series on hyperkalemia: hyperkalemia, the sodium potassium pump and the heart.
  • Activation and inactivation curves were fitted to a Boltzmann function:. Inhibitory effects of midazolam on cloned Kv1. When activated with the depolarizing voltage step, Kv1.

    Geoffrey Winston Abbott

    Figure 1A exemplarily displays a single Kv1. Under control conditions, Kv1. The IC 50 in the Xenopus oocyte expression system was To underline the relevance of the observed effects, inhibitory effects of midazolam were next analyzed in a mammalian cell line HEK stably expressing Kv1. The IC 50 of inhibition was Figure 1 Midazolam inhibits cloned cardiac Kv1.

    Notes: A Representative current trace of a typical Kv1. B Dose—response curves for inhibition of Kv1. C Representative current trace of a typical Kv1. Effects of midazolam on biophysical properties of Kv1. Figure 2A and B display typical families of Kv1. The corresponding current—voltage relationship measured at peak current amplitude measured at the first dashed line in Figure 2A and B is displayed in Figure 2C. Figure 2 Pharmacological properties of Kv1. Notes: Typical families of Kv1. C Current—voltage relationship of Kv1.

    D Kv1. E Kv1. Channel inactivation curves were established by plotting tail current amplitude during the constant return pulse measured at the second dashed line in Figure 2A and B versus the test pulse potential of the preceding variable voltage step Figure 2E.

    Half-maximal inactivation voltages before and after midazolam application were obtained by fitting the data with a Boltzmann function. Time course of block development could be obtained by dividing the current trace after midazolam incubation by the corresponding current trace under control conditions Figure 3C and D. In both cases, block development was fast, yielding a mean time constant of 9. Figure 3 Time constants of channel inhibition. Time course of block development was determined by division. Frequency dependence of block is a common finding among ion channel inhibitors.

    In order to analyze if Kv1. Peak current amplitude of each pulse before and after drug incubation was measured to determine the degree of block. Figure 4D summarizes the inhibitory effects of midazolam on current amplitude. In order to achieve a clear presentation, data are only presented for every full second Figure 4D. Figure 4 Frequency dependence of Kv1. Notes: Frequency dependence of block was analyzed in Xenopus oocytes using three different pacing rates 1 Hz, 2 Hz, and 4 Hz. Abbreviations: t, time; s, seconds. We have shown that the anesthetic midazolam is a typical open-channel blocker of cardiac Kv1.

    So far, inhibitory effects of midazolam on Kv1. Pharmacological effects of midazolam on Kv1. Compared to native cardiomyocytes, the main advantage of these simplified cell models mainly relates to the absence of interfering ion currents. Strategies aimed at blocking these currents, either by using elaborated voltage protocols or small molecule inhibitors, might negatively influence the current under analysis.

    Within several pharmacological studies, we were able to prove that the human kidney cell line HEK represents a suitable cell model for the expression and analysis of cardiac ion channels. As expected, when analyzed in Xenopus oocytes, we found that considerably higher midazolam concentrations were necessary to achieve similar effects.

    This phenomenon is well recognized and has been attributed to diffusion barriers within Xenopus oocytes caused by the vitelline membrane and yolk sac. The dose—response relationship obtained in these cells is in line with previously published data on pharmacological inhibition of ion channels by the anesthetic midazolam. For the induction of anesthesia, the recommended intravenous midazolam dose is approximately 0.

    However, it has to be taken into account that midazolam acts as a multichannel inhibitor. Only recently, So et al reported inhibitory effects of midazolam on a neural delayed rectifier potassium current I K DR. Considering these additional effects, it is tempting to speculate that inhibitory effects on cardiac potassium channels might act in an additive manner. On the other hand, midazolam has also been shown to interfere with depolarizing ion channels.

    Action potential recordings obtained from human atrial myocytes would help with analysis of the net effect of midazolam on atrial electrophysiology. Taking all evidence, due to the complex electrophysiological mechanisms, definite conclusions of midazolam-induced effects on the shape and duration of cardiac action potential can only be drawn with great caution. From the in vitro and in vivo data available, the use of midazolam seems safe in clinical practice and the clinical relevance of its side effects on cardiac electrophysiology seem negligible under therapeutic dosages.

    Potassium Channels in Cardiovascular Biology Potassium Channels in Cardiovascular Biology
    Potassium Channels in Cardiovascular Biology Potassium Channels in Cardiovascular Biology
    Potassium Channels in Cardiovascular Biology Potassium Channels in Cardiovascular Biology
    Potassium Channels in Cardiovascular Biology Potassium Channels in Cardiovascular Biology
    Potassium Channels in Cardiovascular Biology Potassium Channels in Cardiovascular Biology
    Potassium Channels in Cardiovascular Biology Potassium Channels in Cardiovascular Biology
    Potassium Channels in Cardiovascular Biology Potassium Channels in Cardiovascular Biology

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