Explore chapters and articles related to this topic
Effects of Calcium Channel Antagonists on The Myometrium
Published in Gabor Huszar, The Physiology and Biochemistry of the Uterus in Pregnancy and Labor, 2020
Ronald A. Janis, David J. Triggle
Fleckenstein1 describes two different actions of these drugs on uterine and visceral smooth muscle response: (1) inhibition of electrogenic Ca2+ influx; (2) inhibition of excitation-contraction coupling. The former refers, in part, to the blockade of spontaneous or evoked action potentials. This mechanism of drug action is considered to be very similar to that for the inhibition of cardiac pacemaker current. Ca2+-dependent action potentials of uterine muscle are inhibited by these drugs independent of whether the action potential is spontaneous or is evoked by stretch, high K+, OT or prostaglandins.145,46 Spontaneous action potentials are very sensitive to Ca2+ channel antagonists. For example, in 1 m M Ca2+ they are completely blocked with 200 nM gallopamil (D600). This inhibition was potentiated by lowering the extracellular Ca2+ concentration and was completely reversed from standstill by elevation of extracellular Ca2+ from 1 mM to only 3 to 5 mM.1 Other examples of the effect of these drugs on uterine electrical and mechanical activation are shown in Figure 2. A marked reduction in the amplitude of the so-called “slow waves” was seen with gallopamil, as was a decrease in the slope of the prepotential in cells in the pacemaker areas of the muscle, but no change in resting membrane potential was observed.47
Adrenoceptors: Classification and Distribution
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The rate of development of Phase 4 depolarization of the SA node is increased by β-adrenoceptor stimulation through increased rate of activation of the pacemaker current. Precisely which ion channels are involved in this process is not known, β-Adrenoceptor stimulation increases the outward K+ current (?iK). However, this alone would paradoxically have the effect of slowing pacemaker activity since it would reverse the decay of the outward K+ current. Thus, increased pacemaker activity appears to be due to activation of the inward pacemaker current (if). The role of the activation of the iK current is to accelerate repolarization (Phase 3) and shorten the action potential duration. This will allow the heart to speed up by keeping action potential duration within the shorter cycle length (DiFrancesco 1993). The normally quiescent Purkinje fibres can display spontaneous activity when exposed to β-adrenoceptor agonists, an effect probably only mediated via β1-adrenoceptors (Masini et al. 1991). Catecholamines also cause disturbances of rhythm due to induction of delayed after-depolarizations. These are secondary depolarizations that take place after repolarization has occurred and which precede the Phase 0 spontaneous depolarizations. When these reach the threshold level, they trigger a single premature depolarization and contraction. If these are repetitive they cause tachyarrhythmias or multiple extrasystoles.
Electrical Properties of the Heart
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
The maximum diastolic potential of a sinus node cell is −65 mV. Phases 1 and 2 (of the fast response cardiac action potential) are absent in the SA node as there is no depolarization plateau (Figure 24.1). Phase 4. The pacemaker current is determined by hyperpolarization-activated cyclic nucleotide (HCN)–gated channels. From the maximum diastolic potential (−65 mV), a slow, spontaneous depolarization occurs towards a threshold potential of approximately −40 mV. The pacemaker potential is produced by a fall in potassium permeability (iK) and an inward sodium ‘funny’ current (If) produced by the opening of sodium channels. The funny current is a mixed sodium–potassium current that is activated when the SA action potential is repolarized below about −40 to −50 mV and provides the inward current that is responsible for initiating the diastolic depolarization phase. The funny current is also activated by cAMP. The binding of cAMP to the If channels enhances the opening of the channels. Sympathetic stimulation increases cAMP molecules, which bind to the If channels and increase the diastolic current, resulting in an increase in the steepness of the diastolic depolarization phase. Ivabradine is a selective If inhibitor used to control tachycardia that is resistant to conventional anti-arrhythmic drugs. The slow, inward current brings the membrane to the threshold potential (−40 mV) of T-type calcium channels, which open for the upstroke. The voltage-gated increase in calcium permeability via transient calcium channels results in an inward movement of calcium ions. The SA node exhibits automaticity because it spontaneously generates action potentials without neural input.Phase 0. Depolarization is produced by the opening of long-lasting (L-type), voltage-gated calcium channels (iCaL) and inward movement of Ca++ ions. No sodium current is involved in the SA node potential. The SA node potential reaches a peak at about 20 mV.Phase 3. Repolarization is accomplished by a late increase in potassium permeability and outward flow of K+ ions. This is the result of an increase in repolarizing currents (iK becomes activated by positive potentials), causing a late increase in potassium permeability and outward flow of ions.
A review on qualifications and cost effectiveness of induced pluripotent stem cells (IPSCs)-induced cardiomyocytes in drug screening tests
Published in Archives of Physiology and Biochemistry, 2023
Golrokh Malihi, Vahid Nikoui, Elliot L. Elson
(Karakikes et al.2015, Denning et al.2016). In addition, hiPSC-CMs’ spontaneously beating suggests that pacemaker current is expressed more excessively (Denning et al.2016). Numerous investigators have extensively searched for the use of electrical and/or mechanical stimulation in order to get their impact on their maturation in cardiomyocyte cell culture (Zhu et al.2014). It has been found that electrical pacing can induce activation of L-type Ca++ channels to increase intracellular Ca++ concentration and therefore stimulate contractility Devices have been created to provide both electrical stimulation and mechanical stretch or cyclic stretch in order to reach this purpose. Using devices that have a control interface and special plates out fitted with electrodes that could not only improve and mature functionality, but also can induce arrhythmia and tachycardia. Cells must be subjected to electrical pacing and/or electrical cyclic stretch for a period of time, but it may be costly and unaffordable for some laboratories. The mechanism by which the above protocol works for maturation, remains to be well understood. It has been suggested that conditional cues can stimulate the expression of certain genes involved in changes in maturation of cardiomyocyte structure and contractility. Increased expression of SERCA2 and RYR2 have been shown after static stress (Prana and Greenway 2019).
The roles of human induced pluripotent stem cell-derived cardiomyocytes in drug discovery: managing in vitro safety study expectations
Published in Expert Opinion on Drug Discovery, 2020
iPSC-CMs do not fully resemble the electrophysiological phenotype of adult ventricular cardiomyocytes, with automaticity being a primary phenotypic characteristic of hiPSC-CMs (acutely isolated adult ventricular myocytes are not spontaneously active and need repetitive stimulation to elicit contractions and maintain an adult phenotype). Automaticity in hiPSC-CMs causes spontaneous beating, so no external stimulation is required (a convenient characteristic of myocytes in multi-well plates). hiPSC-CM automaticity is attributed partly to enhanced net inward current resulting from a) greater depolarizing current density of the pacemaker current IF (the predominant current found in the sinoatrial node of the adult heart [13]), and b) lesser repolarizing current density of the inward rectifier potassium current iK1 (which stabilizes the resting membrane potential in adult cardiomyocytes and is responsible for the final phase of repolarization [14]. Differences in the contributions of IF and iK1 in hiPSC-CMs vs. also contribute to the partially depolarized diastolic potentials of hiPSC-CMS (~−57 to −70 mV instead of −85 mV) [15]. These deficits also impact conduction and upstroke velocities of the cardiac action potentials by increasing the resting level of sodium current inactivation and thereby reducing the depolarizing current density responsible for impulse conduction.
Comparing the effect of oral ivabradine versus oral propranolol premedication during controlled hypotensive anesthesia in functional endoscopic sinus surgery
Published in Egyptian Journal of Anaesthesia, 2022
Mostafa Abdallah Lotfy Mohamed, Raafat Abdelazim Hammad, Heba Abdelazim Labib, Hany Attia Abdelgalial, Ahmed Moustafa Mohamed
Ivabradine inhibits specific ionic current (If) channels (pacemaker current) in the sinoatrial node. It is used in patients with heart failure and ischemic heart disease. Compared to beta-blockers, ivabradine causes a reduction in heart rate without significantly affecting the hemodynamics in unwell, compromised patients. It is absorbed entirely and rapidly from the gastrointestinal tract when taken orally. It reaches its maximal plasma level within 1 hour of dosing [6].