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Abstract
Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias.
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Affiliation(s)
- Christopher L-H Huang
- Physiological Laboratory and the Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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2
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Wen H, Gwathmey JK, Xie LH. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system. World J Hypertens 2012; 2:34-44. [PMID: 24587981 PMCID: PMC3936474 DOI: 10.5494/wjh.v2.i4.34] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Angiotensin II (Ang II), an endogenous peptide hormone, plays critical roles in the pathophysiological modulation of cardiovascular functions. Ang II is the principle effector of the renin-angiotensin system for maintaining homeostasis in the cardiovascular system, as well as a potent stimulator of NAD(P)H oxidase, which is the major source and primary trigger for reactive oxygen species (ROS) generation in various tissues. Recent accumulating evidence has demonstrated the importance of oxidative stress in Ang II-induced heart diseases. Here, we review the recent progress in the study on oxidative stress-mediated effects of Ang II in the cardiovascular system. In particular, the involvement of Ang II-induced ROS generation in arrhythmias, cell death/heart failure, ischemia/reperfusion injury, cardiac hypertrophy and hypertension are discussed. Ca2+/calmodulin-dependent protein kinase II is an important molecule linking Ang II, ROS and cardiovascular pathological conditions.
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3
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Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ Res 2010; 106:659-73. [PMID: 20203315 PMCID: PMC2837285 DOI: 10.1161/circresaha.109.206078] [Citation(s) in RCA: 475] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface "membrane clock" (M clock). Localized subsarcolemmal Ca(2+) releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular "Ca(2+) clock," because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca(2+) clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca(2+), and protein kinase A and CaMKII-dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein-coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs.
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Affiliation(s)
- Edward G Lakatta
- Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging/NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825, USA.
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4
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Abstract
The heart automaticity is a fundamental physiological function in higher organisms. The spontaneous activity is initiated by specialized populations of cardiac cells generating periodical electrical oscillations. The exact cascade of steps initiating the pacemaker cycle in automatic cells has not yet been entirely elucidated. Nevertheless, ion channels and intracellular Ca(2+) signaling are necessary for the proper setting of the pacemaker mechanism. Here, we review the current knowledge on the cellular mechanisms underlying the generation and regulation of cardiac automaticity. We discuss evidence on the functional role of different families of ion channels in cardiac pacemaking and review recent results obtained on genetically engineered mouse strains displaying dysfunction in heart automaticity. Beside ion channels, intracellular Ca(2+) release has been indicated as an important mechanism for promoting automaticity at rest as well as for acceleration of the heart rate under sympathetic nerve input. The potential links between the activity of ion channels and Ca(2+) release will be discussed with the aim to propose an integrated framework of the mechanism of automaticity.
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Affiliation(s)
- Matteo E Mangoni
- Institute of Functional Genomics, Department of Physiology, Centre National de la Recherche Scientifique UMR5203, INSERM U661, University of Montpellier I and II, Montpellier, France.
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5
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Browe DM, Baumgarten CM. Angiotensin II (AT1) receptors and NADPH oxidase regulate Cl- current elicited by beta1 integrin stretch in rabbit ventricular myocytes. ACTA ACUST UNITED AC 2005; 124:273-87. [PMID: 15337822 PMCID: PMC2233887 DOI: 10.1085/jgp.200409040] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Direct stretch of β1 integrin activates an outwardly rectifying, tamoxifen-sensitive Cl− current (Cl− SAC) via focal adhesion kinase (FAK) and/or Src. The characteristics of Cl− SAC resemble those of the volume-sensitive Cl− current, ICl,swell. Because myocyte stretch releases angiotensin II (AngII), which binds AT1 receptors (AT1R) and stimulates FAK and Src in an autocrine-paracrine loop, we tested whether AT1R and their downstream signaling cascade participate in mechanotransduction. Paramagnetic beads coated with mAb for β1-integrin were applied to myocytes and pulled upward with an electromagnet while recording whole-cell anion current. Losartan (5 μM), an AT1R competitive antagonist, blocked Cl− SAC but did not significantly alter the background Cl− current in the absence of integrin stretch. AT1R signaling is mediated largely by H2O2 produced from superoxide generated by sarcolemmal NADPH oxidase. Diphenyleneiodonium (DPI, 60 μM), a potent NADPH oxidase inhibitor, rapidly and completely blocked both Cl− SAC elicited by stretch and the background Cl− current. A structurally unrelated NADPH oxidase inhibitor, 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF, 0.5 and 2 mM), also rapidly and completely blocked Cl− SAC as well as a large fraction of the background Cl− current. With continuing integrin stretch, Cl− SAC recovered upon washout of AEBSF (2 mM). In the absence of stretch, exogenous AngII (5 nM) activated an outwardly rectifying Cl− current that was rapidly and completely blocked by DPI (60 μM). Moreover, exogenous H2O2 (10, 100, and 500 μM), the eventual product of NADPH oxidase activity, also activated Cl− SAC in the absence of stretch, whereas catalase (1,000 U/ml), an H2O2 scavenger, attenuated the response to stretch. Application of H2O2 during NADPH oxidase inhibition by either DPI (60 μM) or AEBSF (0.5 mM) did not fully reactivate Cl− SAC, however. These results suggest that stretch of β1-integrin in cardiac myocytes elicits Cl− SAC by activating AT1R and NADPH oxidase and, thereby, producing reactive oxygen species. In addition, NADPH oxidase may be intimately coupled to the channel responsible for Cl− SAC, providing a second regulatory pathway.
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Affiliation(s)
- David M Browe
- Department of Physiology, Medical College of Virginia, Box 980551, Richmond, VA 23298-0551, USA
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7
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Verkerk AO, Wilders R, Zegers JG, van Borren MMGJ, Ravesloot JH, Verheijck EE. Ca(2+)-activated Cl(-) current in rabbit sinoatrial node cells. J Physiol 2002; 540:105-17. [PMID: 11927673 PMCID: PMC2290232 DOI: 10.1113/jphysiol.2001.013184] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2001] [Accepted: 12/20/2001] [Indexed: 11/08/2022] Open
Abstract
The Ca(2+)-activated Cl(-) current (I(Cl(Ca))) has been identified in atrial, Purkinje and ventricular cells, where it plays a substantial role in phase-1 repolarization and delayed after-depolarizations. In sinoatrial (SA) node cells, however, the presence and functional role of I(Cl(Ca)) is unknown. In the present study we address this issue using perforated patch-clamp methodology and computer simulations. Single SA node cells were enzymatically isolated from rabbit hearts. I(Cl(Ca)) was measured, using the perforated patch-clamp technique, as the current sensitive to the anion blocker 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). Voltage clamp experiments demonstrate the presence of I(Cl(Ca)) in one third of the spontaneously active SA node cells. The current was transient outward with a bell-shaped current-voltage relationship. Adrenoceptor stimulation with 1 microM noradrenaline doubled the I(Cl(Ca)) density. Action potential clamp measurements demonstrate that I(Cl(Ca)) is activate late during the action potential upstroke. Current clamp experiments show, both in the absence and presence of 1 microM noradrenaline, that blockade of I(Cl(Ca)) increases the action potential overshoot and duration, measured at 20 % repolarization. However, intrinsic interbeat interval, upstroke velocity, diastolic depolarization rate and the action potential duration measured at 50 and 90 % repolarization were not affected. Our experimental data are supported by computer simulations, which additionally demonstrate that I(Cl(Ca)) has a limited role in pacemaker synchronization or action potential conduction. In conclusion, I(Cl(Ca)) is present in one third of SA node cells and is activated during the pacemaker cycle. However, I(Cl(Ca)) does not modulate intrinsic interbeat interval, pacemaker synchronization or action potential conduction.
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Affiliation(s)
- Arie O Verkerk
- Academic Medical Center, University of Amsterdam, Task Force Heart Failure and Aging, Department of Physiology, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
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8
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Abstract
Anion transport proteins in mammalian cells participate in a wide variety of cell and intracellular organelle functions, including regulation of electrical activity, pH, volume, and the transport of osmolites and metabolites, and may even play a role in the control of immunological responses, cell migration, cell proliferation, and differentiation. Although significant progress over the past decade has been achieved in understanding electrogenic and electroneutral anion transport proteins in sarcolemmal and intracellular membranes, information on the molecular nature and physiological significance of many of these proteins, especially in the heart, is incomplete. Functional and molecular studies presently suggest that four primary types of sarcolemmal anion channels are expressed in cardiac cells: channels regulated by protein kinase A (PKA), protein kinase C, and purinergic receptors (I(Cl.PKA)); channels regulated by changes in cell volume (I(Cl.vol)); channels activated by intracellular Ca(2+) (I(Cl.Ca)); and inwardly rectifying anion channels (I(Cl.ir)). In most animal species, I(Cl.PKA) is due to expression of a cardiac isoform of the epithelial cystic fibrosis transmembrane conductance regulator Cl(-) channel. New molecular candidates responsible for I(Cl.vol), I(Cl.Ca), and I(Cl.ir) (ClC-3, CLCA1, and ClC-2, respectively) have recently been identified and are presently being evaluated. Two isoforms of the band 3 anion exchange protein, originally characterized in erythrocytes, are responsible for Cl(-)/HCO(3)(-) exchange, and at least two members of a large vertebrate family of electroneutral cotransporters (ENCC1 and ENCC3) are responsible for Na(+)-dependent Cl(-) cotransport in heart. A 223-amino acid protein in the outer mitochondrial membrane of most eukaryotic cells comprises a voltage-dependent anion channel. The molecular entities responsible for other types of electroneutral anion exchange or Cl(-) conductances in intracellular membranes of the sarcoplasmic reticulum or nucleus are unknown. Evidence of cardiac expression of up to five additional members of the ClC gene family suggest a rich new variety of molecular candidates that may underlie existing or novel Cl(-) channel subtypes in sarcolemmal and intracellular membranes. The application of modern molecular biological and genetic approaches to the study of anion transport proteins during the next decade holds exciting promise for eventually revealing the actual physiological, pathophysiological, and clinical significance of these unique transport processes in cardiac and other mammalian cells.
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Affiliation(s)
- J R Hume
- Department of Physiology, University of Nevada School of Medicine, Reno, Nevada, USA.
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9
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Schmid HA. Effect of glutamate and angiotensin II on whole cell currents and release of nitric oxide in the rat subfornical organ. Amino Acids 1999; 14:113-9. [PMID: 9871450 DOI: 10.1007/bf01345251] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Blood-borne angiotensin II (AngII) is known to mediate water-intake by its excitatory effect on neurons in the subfornical organ (SFO). Conversely, nitric oxide (NO) has exclusively inhibitory effects on rat SFO-neurons and on SFO-mediated water-intake. Extracellular and patch-clamp recordings from freshly dissociated rat SFO-neurons showed that glutamate activates AngII-sensitive SFO-neurons by opening ligand-gated cation channels. An immunocytochemical study showed that activation of glutamate receptors increased the concentration of the inhibitory second messenger cGMP in the SFO. A model is proposed suggesting that NO protects SFO-neurons from overexcitability by excitatory neurotransmitters.
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Affiliation(s)
- H A Schmid
- Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Federal Republic of Germany
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10
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Albrecht D, Broser M, Krüger H, Bader M. Effects of angiotensin II and IV on geniculate activity in nontransgenic and transgenic rats. Eur J Pharmacol 1997; 332:53-63. [PMID: 9298925 DOI: 10.1016/s0014-2999(97)01062-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Microiontophoretic ejection of angiotensin II and angiotensin IV in the vicinity of geniculate neurons was used to study the effects of these peptides on the discharge rate and the discharge pattern of extracellularly recorded activity. The main aim of the experiments was to study the effects of angiotensins in different strains of rats anesthetized with urethane (normotensive Wistar, normotensive Sprague-Dawley and hypertensive, transgenic (TGR(mREN2)27) rats). Both angiotensins mostly increased the spontaneous activity of angiotensin-sensitive geniculate neurons in all strains. Angiotensin II reduced the number of bursts in most neurons, whereas angiotensin IV significantly enhanced it. Inhibitory effects of angiotensins on spontaneous as well as on light-evoked activity could be effectively blocked by GABA(A) or GABA(B) receptor antagonists. Therefore, it can be supposed that angiotensin-containing afferent fibers innervate both projection and local circuit neurons of the dorsal lateral geniculate nucleus. In addition, angiotensin II suppressed excitation induced by glutamate receptor agonists in most neurons tested. Angiotensin-induced effects could be blocked by specific receptor antagonists. There were no significant differences in the effects of angiotensins in the various strains of rats, except for the latencies of the neuronal responses to the iontophoretic ejection of angiotensins.
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Affiliation(s)
- D Albrecht
- Institute of Physiology, Faculty of Medicine (Charité), Humboldt University, Berlin, Germany.
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11
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Albrecht D, Broser M, Krüger H. Excitatory action of angiotensins II and IV on hippocampal neuronal activity in urethane anesthetized rats. REGULATORY PEPTIDES 1997; 70:105-9. [PMID: 9272622 DOI: 10.1016/s0167-0115(97)00015-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The renin-angiotensin system of the mammalian brain seems to interfere with the process of cognition and has been associated with the hippocampal function in relation to mechanisms of learning and memory. In our investigation, the effects of angiotensin II (Ang II) and angiotensin IV (Ang II) on neuronal activity have been studied in the hippocampus of adult rats anesthetized with urethane. Excitatory effects of both angiotensins predominated over inhibitory effects. Angiotensins also induced an enhancement of burst discharges. These angiotensin-induced effects were blocked by the specific angiotensin antagonists. Our findings showed that the different effects of Ang II and Ang IV in behavioral studies are not similarly reflected in a different change of the discharge rate and/or pattern of hippocampal neurons after microiontophoretic administration of both substances.
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Affiliation(s)
- D Albrecht
- Institute of Physiology, Faculty of Medicine (Charité), Humboldt University, Berlin, Germany.
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12
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Guibert C, Marthan R, Savineau JP. Oscillatory Cl- current induced by angiotensin II in rat pulmonary arterial myocytes: Ca2+ dependence and physiological implication. Cell Calcium 1997; 21:421-9. [PMID: 9223678 DOI: 10.1016/s0143-4160(97)90053-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We have previously reported that angiotensin II (ANG II) induces oscillations in the cytoplasmic calcium concentration ([Ca2+]i) of pulmonary vascular myocytes. The present work was undertaken to investigate the effect of ANG II in comparison with ATP and caffeine on membrane currents and to explore the relation between these membrane currents and [Ca2+]i. In cells clamped at -60 mV, ANG II (10 microM) or ATP (100 microM) induced an oscillatory inward current. Caffeine (5 mM) induced only one transient inward current. In control conditions, the reversal potential (Erev) of these currents was close to the equilibrium potential for Cl- ions (Ecl = -2.1 mV) and was shifted towards more positive values in low-Cl- solutions. Niflumic acid (10-50 microM) and DIDS (0.25-1 mM) inhibited this inward current. Combined recordings of membrane current and [Ca2+]i by indo-1 microspectrofluorimetry revealed that ANG II- and ATP-induced currents occurred simultaneously with oscillations in [Ca2+]i whereas the caffeine-induced current was accompanied by only one transient increase in [Ca2+]i. Niflumic acid (25 microM) had no effect on agonist-induced [Ca2+]i responses, whereas thapsigargin (1 microM) abolished both membrane current and the [Ca2+]i response. Heparin (5 mg/ml in the pipette solution) inhibited both [Ca2+]i responses and membrane currents induced by ANG II and ATP, but not by caffeine. In pulmonary arterial strips, ANG II-induced contraction was inhibited by niflumic acid (25 microM) or nifedipine (1 microM) to the same extent and the two substances did not have an additive effect. This study demonstrates that, in pulmonary vascular smooth muscle, ANG II, as well as ATP, activate an oscillatory calcium dependent chloride current which is triggered by cyclic increases in [Ca2+]i and that both oscillatory phenomena are primarily IP3-mediated. It is suggested that ANG II-induced oscillatory chloride current could depolarise the cell membrane leading to activation of voltage-operated Ca2+ channels. The resulting Ca2+ influx contributes to the component of ANG II-induced contraction that is equally sensitive to chloride or calcium channel blockade.
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Affiliation(s)
- C Guibert
- Laboratoire de Physiologie Cellulaire Respiratoire, Université Bordeaux 2, France
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Chorvatova A, Gallo-Payet N, Casanova C, Payet MD. Modulation of membrane potential and ionic currents by the AT1 and AT2 receptors of angiotensin II. Cell Signal 1996; 8:525-32. [PMID: 9115844 DOI: 10.1016/s0898-6568(96)00117-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Angiotensin II, the principal effector of the renin-angiotensin system, modulates various ionic currents. Its effects on potassium currents, including outward transient potassium current, the inward or outward rectifiers, as well as Ca(2+)- activated potassium currents, is well described. Other ionic currents, such as voltage-dependent calcium currents, cationic or chloride currents, are also altered by the hormone. All these effects provoke changes in membrane potential, such as modulation of action potential firing or resting membrane potential and control intracellular calcium concentration. Summarized here are the results obtained on these membrane electrical properties using electrophysiological recordings.
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Affiliation(s)
- A Chorvatova
- Department of Physiology and Biophysics, Faculty of Medicine, Sherbrooke, Québec, Canada
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Rials SJ, Wu Y, Pauletto FJ, Abramson SV, Marinchak RA, Kowey PR. Effect of an intravenous angiotensin-converting enzyme inhibitor on the electrophysiologic features of normal and hypertrophied feline ventricles. Am Heart J 1996; 132:989-94. [PMID: 8892773 DOI: 10.1016/s0002-8703(96)90011-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmia and multiple electrophysiologic abnormalities that normalize with regression of hypertrophy. For patients who have hypertension, treatment with angiotensin-converting enzyme (ACE) inhibitors produces regression of hypertrophy and a reduction in ventricular arrhythmia. It is unclear whether the reduction in ventricular arrhythmia associated with ACE inhibitor therapy is due to regression of hypertrophy alone, a direct antiarrhythmic effect of ACE inhibition, or both. We performed electrophysiologic studies in normal cats and cats with fixed left ventricular hypertrophy before and after acute intravenous administration of trandolopril. Trandolopril produced a small, consistent prolongation of monophasic action potential duration in normal and hypertrophied ventricles although this prolongation did not reach statistical significance. Trandolopril had no significant effect on effective refractory period, inducibility of arrhythmia, or ventricular fibrillation threshold in normal or hypertrophied ventricles. These data suggest that the reduction in arrhythmia associated with ACE inhibitors is not caused by a direct electrophysiologic effect but is more likely caused by regression of hypertrophy.
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Affiliation(s)
- S J Rials
- Cardiovascular Division, The Lankenau Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
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