MINIREVIEW
Electrophysiological effects of angiotensin II. Part I: signal transduction and basic electrophysiological mechanisms
1 Division of Cardiology, University Hospital Magdeburg, Leipzigerstr. 44, Magdeburg 39120, Germany; 2 Institute of Experimental Internal Medicine, University Hospital Magdeburg, Magdeburg 39120, Germany
Manuscript submitted 17 October 2007. Accepted after revision 28 November 2007.
* Corresponding author. Tel: +49 391 6713225; fax: +49 391 671 3202.E-mail address: andreas.goette{at}medizin.uni-magdeburg.de
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Abstract |
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 Top Abstract IntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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In the recent years, a tremendous amount has been learned about the pathophysiology and molecular biology of the cardiac angiotensin II system. Interestingly, the angiotensin II appears to have several effects on cardiac electrophysiology, which have not been fully appreciated so far. Therefore, this review will highlight on the basic knowledge of signal transduction and electrophysiological effects of angiotensin II, which may have an impact on the occurrence of cardiac arrhythmia.
Key Words: Angiotensin, Arrhythmias, Fibrillation, Molecular biology, Receptors, Signal transduction
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Introduction |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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The renin–angiotensin II system has a significant impact on cardiac performance.1
,2 Decades ago it was shown that angiotensin II contributes to the remodelling of the ventricles after myocardial infarction (MI). Therefore, inhibitors of the angiotensin converting enzyme (ACE) or of angiotensin II type 1 receptors (ARB) have gained popularity to prevent ventricular remodelling after MI, to treat left ventricular systolic failure, and to lower systemic blood pressure. However, in recent it was realized that angiotensin II influences properties of ion channels and ion pumps. Furthermore, angiotensin II-induced interstitial fibrous tissue accumulation was noted to impair electrical conduction. Thus, inhibition of the angiotensin II-induced signal transduction may influence via direct antiarrhythmic effects the occurrence of atrial and ventricular arrhythmias. This review summarizes the basic effects of angiotensin II on cardiac electrophysiology. Signalling pathways including common abbreviations are summarized/explained in Figure 1.
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Angiotensin II signalling |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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Angiotensin II, a vasoactive peptide, is generated from angiotensin I by either the ACE, tissue chymase, cathepsin G, or CAGE (chymostatin-sensitive angiotensin generating enzyme). Angiotensin I can also be cleaved by neutral endopeptidases (NEP) to angiotensin peptide 1–7 which antagonizes some of the effects of angiotensin II. Recently, a second converting enzyme called ACE 2 has recently been described that cleaves angiotensin I to angiotensin peptide 1–9.1
–3
Angiotensin II receptors belong to the so-called heptahelical receptors. Heptahelical receptors contain seven membrane-spanning 
-helices. Because these receptors interact with guanyl nucleotide-binding proteins (G proteins), they are called G protein-coupled receptors. The ligand-binding site of these receptors is on the extracellular surface of the plasma membrane, while the G protein binding site faces the cytosol. G proteins consist of three subunits (, β, and 
), of which has guanosinetriphosphat (GTP) binding and GTPase activity. The activated -subunits regulate effector molecules such as adenylyl cyclase, and phospholipase C. Signalling is terminated after hydrolysis of GTP to guanosinediphosphat (GDP). Desensitization of G protein-coupled receptor leads to uncoupling from the G protein, which is associated with receptor phosphorylation, internalization and recycling. Receptor phosphorylation is mediated by G protein receptor kinases.1–3
Two major classes of angiotensin II receptors have been described. Activation of the angiotensin II type 1 receptors (AT-1) induces a cascade of phosphorylations that activate so-called mitogen-activated protein kinases (MAP kinases), which stimulate proliferation of fibroblasts, cellular hypertrophy, and apoptosis. Signalling pathways mediated by AT-1 receptors are linked predominantly to Gq/11, G12/13, and Gi classes of G proteins (Figure 1). Thereafter, a Shc/Grb2/SOS complex is formed that leads to activation of a monomeric protein called Ras. Ras-GTP interacts with Raf-1 and activated Raf-1 then phosphorylates MEK-1 and MEK-2 (MEK: Erk-activating kinases). In the final step of this signalling cascade, ERK-1 and ERK-2 (Erk1/2: extracellular-signal regulated kinases) are activated by phosphorylation. ERKs lead to activation of transcription factors, which are responsible for the cellular effects. In addition to ERKs, angiotensin II causes activation of other MAP kinases, such as p38 MAP kinase and c-Jun NH2-terminal kinase, which can induce apoptotic cells death. Activation of AT-1 stimulates also phospholipase C, leading to DAG (diacylglycerol)-mediated activation of protein kinase C (PKC) and to IP3 (inositol, 1,4,5-trisphosphate) mediated release of calcium from intracellular stores. Furthermore, PKC phosphorylates L-type calcium channels, which increases calcium influx and it can inhibit potassium channels, such as Ito and the delayed rectifier (Figure 1). Regulation of AT-1 receptors depends on G protein receptor kinases and possibly PKC, which induce phosphorylation and desensitization. In contrast to the effects observed after activation of AT-1 receptors, activation of the angiotensin II type 2 receptor (AT-2) inhibits MAP kinases via activation of different phosphatases (Figure 1). Thus, activation of AT-2 receptors has antiproliferative effects and supports cell survival.
Traditionally, G-protein-coupled receptors were thought to act as monomers, in which one ligand binds and activates a single receptor-G-protein complex. Newer evidence, however, points to the existence of higher-order complexes (dimers or oligomers) with altered pharmacology, responsiveness, or both. A recent report by AbdAlla et al.4 not only underscores the critical nature of a dimer made up of AT-1 receptors, but also describes a pivotal event in the formation of the dimer. They first confirmed that monocytes from patients with essential hypertension were activated in an angiotensin II-dependent manner, responding to the peptide with enhanced cytokine release and adhesion to endothelial cells.4 Nevertheless, it needs to be determined whether dimerization of AT-1 receptors also contributes to enhanced cardiac angiotensin II effects.
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Effects of angiotensin II on ion channels |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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Angiotensin II activates PKC, and thereby, phosphorylation of L-type calcium channels, which increases calcium influx (Figure 1). This effect contributes to the positive inotropic effect of angiotensin II. Inhibition of the angiotensin II activity on L-type calcium channels may reduce cellular calcium load. This action appears of particular interest in situation of increased cellular calcium load or even calcium overload. Nakashima et al.5
have shown that candesartan and captopril have a beneficial effect on atrial electrical remodelling (induced by cellular calcium overload and feedback inhibition of L-type calcium channels) induced by rapid atrial pacing.
Besides the effects on calcium channels, angiotensin II effects potassium currents (e.g. transient outward current, delayed rectifier), and thereby, influences the voltage of the plateau of the action potential (AP). A recent study has investigated the immediate effects of angiotensin II on the slow component of delayed rectifier K+ current (IKs) and APs in guinea pig atrial myocytes using the whole-cell patch-clamp technique.6 Bath application of angiotensin II increased the amplitude of IKs concentration dependently. The voltage dependence of IKs activation and the kinetics of deactivation were not significantly affected by angiotensin II. The enhancement of IKs was blocked by the AT-1 receptor antagonist valsartan and was markedly attenuated by inclusion of GDPßS, indicating an involvement of G protein-coupled AT-1 receptor. The stimulatory effect was also significantly reduced by the phospholipase C inhibitor compound and the PKC inhibitors, suggesting that AT-1 receptor acts through phospholipase C–PKC signalling cascade to potentiate IKs. It was concluded that the potentiation of IKs via AT-1 stimulation in atrial myocytes, accompanied by a shortening of the AP duration, suggests a potential mechanism by which elevated levels of angiotensin II may promote atrial fibrillation (AF).6 In addition to the atrial effects, losartan decreases Ether-A-Go-Go Related Gen (HERG) currents in ventricular myocytes. It has been shown that losartan shifts the midpoint of the activation curve of HERG channels to more negative potentials. Thus, losartan can lengthen the duration of the ventricular APs at both 50 and 90% of repolarization, which may affect QT dispersion.
Angiotensin II may not only affect ion channels by receptor-channel interactions, it may further contribute to channel expression. Hypertrophied ventricular myocytes exhibit prolonged APs and decreased transient outward potassium current (Ito).7 Kv4.3 is a major contributor to Ito. A recent study examined regulation of Kv4.3 expression in neonatal rat cardiac myocytes in response to angiotensin II and phenylephrine (PE). Of note, RNase protection assays and immunoblots revealed that angiotensin II and PE each downregulate Kv4.3 mRNA and protein. However, although PE induces a faster and more extensive hypertrophic response than angiotensin II, the PE effect on Kv4.3 mRNA develops slowly and is sustained, whereas angiotensin II rapidly and transiently decreases Kv4.3 mRNA expression. Pharmacological experiments also indicate that PE and angiotensin II act independently to downregulate Kv4.3 gene expression. Thus, regulation of Kv4.3 gene expression is not a simple secondary response to hypertrophy.7
Recently, a transmural gradient for Ito has been shown. Ito is responsible for the notch of the ventricular AP seen in myocardial layers close to the epicardium.8 In contrast, this notch is absent at the endocardium (Figure 2). Interestingly, it was shown that angiotensin II causes via inhibition of Ito the endocardial differences in AP shape. The use of an ARB induced epicardial AP morphology in endocardial myocytes, whereas application of angiotensin II to epicardial myocytes caused the loss of the AP-notch. An increased level of angiotensin II at the ventricular endocardium, possibly due to an increased expression of ACE, is one possible explanation for the shape of the AP. Thus, inhibition of PKC-dependent activation of potassium currents (Ito, IKs) by ARBs and ACE inhibitors may influence repolarization and the QT dispersion, especially in situations, in which cardiac angiotensin levels are increased (hypertensive heart disease, heart failure, etc). Besides such indirect effects of ARBs and ACE inhibitors on ion currents, studies have also shown that irbesartan binds directly to Kv4.3 (Ito) and hKv1.5 channels (IKur). Moreno et al.9 demonstrated that irbesartan blocks these channels at therapeutic concentrations. Irbesartan exhibits a high affinity for Kv4.3 (Ito) and hKv1.5 channels (IKur). However, the efficacy of block appears low because the maximum blockade obtained was <60 and 30%, respectively. Elegant molecular modelling of the binding sites of irbesartan revealed a receptor site on each of the four -subunits of the hKv1.5 channel. Binding of irbesartan to one -subunit decreases the affinity for the binding to the other non-occupied sites. Interaction of irbesartan is voltage-dependent and occurs in the open state of the channel. In contrast to the effects on Kv4.3 (Ito) and hKv1.5 channels (IKur), other potassium channels like HERG and KvLQT1 are blocked by irbesartan at supratherapeutic levels only. Similar to the results obtained for irbesartan, other ARBs like candesartan exert comparable effects on ion channels. However, caution should be still exerted at present before experimental data obtained are extrapolated on clinical practise.
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Effects of angiotensin II on gap junctions |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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Angiotensin II causes a decrease in gap junctional conduction, which increases the likelihood for re-entrant ventricular arrhythmia. Fischer et al.10
showed in rats harbouring the human renin and angiotensinogen genes pronounced changes in Cx43 immunoreactivity. In that model the structure of intercalated discs appears disorganized, with broad and diffuse gap-junction plaques. Furthermore, there is an increased diffuse localization of Cx43 in the transitional junction zone and within the cytosol. Importantly, losartan treatment results in a nearly normal Cx43 distribution pattern in this animal model. Nevertheless, the exact intracellular signalling pathway, how angiotensin II causes alterations in CX43 expression remains to be determined. Besides angiotensin II induced changes on ion channels and gap junctions, angiotensin II contributes to the occurrence of tachyarrhythmias by increasing calcium release from sarcoplasmic reticulum in myocytes and by an increased activity of the Na+/Ca2+ antiporter (Figure 1). |
Interaction of angiotensin II and catecholamines |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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Endogenous catecholamines, norepinephrine, and epinephrine, are released by postganglionic nerve terminals. After interaction with their heptahelical receptors, catecholamines activate intracellular signalling cascades. There is increasing evidence of ‘cross-talk’ between the adrenergic system and the rennin–angiotensin–aldosterone system. Angiotensin II increases norepinephrine release from sympathetic nerves via activation of prejunctional AT-1 receptors.11
Thus, an angiotensin II-induced local catecholamine excess increases automaticity in atrial and ventricular tissue. |
Angiotensin II and arrhythmogenesis |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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Increased mechanical stress/stretch induced by cardiac volume or pressure overload increases myocardial generation of angiotensin II. Thus, cardiovascular diseases like arterial hypertension and left ventricular failure (systolic/diastolic) induce angiotensin II-dependent electrophysiological and structural changes within atrial and ventricular myocardium.
The potentiation of IKs via AT-1 stimulation in atrial myocytes, accompanied by a shortening of the AP duration, is a potential mechanism for the occurrence of AF.6 Furthermore, studies also suggest that angiotensin II increases via interaction with Ca2+/Na+antiporter and/or increased catecholamine release, the rate of ectopy originating from the pulmonary veins and the posterior left atrium. Experiments have shown that AF is associated with an increased atrial expression and activity of ACE.12,13 Thus, inhibition of atrial angiotensin II-dependent effects by ACE inhibitors and ARBs reduce the degree of atrial fibrosis, and thereby the inducibility of AF.12,13 In experimental settings, ACE inhibitors and AT-1 receptor blockers were similarly effective (Figure 1). Kumagai et al.13 could show in a rapid atrial pacing model that candesartan reduces the development of atrial fibrosis after 4 weeks of rapid atrial pacing compared with untreated controls. In addition, candesartan shortened the duration of induced episodes of AF. A recent study could demonstrate that the increasing atrial collagen content in patients with AF is inversely correlated with microcapillary density. Molecular studies have clearly shown that ACE expression is upregulated and profibrotic MAP kinase pathway is activated in patients with AF.11,12 Of note, treatment with ACE-inhibitors attenuated the amount of interstitial fibrosis and diminished the rarification of microcapillaries in human atria.14 Besides these interstitial structural changes in fibrillating atria, recent studies also demonstrate the importance of cellular remodelling. Hypertrophy of atrial myocytes is known to induce substantial inhomogeneities in electrical conduction (anisotropy). Thereby, atrial hypertrophy, potentially influenced by alterations in gap junction expression/conductivity, is an important factor facilitating the inducibility of AF. In addition, AF itself contributes to the development of atrial hypertrophy.12 The experimental results showing antiarrhythmic effects of ACE inhibitors and ARBs to prevent AF are supported by retrospective clinical trials.15
Besides the proarrhythmic effects of angiotensin II in the atria, angiotensin II increases transmural dispersion of refractoriness in the ventricles. Xiao et al.16 could clearly show a substantial increased rate of sudden cardiac death in mice with 100-fold normal cardiac ACE expression. Interestingly, the myocardium of these mice do not show increased amounts of interstitial tissue suggesting ‘non-structural’ mechanisms as the cause of SCD. Furthermore, a recent study by Fischer et al.10 analysed the electrocardiogram telemetry in a double-transgenic, angiotensin II-induced rat model (rats harbouring the human renin and angiotensinogen genes; dTGR) of target organ damage. They found that ventricular tachycardia (VT) is a common terminal event in these animals. Already by 5 weeks of age, untreated dTGR showed increased perivascular and interstitial fibrosis, connective tissue growth factor expression, and monocyte infiltration compared with Sprague-Dawley rats, differences that progressed through time. Left-ventricular mRNA expression of potassium channel subunit Kv4.3 and gap-junction protein connexin 43 were significantly reduced in dTGR compared with losartan-treated dTGR. QT intervals were significantly prolonged in dTGR. Interestingly, VT could be induced in 88% of dTGR, but only in 33% of losartan-treated dTGR.10 In summary, angiotensin II has several proarrhythmic electrophysiological and structural effects (Figure 1), which might be attenuated or prevented by the use of ARBs or ACE inhibitors, and therefore, these substances may serve as add-on therapy to antiarrhythmic treatment.
Conflict of interest: none declared.
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Funding |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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Funding to pay the Open Access publication charges for this article was provided by the University Hospital Magdeburg.
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References |
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TopAbstractIntroductionAngiotensin II signallingEffects of angiotensin II...Effects of angiotensin II...Interaction of angiotensin II...Angiotensin II and...FundingReferences |
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