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Beneficial versus harmful effects of Angiotensin (1-7) on impulse propagation and cardiac arrhythmias in the failing heart

Department of Pharmacology, Medical Sciences Campus, School of Medicine, UPR, PR, USA, wmello{at}rcm.upr.edu

Carlos M Ferrario

Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Jewell A Jessup

Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Introduction. The presence of Angiotensin (1-7) (Ang 1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters as well as the influence of Ang (1-7) on membrane potential, impulse propagation and cardiac excitability were investigated.

Methods. Histology and immunochemistry were used to demonstrate the presence of Ang (1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters. Measurements of transmembrane potentials, conduction velocity and refractoriness were made using conventional intracellular microelectrodes. The influence of Ang (1-7) on sodium pump current was investigated in voltageclamped myocytes isolated from the ventricle.

Results. The results indicated the presence of Ang (1-7) and ACE 2 in myocytes of cardiomyopathic hamsters. Moreover, Ang (1-7) (10-⁸ M) hyperpolarised the heart cell, increased the conduction velocity, and I reduced transiently the action potential duration. The cardiac refractoriness was also increased by the heptapeptide, an effect in part reduced by an inhibitor of mas receptor. These findings indicate that Ang (1-7) has important antiarrhythmic properties. However, the beneficial effects of Ang (1-7) are dose-dependent because at higher concentration (10-⁷ M) the heptapeptide elicited an appreciable increase of action potential duration and early-after depolarisations. Since losartan (10-7 M) did not counteract this effect of the high dose of the heptapeptide, it is possible to conclude that activation of AT1-receptors is not involved in this effect of Ang (1-7).To investigate the mechanism of the hyperpolarising action of Ang (1-7) the influence of the heptapeptide on the sodium potassium pump current was studied in myocytes isolated from the ventricle of cardiomyopathic hamsters. The peak pump current density was measured under voltage clamp using the whole cell configuration. The results indicated that Ang (1-7) (10—8 M) enhanced the electrogenic sodium pump, an effect suppressed by ouabain (10—7 M).

Conclusions. Ang (1-7) has beneficial effects on the failing heart by activating the sodium pump, hyperpolarising the cell membrane and increasing the conduction velocity. These effects as well as the increment of refractoriness indicate that Ang (1-7) has antiarrhythmic properties. At higher concentrations (10—7 M), however, the heptapeptide induced early-after depolarisations which leads to the conclusion that an optimal generation of Ang (1-7) must be achieved to permit a protective role of Ang (1-7) on cardiac arrhythmias.

Key Words: ACE 2 • angiotensin (1-7) • failing heart • impulse propagation • refractoriness • sodium pump

References

• De Mello WC Cardiac arrhythmias; the possible role of the renin angiotensin system. J Mol Med 2001;79:103-08.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• De Mello WC Cell coupling and impulse propagation in the failing heart. J Cardiovasc Electrophysiol 1999;10:1409-30.[Web of Science][Medline] [Order article via Infotrieve]
• Donahue M., Hsieh F., Baronas E. et al. A novel angiotensin-converting enzyme related carboxypeptidase (ACE 2) converts angiotensin 1 to angiotensin (1-9). Circ Res 2000;87:E1-E9.[Web of Science][Medline] [Order article via Infotrieve]
• Tipnis SR, Hooper NM, Hyde R. et al. A human homolog of angiotensin converting enzyme. Cloning and functional expression as a captopril insensitive carboxypeptidase. J Biol Chem 2000;275:33238-43.[Abstract/Free Full Text]
• Zisman LS, Keller RS, Weaver B. et al. Increased angiotensin (1-7) forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme homolog, ACE 2. Circulation 2003;108:1707-12.[Abstract/Free Full Text]
• Zisman LS ACE 2: Its role in the counter regulatory response to heart failure; In: Renin Angiotensin System and the Heart (De Mello WC, ed). London, John Wiley and Sons, 2004:119-32.
• Ferrario C., Chappell M., Tallant EK et al. Counter regulatory actions of angiotensin (1-7). Hypertension 1997;30:535-41.[Abstract/Free Full Text]
• Ferrario CM, Jessup J., Chappell MC et al. Effect of angiotensin converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin converting enzyme 2. Circulation 2005;111:2605-10.[Abstract/Free Full Text]
• Ferreira AJ, Santos RA, Almeida AP Angiotensin (1-7): cardioprotective effect in myocardial ischemia/reperfusion. Hypertension 2001;38:665-8.[Abstract/Free Full Text]
• De Mello WC Angiotensin (1-7) re-establishes impulse conduction in cardiac muscle during ischemia-reperfusion. The role of the sodium pump. JRAAS 2004;5:203-08.
• De Mello WC, Cherry R., Mannivanan S. Electrophysiologic and morphologic abnormalities in the failing heart; effect of enalapril on the electrical properties. Cardiac Failure 1997;3:53-62.[CrossRef][Medline] [Order article via Infotrieve]
• Powell T., Twist T. A rapid technique for the isolation and purification of adult cardiac muscle cells having respiratory control and a tolerance to calcium. Biochem Biophys Res Commun 1976;72:327-33.[Web of Science][Medline] [Order article via Infotrieve]
• Tanigushi Y., Kokubun S., Noma A., Hirisawa H. Spontaneously active cells isolated from the sinoatrial and atrioventricular node of the rabbit heart. Jpn J Physiol 1981;31:547-58.[Web of Science][Medline] [Order article via Infotrieve]
• Moriuchi A., Tallant E Ann, Matsumura K. et al. Opposing actions of angiotensin (1-7) and angiotensin II in the brain of transgenic hypertensive rats. Hypertension 1995;25:1260-5.[Abstract/Free Full Text]
• Igase M., Strawn WB, Gallagher PF, Geary RL, Ferrario CM Angiotensin II AT1-receptors regulate ACE 2 and angiotensin (1-7) in the aorta of hypertensive rats. Am J Physiol Heart Circ Physiol 2005;289:H1013-H1019.[Abstract/Free Full Text]
• De Mello WC Heart failure: how important is cellular sequestration? The role of the renin-angiotensin-aldosterone system. J Mol Cell Cardiol 2004;37:431-8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Donoghue M., Wakimoto H., Maguire CT et al. Heart block, ventricular tachycardia and sudden death in ACE 2 transgenic mice with downregulated connexins. J Mol Cell Cardiol 2003;35:1042-53.
• Silva DM, Vianna HR, Cortes SF, Campagnole-Santos MJ, Santos RA, Lemos VS Evidence for a new angiotensin (1-7) receptor subtype in the aorta of Sprague-Dawley rats. Peptides 2007;28:702-07.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Oudot A., Vergely C., Ecarnot-Laubriet A., Rochette L. Pharmacological concentration of angiotensin (1-7) activates NADPH oxidase after ischemia-reperfusion in rat heart through AT1-receptor stimulation. Reg Pept 2005;127:101-10.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Castro CH, Santos RA, Ferreira AJ, Bader M., Alenina N., Almeida AP Evidence for a functional interaction of the angiotensin (1-7) receptor Mas with AT1 and AT2-receptors in the mouse heart. Hypertension 2005;46:937-42.[Abstract/Free Full Text]
• Kostenis E., Milligan G., Christopoulus A. et al. G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation 2005;111:1806-13.[Abstract/Free Full Text]
• Clark MA, Tallant EA, Diz DI Downregulation of AT1A receptor by pharmacologic concentrations of angiotensin (1-7). J Cardiovasc Pharmacol 2001;37:437-48.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Buhagiar KA, Hansen PS, Mihailidou AS, Rasmussen HH Angiotensin regulates the selectivity of the Na+ pump for intracellular sodium. Am J Physiol 1999;277:C461-C468.[Web of Science][Medline] [Order article via Infotrieve]
• De Mello WC, Danser AHJ. Angiotensin II and the heart. On the intracrine renin angiotensin system. Hypertension 2000;35:1183-8.[Abstract/Free Full Text]
• De Mello WC Electrical activity of the heart and angiotensin converting enzyme inhibitors; on the hyperpolarizing action of enalapril. J Human Hypertens 2002;16(suppl 1):S89-S92.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Ferrario CM, Cask HJ, Jessup JA Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin (1-7) in regulation of cardiovascular function. J Am Physiol Heart Circ Physiol 2005;209:H2281-H2290.
• Huentelman MJ, Grobe JL, Vazquez J. et al. Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE 2 in rats. Exp Physiol 2005;90:783-90.[Abstract/Free Full Text]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 8, No. 2, 74-80 (2007)
DOI: 10.3317/jraas.2007.015


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by De Mello, W. C Articles by Jessup, J. A Search for Related Content PubMed PubMed Citation Articles by De Mello, W. C Articles by Jessup, J. A Social Bookmarking                         What's this?