Abstract
It has been well established that chronic pressure overload resulting from hypertension leads to ventricular hypertrophy and electrophysiological remodeling. The transient outward potassium current (I to) reduction described in hypertensive animals delays ventricular repolarization, leading to complex ventricular arrhythmias and sudden death. Antihypertensive drugs, as angiotensin-converting enzyme inhibitors (ACEi), can restore I to and reduce the incidence of arrhythmic events. The purpose of this study was to evaluate the differential effects of long-term treatment with ACEi or direct-acting smooth muscle relaxant on the I to of left and right ventricle myocytes of spontaneously hypertensive rats (SHR). Animals were divided into four groups: normotensive Wistar-Kyoto rats (WKY), hypertensive (SHR), SHR treated for 6 weeks with enalapril 10 mg/kg/day (SHRE), or hydralazine 20 mg/kg/day (SHRH). Systolic blood pressure (SBP) and hypertrophy index (heart weight/body weight (HW/BW)) were determined at the end of treatment period. Cell membrane capacitance (C m) and I to were assessed in cardiomyocytes isolated from left and right ventricles. The SHR exhibited significantly increased SBP and HW/BW when compared to the WKY. The treated groups, SHRE and SHRH, restored normal SBP but not HW/BW. The SHR group exhibited a diminished I to in the left but not the right ventricle. Both the treated groups restored I to in the left ventricle. However, in the right ventricle, only enalapril treatment modified I to. The SHRE group exhibited a significant increase in I to compared to all the other groups. These findings suggest that enalapril may increase I to by a pressure overload independent mechanism.
Similar content being viewed by others
References
Aronson RS (1980) Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ Res 47:443–454
Baker KM, Booz GW, Dostal DE (1992) Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol 54:227–241
Bonnemeier H, Schäfer U, Ortak J, Kurz T, Katus HA, Richardt G, Schunkert H (2007) Low doses of intracoronary enalaprilat suppress reperfusion-associated ventricular arrhythmias after primary percutaneous coronary interventions for acute myocardial infarction. Pacing Clin Electrophysiol 30(Suppl 1):S160–S165. doi:10.1111/j.1540-8159.2007.00629.x
Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT (1990) Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 67:1355–1364
Brilla CG, Funck RC, Rupp H (2000) Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 102:1388–1393
Brown NJ, Vaughan DE (1998) Angiotensin-converting enzyme inhibitors. Circulation 97:1411–1420
Carneiro-Júnior MA, Prímola-Gomes TN, Quintão-Júnior JF, Drummond LR, Lavorato VN, Drummond FR, Felix LB, Oliveira EM, Cruz JS, Natali AJ, Mill JG (2013) Regional effects of low-intensity endurance training on structural and mechanical properties of rat ventricular myocytes. J Appl Physiol 115(1):107–115
Casis O, Iriarte M, Gallego M, Sánchez-Chapula JA (1998) Differences in regional distribution of K+ current densities in rat ventricle. Life Sci 63:391–400
Cerbai E, Crucitti A, Sartiani L, De Paoli P, Pino R, Rodriguez ML, Gensini G, Mugelli A (2000) Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes. Cardiovasc Res 45:388–396
Cerbai E, De Paoli P, Sartiani L, Lonardo G, Mugelli A (2003) Treatment with irbesartan counteracts the functional remodeling of ventricular myocytes from hypertensive rats. J Cardiovasc Pharmacol 41:804–812
Chevalier B, Heudes D, Heymes C, Basset A, Dakhli T, Bansard Y, Jouquey S, Hamon G, Bruneval P, Swynghedauw B, Carré F (1995) Trandolapril decreases prevalence of ventricular ectopic activity in middle-aged SHR. Circulation 92:1947–1953
Di Diego JM, Sun ZQ, Antzelevitch C (1996) I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol Heart Circ Physiol 271:H548–H561
Doronin SV, Potapova IA, Lu ZJ, Cohen IS (2004) Angiotensin receptor type 1 forms a complex with the transient outward potassium channel Kv4.3 and regulates its gating properties and intracellular localization. J Biol Chem 279:48231–48237
Goltz D, Schultz JH, Stucke C, Wagner M, Bassalaý P, Schwoerer AP, Ehmke H, Volk T (2007) Diminished Kv4.2/3 but not KChIP2 levels reduce the cardiac transient outward K+ current in spontaneously hypertensive rats. Cardiovasc Res 74:85–95
Gonzalez-Fernandez RA, Altieri PI, Lugo JE, Fernandez-Martinez J (1993) Effects of enalapril on ventricular volumes and neurohumoral status after inferior wall myocardial infarction. Am J Med Sci 305:216–221
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100
Kannel WB (2000) Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol 85:251–255
Kitazawa M, Kubo Y, Nakajo K (2014) The stoichiometry and biophysical properties of the Kv4 potassium channel complex with K+ channel-interacting protein (kchip) subunits are variable, depending on the relative expression level. J Biol Chem 289:17597–17609. doi:10.1074/jbc.M114.563452
Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, Nguyêñ-Trân VT, Gu Y, Ikeda Y, Chu PH, Ross J, Giles WR, Chien KR (2001) A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell 107:801–813
Lane RE, Cowie MR, Chow AW (2005) Prediction and prevention of sudden cardiac death in heart failure. Heart 91:674–680
Li L, Yi-Ming W, Li ZZ, Zhao L, Yu YS, Li DJ, Xia CY, Liu JG, Su DF (2008) Local RAS and inflammatory factors are involved in cardiovascular hypertrophy in spontaneously hypertensive rats. Pharmacol Res 58:196–201
Malhotra R, Sadoshima J, Brosius FC III, Izumo S (1999) Mechanical stretch and angiotensin II differentially upregulate the renin-angiotensin system in cardiac myocytes in vitro. Circ Res 85:137–146
McIntosh MA, Cobbe SM, Kane KA, Rankin AC (1998) Action potential prolongation and potassium currents in left-ventricular myocytes isolated from hypertrophied rabbit hearts. J Mol Cell Cardiol 30:43–53
Medei E, Marocolo M, Rodrigues DC, Arantes PC, Takiya CM, Silva J, Rondinelli E, Goldenberg RC, de Carvalho AC, Nascimento JH (2010) Chronic treatment with anabolic steroids induces ventricular repolarization disturbances: cellular, ionic and molecular mechanism. J Mol Cell Cardiol 49:165–175
Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED (1984) Hypertension and sudden death. Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 77:18–22. doi:10.1016/0002-9343(84)90430-3
Molina CE, Heijman J, Dobrev D (2016) Differences in left versus right ventricular electrophysiological properties in cardiac dysfunction and arrhythmogenesis. Arrhythm Electrophysiol Rev 5:14–19. doi:10.15420/aer.2016.8.2
Momtaz A, Coulombe A, Richer P, Mercadier JJ, Coraboeuf E (1996) Action potential and plateau ionic currents in moderately and severely DOCA-salt hypertrophied rat hearts. J Mol Cell Cardiol 28:2511–2522
Nguyen TP, Singh N, Xie Y, Qu Z, Weiss JN (2015) Repolarization reserve evolves dynamically during the cardiac action potential: effects of transient outward currents on early afterdepolarizations. Circ Arrhythm Electrophysiol 8:694–702. doi:10.1161/CIRCEP.114.002451
Novo S, Abrignani MG, Novo G, Nardi E, Dominguez LJ, Strano A, Barbagallo M (2001) Effects of drug therapy on cardiac arrhythmias and ischemia in hypertensives with LVH. Am J Hypertens 14:637–643. doi:10.1016/S0895-7061(01)01297-3
Oudit GY, Kassiri Z, Sah R, Ramirez RJ, Zobel C, Backx PH (2001) The molecular physiology of the cardiac transient outward potassium current (Ito) in normal and diseased myocardium. J Mol Cell Cardiol 33:851–872
Patel SP, Campbell DL (2005) Transient outward potassium current, ‘Ito’, phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms. J Physiol 569:7–39. doi:10.1113/jphysiol.2005. 086223
Patel SP, Campbell DL, Strauss HC (2002) Elucidating KChIP effects on Kv4.3 inactivation and recovery kinetics with a minimal KChIP2 isoform. J Physiol 545:5–11. doi:10.1113/jphysiol.2002.031856
Potreau D, Gomez JP, Fares N (1995) Depressed transient outward current in single hypertrophied cardiomyocytes isolated from the right ventricle of ferret heart. Cardiovasc Res 30:440–448
Rials SJ, Wu Y, Xu X, Filart RA, Marinchak RA, Kowey PR (1997) Regression of left ventricular hypertrophy with captopril restores normal ventricular action potential duration, dispersion of refractoriness, and vulnerability to inducible ventricular fibrillation. Circulation 96:1330–1336
Rials SJ, Xu X, Wu Y, Marinchak RA, Kowey PR (1998) Regression of LV hypertrophy with captopril normalizes membrane currents in rabbits. Am J Phys 275:H1216–H1224
Sanguinetti MC (2002) Reduced transient outward K+ current and cardiac hypertrophy: causal relationship or epiphenomenon? Circ Res 90:497–499
Shipsey SJ, Bryant SM, Hart G (1997) Effects of hypertrophy on regional action potential characteristics in the rat left ventricle: a cellular basis for T-wave inversion? Circulation 96:2061–2068
Tozakidou M, Goltz D, Hagenström T, Budack MK, Vitzthum H, Szlachta K, Bähring R, Ehmke H (2010) Molecular and functional remodeling of Ito by angiotensin II in the mouse left ventricle. J Mol Cell Cardiol 48:140–151
Villarreal FJ, Kim NN, Ungab GD, Printz MP, Dillmann WH (1993) Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 88:2849–2861
Volders PG, Sipido KR, Carmeliet E, Spätjens RL, Wellens HJ, Vos MA (1999) Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation 99:206–210
WHO (2011) Global atlas on cardiovascular disease prevention and control. Mendis S, Puska P, Norrving B (Ed). World Healthy Organization, Geneve
Yang Z, Yu X, Cheng L, Miao LY, Li HX, Han LH, Jiang WP (2013) Effects of enalapril on the expression of cardiac angiotensin-converting enzyme and angiotensin-converting enzyme 2 in spontaneously hypertensive rats. Arch Cardiovasc Dis 106:196–201. doi:10.1016/j.acvd.2013.01.004
Yokoshiki H, Kohya T, Tomita F, Tohse N, Nakaya H, Kanno M, Kitabatake A (1997) Restoration of action potential duration and transient outward current by regression of left ventricular hypertrophy. J Mol Cell Cardiol 29:1331–1339
Zhang H, Wu S, Huang C, Li X (2014) Long-term treatment of spontaneously hypertensive rats with losartan and molecular basis of modulating Ito of ventricular myocytes. Mol Med Reports 9:1959–1967
Zhao Z, Xie Y, Wen H, Xiao D, Allen C, Fefelova N, Dun W, Boyden PA, Qu Z, Xie LH (2012) Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells. Cardiovasc Res 95:308–316. doi:10.1093/cvr/cvs183
Zou Y, Akazawa H, Qin Y, Sano M, Takano H, Minamino T, Makita N, Iwanaga K, Zhu W, Kudoh S, Toko H, Tamura K, Kihara M, Nagai T, Fukamizu A, Umemura S, Liri T, Fujita T, Komuro I (2004) Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat Cell Biol 6:499–506
Acknowledgements
This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ). JHMN and JGM are research fellows from the CNPq. LFRJ and ACAC received fellowships from the CNPq.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996), and approved by the Institutional Animal Care and Use Committee (IBCCF-010).
Conflict of interest
The authors declare that they have no competing interests.
Rights and permissions
About this article
Cite this article
Rodrigues Junior, L.F., de Azevedo Carvalho, A.C., Pimentel, E.B. et al. Chronic enalapril treatment increases transient outward potassium current in cardiomyocytes isolated from right ventricle of spontaneously hypertensive rats. Naunyn-Schmiedeberg's Arch Pharmacol 390, 225–234 (2017). https://doi.org/10.1007/s00210-016-1322-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-016-1322-7