Cholinergic system of the heart
Authors:
Matej Kučera; Anna Hrabovská
Published in the journal:
Čes. slov. Farm., 2015; 64, 254-263
Category:
Přehledy a odborná sdělení
Summary
The cholinergic system of the heart can be either of neuronal or non-neuronal origin. The neuronal cholinergic system in the heart is represented by preganglionic parasympathetic pathways, intracardiac parasympathetic ganglia and postganglionic parasympathetic neurons projecting to the atria, SA node and AV node. The non-neuronal cholinergic system consists of cardiomyocytes that have complete equipment for synthesis and secretion of acetylcholine. Current knowledge suggests that the non-neuronal cholinergic system in the heart affects the regulation of the heart during sympathetic activation. The non-neuronal cholinergic system of the heart plays also a role in the energy metabolism of cardimyocites. Acetylcholine of both neuronal and non-neuronal origin acts in the heart through muscarinic and nicotinic receptors. The effect of acetylcholine in the heart is terminated by cholinesterases acetylcholinesterase and butyrylcholinesterase. Recently, papers suggest that the increased cholinergic tone in the heart by cholinesterase inhibitors has a positive effect on some cardiovascular disorders such as heart failure. For this reason, the cholinesterase inhibitors might be used in the treatment of certain cardiovascular disorders in the future.
Key words:
cholinergic system • heart innervation • non-neuronal cholinergic system of the heart • receptors • cholinesterases in the heart
Zdroje
1. Trojan S. Lékařská fyziologie. 4. vydání. Praha: Grada Publishing 2003.
2. Jacobowitz D., Cooper T., Barner H. B. Histochemical and chemical studies of the localization of adrenergic and cholinergic nerves in normal and denervated cat hearts. Circ. Res. 1967; 20(3), 289–298.
3. Brodde E. O., Bruck H., Leineweber K., Seyfarth T. Presence,distribution a physiological function of adrenergic and muscarinic receptor subtypes in the human heart. Basic Res. Cardiol. 2001; 69(6), 528–538.
4. Brodde O. E., Michel, M. C. Adrenergic and muscarinic receptors in the human heart. Pharmacol. Rev. 1999; 51(4), 651–690.
5. Olshansky B., Sabbah H. N., Hauptman P. J., Colucci W. S. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008; 118(8), 863–871.
6. Katzung B. G. Základní a klinická farmakologie. 2. vyd. Jinočany: Nakladatelství H & H 2006.
7. Levy M. N., Ng M., Lipman R. I., Zieske H. Vagus nerves and baroreceptor control of ventricular performance. Circ. Res. 1966; 18(1), 101–106.
8. Pauza D. H., Skripka V., Pauziene N., Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat. rec. 2000; 259(4), 353–382.
9. Batulevicius D., Pauziene N., Pauza D. H. Key anatomic data for the use of rat heart in electrophysiological studies of the intracardiac nervous system. Medicina (Kaunas) 2004; 40(3), 253–259.
10. Rysevaite K., Saburkina I., Pauziene N., Noujaim S. F., Jalife J., Pauza D. H. Morphologic pattern of the intrinsic ganglionated nerve plexux in mouse heart. Hearth Rhythm. 2011; 8(3), 448–454.
11. Hopkins D. A., Armour J. A. Localization of sympathetic postganglionic and parasympathetic preganglionic neurons which innervate different regions of the dog heart. J. Comp. Neurol. 1984; 229(2), 186–198.
12. Izzo P. N., Deuchars J., Spyer K. M. Localization of cardiac vagal preganglionic motoneurones in the rat: immunocytochemical evidence of synaptic imputs containing 5-hydroxytryptamine. J. Comp. Neurol. 1993; 327(4), 572–583.
13. Gray A. L., Johnson T. A., Ardell J. L., Massari V. J. Parasympathetic control of the heart. II. A novel interganglionic intrinsic cardiac circuit mediates neural control of heart rate. J. Appl. Physiol. (1985) 2004; 96(6), 2273–2278.
14. Blinder K. J., Johnson T. A., John Massari V. Negative inotropic vagal preganglionic neurons in the nucleus ambiguus of the cat: neuroanatomical comparison with negative chronotropic neurons utilizing dual retrograde tracers. Brain Res. 1998; 804(2), 325–330.
15. Cheng Z., Zhang H., Guo S. Z., Wurster R., Gozal D. Differential control over postganglionic neurons in rat cardiac ganglia by NA and DmnX neurons: anatomical evidence. Am. J. Physiol Regul Integr Comp Physiol. 2004; 286(4), 625–633.
16. Ai J., Epstein P. N., Gozal G., Yang B., Wurster R., Cheng Z. J. Morphology and topography of nucleus ambiguus projections to cardiac ganglia in rats and mice. Neuroscience. 2007; 149(4), 845–860.
17. Johnson T. A., Gray A. L., Lauenstein J. M., Newton S. S., Massari V. J. Parasympathetic control of the heart. I. An interventriculo–septal ganglion is the major source of the vagal intracardiac innervation of the ventricles. J. Appl Physiol. (1985) 2004; 96(6), 2265–2272.
18. Armour J. A., Murphy D. A., Yuan B. X., Macdonald S., Hopkins D. A. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat. Rec. 1997; 247(2), 289–298.
19. Zarzoso M., Rysevaite K., Milstein M. L., Calvo C. J., Kean A. C., Atienza F., Pauza D. H., Jalife J., Noujaim S. F. Nerves projecting from the intrinsic cardiac ganglia of the pulmonary veins modulate sinoatrial node pacemaker function. Cardiovasc. Res. 2013; 99(3), 566–575.
20. Kawano H., Okada R., Yano K. Histological study on the distribution of autonomic nerves in the human heart. Heart Vessels 2003; 18(1), 32–39.
21. Ulphani J. S., Cain J. H., Inderyas F., Gordon D., Gikas P. V., Shade G., Mayor D., Arora R., Kadish A. H., Goldberger J. J. Quantitative analysis of parasympathetic innervation of porcine heart. Heart Rhythm. 2010; 7(8), 1113–1119.
22. Pauza D. H., Saburkina I., Rysevaite K., Inokaitis H., Jokubauskas M., Jalife J., Pauziene N. Neuroanatomy of the murine cardiac conduction system: a combined stereomicroscopic and fluorescence immunohistochemical study. Auton. Neurosci. 2013; 176(1–2), 32–47.
23. Carlson M. D., Geha A. S., Hsu J., Martin P. J., Levy M. N., Jacobs G., Waldo A. L. Selective stimulation of parasympathetic nerve fibers to the human sinoatrial node. Circulation 1992; 85(4), 1311–1317.
24. Lovasova K., Kluchova D., Bolekova A., Dorko F., Spakovska T. Distribution of NADPH-diaphorase and AChE activity in the anterior leaflet of rat mitral valve. Eur. J. Histochem. 2010; 54(1), e5.
25. Hoover D. B., Ganote C. E., Ferguson S. M., Blakely R. D., Parsons R. L. Localization of cholinergic innervation in guinea pig heart by immunohistochemistry for high-affinity choline transporters. Cardiovasc. Res. 2004; 62(1), 112–121.
26. Kakinuma Y., Akiyama T., Sato T. Cholinoceptive and cholinergic properties of cardiomyocytes involving an amplification mechanism for vagal efferent effects in sparsely innervated ventricular myocardium. FEBS J. 2009; 276(18), 5111–5125.
27. Rana O. R., Schauerte P., Kluttig R., Schröder J. W., Koenen R. R., Weber C., Nolte K. W., Weis J., Hoffmann R., Marx N., Saygili E. Acetylcholine as an age-dependent non-neuronal source in the heart. Auton. Neurosci. 2010; 156(1–2), 82–89.
28. Hrabovska A. Localization, processing and function of cholinesterases in striatum. In: Striatum: anatomy, functions and role in disease. 1. vyd. New York: Nova Sciene Publishers, 2012; 1–36.
29. Rocha-Resende C., Roy A., Resende R., Ladeira M. S., Lara A., de Morais Gomes E. R., Prado V. F., Gros R., Guatimosim C., Prado M. A., Guatimosim S. Non-neuronal cholinergic machinery present in cardiomyocytes offsets hypertrophic signals. J. Mol. Cell. Cardiol. 2012; 53(2), 206–216.
30. English B. A., Appalsamy M., Diedrich A., Ruggiero A. M., Lund D., Wright J., Keller N. R., Louderback K. M., Robertson D., Blakely R. D. Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter. Am. J. Physiol. Heart Circ. Physiol. 2010; 299(3), 799–810.
31. Slavíková J., Tuček S. Choline acetyltransferase in the heart of adult rats. Pflugers Arch. 1982; 392(3), 225–229.
32. Roy A., Fields W. C., Rocha-Resende C., Resende R. R., Guatimosim S., Prado V. F., Gros R., Prado M. A. Cardiomyocyte-secreted acetylcholine is required for maintenance of homeostasis in the heart. FASEB J. 2013; 27(12), 5072–5082.
33. Kakinuma Y., Tsuda M., Okazaki K., Akiyama T., Arikawa M., Noguchi T., Sato T. Heart-specific overexpresion of choline acetyltransferase gene protects murine heart against ischemia through hypoxia-inducible factor-α1-related defense mechanisms. J. Am. Heart Assoc. 2013; 2(2), e004887.
34. Kakinuma Y., Akiyama T., Okazaki K., Arikawa M., Noguchi T., Sato T. A non-neuronal cardiac cholinergic system plays a protective role in myocardium salvage during ischemic insults. PLoS One 2012; 7(11), e50761.
35. Dhein S., van Koppen CH. J., Brodde O. E. Muscarinic receptors in the mammalian heart. Pharmacol. Res. 2001; 44(3), 161–182.
36. Abramochkin D. V., Tapilina S. V., Sukhova G. S., Nikolsky E. E., Nurullin L. F. Functional M3 cholinoreceptors are present in pacemaker and working myocardium of murine heart. Pflugers Arch. 2012; 463(4), 523–529.
37. Wang Z., Shi H., Wang H. Functional M3 muscarinic acetylcholine receptors in mammalian hearts. Br. J. Pharmacol. 2004; 142(3), 359–408.
38. Liu Y., Wang S., Wang C., Song H., Han H., Hang P., Jiang Y., Wei L., Huo R., Sun L., Gao X., Lu Y., Du Z. Upregulation of M3 muscarinic receptor inhibits cardiac hypertrophy induced by angiotensin II. J. Transl. Med. 2013; 11: 209.
39. Woo S. H., Lee B. H., Kwon K. I., Lee C. O. Excitatory effect of M1 muscarinic acetylcholine receptor on automaticity of mouse heart. Arch. Pharm. Res. 2005; 28(8), 930–935.
40. Cuevas J., Adams D. J. M4 muscarinic receptor activation modulates calcium channel currents in rat intracardiac neurons. J. Neurophysiol. 1997; 78(4), 1903–1912.
41. Hancock J. C., Hoover D. B., Hougland M. W. Distribution of muscarinic receptors and acetylcholinesterase in the rat heart. J. Auton. Nerv. Syst. 1987; 19(1), 59–66.
42. Nenasheva T. A. Neary M., Mashanov G. I., Birdsall N. J., Breckenridge R. A., Molloy J. E. Abundance, distribution, mobility and oligomeric state of M2 muscarinic acetylcholine receptors in live cardiac muscle. J. Mol. Cell. Cardiol. 2013; 57, 129–136.
43. LaCroix C., Freeling J., Giles A., Wess J., Li Y. F. Deficiency of M2 muscarinic acetylcholine receptors increases ssusceptibility of ventricular function to chronic adrenergic stress. Am. J. Physiol Heart Circ Physiol. 2008; 294(2), 810–820.
44. Yamada M. The role of muscarinic K(+) channels in the negative chronotropic effect of a muscarinic agonist. J. Pharmacol. Exp. Ther. 2002; 300(2), 681–687.
45. Takahashi H., Maehara K., Onuki N., Saito T., Maruyama Y. Decreased contractility of the left ventricle is induced by neurotransmitter acetylcholine, but not by vagal stimulation in rats. Jpn. Heart J. 2003; 44(2), 257–270.
46. Kitazawa T., Asakawa k., Nakamura T., Teraoka H., Unno T., Komori S., Yamada M., Wess J. M3 muscarinic receptors mediate positive inotropic responses in mouse atria: a study with muscarinic receptor knockout mice. J. Pharmacol. Exp. Ther. 2009; 330(2), 487–493.
47. Hussain R. I., Afzal F., Mork H. K., Aronsen J. M., Sjaastad I., Osnes J. B., Skomedal T., Levy F. O., Krobert K. A. Cyclic AMP-dependent inotropic effects are differentially regulated by muscarinic G(i)-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle. Br. J. Pharmacol. 2011; 162(4), 908–916.
48. Yoshizawa A., Nagai S., Baba Y., Yamada T., Matsui M., Tanaka H., Miyoshi S., Amagai M., Yoshikawa T., Fukuda K., Ogawa S., Koyasu S. Autoimmunity against M2muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy–like phenotype. Eu. J. Immunol. 2012; 42(5), 1152–1163.
49. Wang N., Orr-Urtreger A, Chapman J., Rabinowitz R., Korczyn A. D. Deficiency of nicotinic acetylcholine receptor beta 4 subunit causes autonomic cardiac and intestinal dysfunction. Mol. Pharmacol. 2003; 63(3), 574–580.
50. Pan Z., Guo Y., Qi H., Fan K., Wang S., Zhao H., Fan Y., Xie J., Guo F., Hou Y., Wang N., Huo Y., Zhang Y., Liu Y., Du Z. M3 subtype of muscarinic acetylcholine receptor promotes cardioprotection via the suppression of miR-376b-5p. PLoS One 2012; 7(3), e32571.
51. van Koppen C. J., Kaiser B. Regulation of muscarinic acetylcholine receptor signaling. Pharmacol. Ther. 2003; 98(2), 197–220.
52. Mysliveček J., Trojan S., Tuček S. Biphasic changes in the density of muscarinic and beta-adrenergic receptors in cardiac atria of rats treated with diisopropylfluorophosphate. Life Sci. 1996; 58(26), 2423–2430.
53. Lindstrom J. M. Nicotinic acetylcholine receptors of muscles and nerves: comparison of their structures, functional roles, and vulnerability to pathology. Ann. N. Y. Acad. Sci. 2003; 998, 41–52.
54. Poth K., Nutter T. J., Cuevas J., Parker M. J., Adams D. J., Luetje C. W. Heterogenity of nicotinic receptor class and subunit mRNA expression among individual parasympathetic neurons from rat intracardiac ganglia. J. Neurosci. 1997; 17(2), 586–596.
55. de Biasi M. Nicotinic mechanisms in the autonomic control of organ systems. J. Neurobiol. 2002; 53(4), 568–579.
56. Bibevski S., Zhou Y., McIntosh J. M., Zigmond R. E., Dunlap M. E. Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasypathetic neurons. J. Neurosci. 2000; 20(13), 5076–5082.
57. Li Y. F., LaCroix C., Freeling J. Specific subtypes of nicotinic cholinergic receptors involved in sypathetic and parasypathetic cardiovascular responses. Neurosci Lett. 2009; 462(1), 20–23.
58. Li Y. F., LaCroix C., Freeling J. Cytisine induces autonomic cardiovascular responses via activations of different nicotinic receptors. Auton. Neurosci. 2010; 154(1–2), 14–19.
59. Ji S., Tosaka T., Whitfield B. H., Katchman A. N., Kandil A., Knollmann B. C., Ebert S. N. Differential rate responses to nicotine in rat heart: evidence for two classes of nicotinic receptors. J. Pharmacol. Exp. Ther. 2002; 301(3), p. 893–899.
60. Xu W., Orr-Urtreger A., Nigro F., Gelber S., Sutcliffe C. B., Armstrong D., Patrick J. W., Beaudet A. L., De Biasi M. Multiorgan autonomic dysfunction in mice lacking the beta2 and the beta4subunits of neuronal nicotinic acetylcholine receptors. J. Neurosci. 1999; 19(21), 9298–9305.
61. Dvořáková M., Lipd K. S., Brüggmann D., Slavíková J., Kuncová J., Kummer W. Developmental changes in the expression of nicotinic acetylcholine receptor alpha-subunits in the rat heart. Cell Tissue Res. 2005; 319(2), 201–209.
62. Deck J., Bibevski S., Gnecchi-Ruscone T., Bellina V., Montano N., Dunlap M. E. Alpha7-nicotinic acetylcholine receptor subunit is not required for parasympathetic control of the heart in the mouse. Physiol. Genomics. 2005; 22(1), 86–92.
63. Yu J. G., Song S. W., Shu H., Fan S. J., Liu A. J., Liu C., Guo J. M., Miao C. Y., Su D. F. Baroreflex deficiency hampers angiogenesis after myocardial infarction via acetylcholine- α7-nicotinic ACh receptor in rats. Eu. Heart J. 2013; 34(30), 2412–2420.
64. Ni M., Yang Z. W., Li D. J., Li Q., Zhang S. H., Su D. F., Xie H. H., Shen F. M. A potential role of alpha-7 nicotinic acetylcholine receptor in cardiac angiogenesis in a pressure-overload rat model. J. Pharmacol. Sci. 2010; 114(3), 311–319.
65. Li B., Stribley J. A., Ticu A., Xie W., Schopfer L. M., Hammond P., Brimijoin S., Hinrichs S. H., Lockridge O. Abundant tissue butyrylcholinesterase and its possible function in the acetylcholinesterase knockout mouse. J. Neurochem. 2000; 75(3), 1320–1231.
66. Sinha S. N., Keresztes-Nagy S., Frankfater A. Studies on the distribution of cholinesterases: activity in the human and dog heart. Pediatr. Res. 1976; 10(8), 754–758.
67. Slavíková J., Vlk J., Hlavičková V. Acetylcholinesterase and butyrylcholinesterase activity in the atria of the heart of adult albino rats. Physiol. Bohemoslov. 1982; 31(5), 407–414.
68. Jbilo O., L’Hermite Y., Talesa V., Toutant J. P., Chatonnet A. Acetylcholinesterase and butyrylcholinesterase expression in adult rabit tissues and during development. Eu. J. Biochem. 1994; 225(1), 115–124.
69. Nyquist-Battie C., Dowell R. T., Fernandez H. Regional distribution of the molecular forms of acetylcholinesterase in adult rat heart. Circ. Res. 1989; 65, 55–62.
70. Nyquist-Battie C., Chodges-Savola C., Fernandez H. Acetylcholinesterase molecular forms in rat heart. J. Mol. Cell. Cardiol. 1987; 19(9), 935–943.
71. Gómez J. L., Moral-Naranjo M. T., Campoy F. J., Vidal C. J. Characterization of acetylcholinesterase and butyrylcholinesterase forms in normal and dystrophic Lama2dy m ouse heart. J. Neurosci Res. 1999; 56(3), 295–306.
72. Krejci E., Thomine S., Boschetti N., Legay C., Sketelj J., Massoulié J. The mammalian gene of acetylcholinesterase-associated collagen. J. Biol. Chem. 1997; 272(36), 22840–22847.
73. Perrier A. L., Massoulié J., Krejci E. PRiMA: The Membrane Anchor of Acetycholinesterses in the Brain. Neuron 2002; 33, 275–285.
74. Skau K. A., Brimijoin S. Multiple molecular forms of acetylcholinesterase in rat vagus nerve, smooth muscle, and heart. J. Neurochem. 1980; 35(5), 1151–1154.
75. Gonzáles R., Campos E. O., Morán S., Inestrosa N. C. Characterization of acetylcholinesterase from human heart auricles: evidence for the presence of a G-form sensitive to phosphatidylinositol-specific phospholipase C. Gen. Pharmacol. 1991; 22(1), 107–110.
76. Eghbali M., Silman I., Robinson T. F., Seifter S. Visualization of collagenase-sensitive acetylcholinesterase in isolated cardiomyocytes and in heart tissue. Cell Tissue Res. 1988; 253(2), 281–286.
77. Kučera M., Hrabovská A. Molekulové formy cholínesteráz a ich kotviace proteíny. Chem. Listy 2013; 107, 695–700.
78. Howard M. D., Mirajkar N., Karanth S., Pope C. N Comparative effects of oral chlorpyrifos exposure on cholinesterase activity and muscarinic receptor binding in neonatal and adult rat heart. Toxicology 2007; 238(2–3), 157–165.
79. Manoharan I., Boopathy R., Darvesh S., Lockridge O. A medical health report on individuals with silent butyrylcholinesterase in the Vysya community of India. Clin. Chim. Acta 2007; 378(1–2), 128–135.
80. Mirossay L., Mojžiš J. Základná farmakológia a farmakoterapia. 1. vydanie. Košice: EQUILIBRIA 2006.
81. Lullmann H., Mohr K., Wehling M. Farmakologie a Toxikologie. 15. vydání. Praha: Grada Publishing 2004.
82. Androne A. S., Hryniewicz K., Goldsmith R., Arwady A., Katz S. D. Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure. Heart 2003; 89(9), 854–858.
83. Behling A., Moraes R. S., Rohde L. E., Ferlin E. L., Nóbrega A. C., Ribeiro J. P. Cholinergic stimulation with pyridostigmine reduces ventricular arrythmia and enhances heart rate variability in heart failure. Am. Heart J. 2003; 146(3), 494–500.
84. Serra S. M., Costa R. V., Teixeira de Castro R. R., Xavier S. S., Nóbrega A. C. Cholinergic stimulation improves autonomic and hemodynamic profile during dynamic exercise in patients with heart failure. J. Card. Fail. 2009; 15(2), 124–129.
85. Kanjwal K., Karabin B., Sheikh M., Elmer L., Kanjwal Y., Saeed B., Grubb B. P. Pyridostigmine is the treatment of postural orthostatic tachycardia: a single-center experience. Pacing Clin. Electrophysiol. 2011; 34(6), 750–755.
86. Raj S. R., Black B. K., Biaggioni I., Harris P. A., Robertson D. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation 2005; 111(21), 2734–2740.
87. Nordström P., Religa D., Wimo A., Eriksdotter M. The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer’s disease. Eu. Heart J. 2013; 34(33), 2585–2591.
88. Lara A., Damasceno D. D., Pires R., Gros R., Gomes E. R., Gavioli M., Lima R. F., Guinaraes D., Lima P., Bueno C. R. Jr., Vasconcelos A., Roman-Campos D., Menezes C. A., Sirvente R. A., Salemi V. M., Mady C., Caron M. G., Ferreira A. J., Brum P. C., Resende R. R., Cruz J. S., Gomez M. V., Prado V. F., de Almeida A. P., Prado m. A., Guatimosim S. Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure. Mol. Cell. Biol. 2010; 30(7), 1746–1756.
89. Roy A., Guatimosim S., Prado V. F., Gros R., Prado M. A. Cholinergic activity as a new target in diseases of the heart. Mol. Med. 2015; 20, 527–537.
90. Lataro R. M., Silva C. A., Fazan R Jr., Rossi M. A., Prado C. M., Godinho R. O., Salgado H. C. Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013; 305(8), 908–916.
91. Freeling J., Wattier K., LaCroix C., Li Y. F. Neostigmine and pilocarpine attenuated tumor necrosis factor alpha expression and cardiac hypertrophy in the heart with pressure overload. Exp. Physiol. 2008; 93(1), 75–82.
92. Handa T., Katare R. G., Kakinuma Y., Arikawa M., Ando M., Sasaguri S., Yamasaki F., Sato T. Anti-Alzheimer’s drug, donepezil, markedly improves long-term survival after chronic heart failure in mice. J. Card. Fail. 2009; 15(9), 805–811.
93. Sato K., Urbano R., Yu C., Yamasaki F., Sato T., Jordan J., Robertson D., Diedrich A. The effect of donepezil treatment on cardiovascular mortality. Clin. Pharmacol. Ther. 2010; 88(3), 335–338.
94. Isik A. T., Bozoglu E., Yay A., Soysal P., Ateskan U. Which cholinesterase inhibitor is the safest for the heart in eldery patients with Alzheimer’s disease? Am. J. Alzheimers Dis Other Demen. 2012; 27(3), 171–174.
95. Isik A. T., Yildiz G. B., Bozoglu E., Yay A., Aydemir E. Cardiac safety of donepezil in eldery patients with Alzheimer disease. Intern. Med. 2012; 51(6), 575–578.
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