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. Author manuscript; available in PMC: 2017 Jan 15.
Published in final edited form as: Adv Drug Deliv Rev. 2015 May 5;96:110–134. doi: 10.1016/j.addr.2015.04.019

Table 4.

A comparison of the pharmacological responses of hECTs.

Reference Measurement Conditions Catecholamines Calcium L-type Ca2+ channel blocker Other
Kensah et al [1] Microelectrode Array: hECT; spontaneous beating
Custom-Made Reactor: field stimulation (25V, 10ms)
Isoproterenol: 0.1μM ↑rate (MEA) ↑rate, ↑force (custom-made reactor) Carbachol: 10μM added after isoproterenol ↓rate (custom-made reactor)
Streckfuss-Bömeke et al [2] Custom-Made Reactor: field stimulation (1.5Hz, 5ms, V = ET+10%) Isoproterenol: 1μM ↑force, ↑relaxation velocity (custom-made reactor) 0.2–2.8mM ↑force EC50 = 0.4mM (custom-made reactor)
Schaaf et al [3] Post-deflection: spontaneous
Patch clamping: spontaneous
Isoproterenol: 100nM ↑rate (post-deflection) 0.2–3.0mM ↑force EC50 = 0.8–1.0mM (post-deflection) Nisoldipine: 1μM ↓amplitude (patch clamp) Carbachol: 10μM after isoproterenol ↓rate (post-deflection)
E-4031: 300nM ↑APD (patch clamp)
1–30nM ↓force, ↓Vmax, ↑beat-to-beat variability (post-deflection)
Tetrodotoxin: 3μM ↓Vmax, ↑APD, ↑DI (patch clamp)
Turnbull et al [4] Post-Deflection: spontaneous
Physiological Muscle Bath: field stimulation (2Hz, 5ms)
Isoproterenol: 1nM–1μM ↑rate (post-deflection)
1nM–10μM ↑force EC50 = 750nM (muscle bath)
0.5–2.5mM ↑force EC50 = 1.8mM (muscle bath) Verapamil: 1nM–10μM ↓force IC50 = 0.61μM (muscle bath)
Thavandiran et al [5] Optical Mapping: voltage sensitive dye; point stimulation (1Hz)
Optical Mapping: calcium-sensitive dye
Epinephrine: 500nM ↑rate (AP propagation) Verapamil: 500nM ↓amplitude (Ca2+ transient) Lidocaine: 8.5uM after epinephrine ↓rate (AP propagation)
Nunes et al [6] Optical Mapping: calcium-sensitive dye; spontaneous Verapamil: 1mM no Ca2+ transients
Nifidipine: 10μM no Ca2+ transients
Caffeine: 5mM ↑Ca2+ amplitude
Thapsigargin: 2μM no Ca2+ transients
Zhang et al [7] Custom-Made Reactor: field stimulation (1Hz) Isoproterenol: 0.1nM–1μM ↑rate, ↑force EC50 = 95.1 nM
Lu et al [8] Optical Mapping: calcium-sensitive dye (spontaneous)
Force Transducer: field stimulation (1.5Hz, 5ms, V = ET+20%)
Isoproterenol: 1nM–5μM ↑rate = 10-EC50 100nM (Ca2+ transient) 5mM ↑force (force transducer) E-4031: 1μM ↓amplitude, pulsus alternans (Ca2+ transient)
hPSC-CMs Isoproterenol: EC50 = 12.9nM [9] EC50 = 0.4–1.8mM [2, 4] Nifedipine: IC50 = 39nM [10] E-4031: IC50 = 17nM [10, 11]
Human Adult Isoproterenol: EC50 = 11–80nM [1215] EC50 = 3.0mM [16] Verapamil: IC50 = 143 nM (hERG) [11, 17]
IC50 = 0.24–4.3μM (Cav1.2) [1820]
IC50 = 123.0nM (inotropic) [21]
Nifedipine: IC50 = 16–24 nM [19]
Nisoldipine: IC50 = 67–81 nM [22]
Carbachol: EC50 = 140nM [23]
E-4031: IC50 = 7–32nM [11, 20]
Tetrodotoxin: IC50 ≥ 1 μM [27, 28]
Lidocaine: IC50 = 34–38μM [29]
[1]

G. Kensah, I. Gruh, J. Viering, H. Schumann, J. Dahlmann, H. Meyer, D. Skvorc, A. Bar, P. Akhyari, A. Heisterkamp, A. Haverich, U. Martin, A novel miniaturized multimodal bioreactor for continuous in situ assessment of bioartificial cardiac tissue during stimulation and maturation, Tissue Eng. Part C. Methods 17 (2011) 463–473.

[2]

K. Streckfuss-Bomeke, F. Wolf, A. Azizian, M. Stauske, M. Tiburcy, S. Wagner, D. Hubscher, R. Dressel, S. Chen, J. Jende, G. Wulf, V. Lorenz, M.P. Schon, L.S. Maier, W.H. Zimmermann, G. Hasenfuss, K. Guan, Comparative study of human-induced pluripotent stem cells derived from bone marrow cells, hair keratinocytes, and skin fibroblasts, Eur. Heart J. 34 (2013) 2618–2629.

[3]

S. Schaaf, A. Shibamiya, M. Mewe, A. Eder, A. Stohr, M.N. Hirt, T. Rau, W.H. Zimmermann, L. Conradi, T. Eschenhagen, A. Hansen, Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology, PLoS One 6 (2011) e26397.

[4]

I.C. Turnbull, I. Karakikes, G.W. Serrao, P. Backeris, J.J. Lee, C. Xie, G. Senyei, R.E. Gordon, R.A. Li, F.G. Akar, R.J. Hajjar, J.S. Hulot, K.D. Costa, Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium, FASEB J. 28 (2014) 644–654.

[5]

N. Thavandiran, N. Dubois, A. Mikryukov, S. Masse, B. Beca, C.A. Simmons, V.S. Deshpande, J.P. McGarry, C.S. Chen, K. Nanthakumar, G.M. Keller, M. Radisic, P.W. Zandstra, Design and formulation of functional pluripotent stem cell-derived cardiac microtissues, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) E4698–707.

[6]

S.S. Nunes, J.W. Miklas, J. Liu, R. Aschar-Sobbi, Y. Xiao, B. Zhang, J. Jiang, S. Masse, M. Gagliardi, A. Hsieh, N. Thavandiran, M.A. Laflamme, K. Nanthakumar, G.J. Gross, P.H. Backx, G. Keller, M. Radisic, Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes, Nat. Methods 10 (2013) 781–787.

[7]

D. Zhang, I.Y. Shadrin, J. Lam, H.Q. Xian, H.R. Snodgrass, N. Bursac, Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes, Biomaterials 34 (2013) 5813–5820.

[8]

T.Y. Lu, B. Lin, J. Kim, M. Sullivan, K. Tobita, G. Salama, L. Yang, Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells, Nat. Commun. 4 (2013) 2307.

[9]

M. Brito-Martins, S.E. Harding, N.N. Ali, Beta(1)- and Beta(2)-Adrenoceptor Responses in Cardiomyocytes Derived from Human Embryonic Stem Cells: Comparison with Failing and Non-Failing Adult Human Heart, Br. J. Pharmacol. 153 (2008) 751–759.

[10]

J.K. Gibson, Y. Yue, J. Bronson, C. Palmer, R. Numann, Human stem cell-derived cardiomyocytes detect drug-mediated changes in action potentials and ion currents, J. Pharmacol. Toxicol. Methods 70 (2014) 255–267.

[11]

K. Harris, M. Aylott, Y. Cui, J.B. Louttit, N.C. McMahon, A. Sridhar, Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays, Toxicol. Sci. 134 (2013) 412–426.

[12]

M. Flesch, R.H. Schwinger, F. Schiffer, K. Frank, M. Sudkamp, F. Kuhn-Regnier, G. Arnold, M. Bohm, Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium, Circulation 94 (1996) 992–1002.

[13]

C. Holubarsch, R. Schneider, B. Pieske, T. Ruf, G. Hasenfuss, G. Fraedrich, H. Posival, H. Just, Positive and negative inotropic effects of DL-sotalol and D-sotalol in failing and nonfailing human myocardium under physiological experimental conditions, Circulation 92 (1995) 2904–2910.

[14]

M. Bohm, I. Morano, B. Pieske, J.C. Ruegg, M. Wankerl, R. Zimmermann, E. Erdmann, Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium, Circ. Res. 68 (1991) 689–701.

[15]

M. White, R. Roden, W. Minobe, M.F. Khan, P. Larrabee, M. Wollmering, J.D. Port, F. Anderson, D. Campbell, A.M. Feldman, Age-related changes in beta-adrenergic neuroeffector systems in the human heart, Circulation 90 (1994) 1225–1238.

[16]

B.S. Cain, D.R. Meldrum, X. Meng, B.D. Shames, A. Banerjee, A.H. Harken, Calcium preconditioning in human myocardium, Ann. Thorac. Surg. 65 (1998) 1065–1070.

[17]

S. Zhang, Z. Zhou, Q. Gong, J.C. Makielski, C.T. January, Mechanism of block and identification of the verapamil binding domain to HERG potassium channels, Circ. Res. 84 (1999) 989–998.

[18]

B.S. Freeze, M.M. McNulty, D.A. Hanck, State-dependent verapamil block of the cloned human Ca(v)3.1 T-type Ca(2+) channel, Mol. Pharmacol. 70 (2006) 718–726.

[19]

Y.A. Kuryshev, A.M. Brown, E. Duzic, G.E. Kirsch, Evaluating state dependence and subtype selectivity of calcium channel modulators in automated electrophysiology assays, Assay Drug Dev. Technol. 12 (2014) 110–119.

[20]

K. Yamazaki, T. Hihara, H. Kato, T. Fukushima, K. Fukushima, T. Taniguchi, T. Yoshinaga, N. Miyamoto, M. Ito, K. Sawada, Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application, Pharmacology and Pharmacy 5 (2014) 117–128.

[21]

D. Sarsero, T. Fujiwara, P. Molenaar, J.A. Angus, Human vascular to cardiac tissue selectivity of L- and T-type calcium channel antagonists, Br. J. Pharmacol. 125 (1998) 109–119.

[22]

I. Splawski, K.W. Timothy, L.M. Sharpe, N. Decher, P. Kumar, R. Bloise, C. Napolitano, P.J. Schwartz, R.M. Joseph, K. Condouris, H. Tager-Flusberg, S.G. Priori, M.C. Sanguinetti, M.T. Keating, Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism, Cell 119 (2004) 19–31.

[23]

J. Koglin, M. Bohm, W. von Scheidt, A. Stablein, E. Erdmann, Antiadrenergic effect of carbachol but not of adenosine on contractility in the intact human ventricle in vivo, J. Am. Coll. Cardiol. 23 (1994) 678–683.

[24]

W.A. Catterall, A.L. Goldin, S.G. Waxman, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels, Pharmacol. Rev. 57 (2005) 397–409.

[25]

A.L. Goldin, Resurgence of sodium channel research, Annu. Rev. Physiol. 63 (2001) 871–894.

[26]

P.B. Bennett, C. Valenzuela, L.Q. Chen, R.G. Kallen, On the molecular nature of the lidocaine receptor of cardiac Na+ channels. Modification of block by alterations in the alpha-subunit III–IV interdomain, Circ. Res. 77 (1995) 584–592.