Endothelin-1 and angiotensin II modulate rate and contraction amplitude in a subpopulation of mouse embryonic stem cell-derived cardiomyocyte-containing bodies.
Embryonic stem cell-derived cardiomyocytes (ESC-CMs) have applications in understanding cardiac disease pathophysiology, pharmacology, and toxicology. Comprehensive characterization of their basic physiological and pharmacological properties is critical in determining the suitability of ESC-CMs as models of cardiac activity. In this study we use video microscopy and quantitative PCR to investigate the responses of mouse ESC-CMs to adrenoceptor, muscarinic, angiotensin II (Ang II), and endothelin-1 (ET-1) receptor activation. Isoprenaline (10 nM-10 μM) increased beating rate and contraction amplitude in all beating bodies (BBs), whereas carbachol (up to 1 μM) and the I(f) channel blocker ZD-7288 (10 μM) decreased contraction frequency. ET-1 (0.01-100 nM) reduced contraction amplitude in all BBs and increased contraction frequency in 50% of BBs; these effects were blocked by the ET(A) receptor antagonist BQ123 (250 nM). Ang II (0.01 nM-1 μM) increased both contraction amplitude (all BBs) and frequency (in 50% of BBs), effects blocked, respectively, by losartan (100 nM) and PD123,319 (200 nM). These results indicate the presence of functional ET(A) and both AT₁ and AT₂ receptors in murine ESC-CMs, but their expression and or activity appears to be evident only in a limited set of BBs.
Lagerqvist
E L
EL
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Melbourne, Australia.
Finnin
B A
BA
Pouton
C W
CW
Haynes
J M
JM
D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*
D019332:Endothelin-1; D000804:Angiotensin II