T. Yamazaki et al., ROLE OF ION CHANNELS AND EXCHANGERS IN MECHANICAL STRETCH-INDUCED CARDIOMYOCYTE HYPERTROPHY, Circulation research, 82(4), 1998, pp. 430-437
We have previously reported that stretching of cardiomyocytes activate
s the phosphorylation cascade of protein kinases, including Raf-l kina
se and mitogen-activated protein (MAP) kinases, followed by an increas
e in protein synthesis partly through enhanced secretion of angiotensi
n II and endothelin-l. Membrane proteins, such as ion channels and exc
hangers, have been postulated to first receive extracellular stimuli a
nd evoke intracellular signals. The present study was performed to det
ermine whether mechanosensitive ion channels and exchangers are involv
ed in stretch-induced hypertrophic responses, Neonatal rat cardiomyocy
tes cultured on expandable silicone dishes were stretched alter pretre
atment with a specific inhibitor of stretch-sensitive cation channels
(gadolinium and streptomycin), of ATPT-sensitive K+ channels (glibencl
amide), of hyperpolarization-activated inward channels (CsCl), or of t
he Na+-H+ exchanger (HOE 694). Pretreatment with gadolinium, streptomy
cin, glibenclamide, and CsCl did not show any inhibitory effects on MA
P kinase activation by mechanical stretch, HOE 694, however, markedly
attenuated stretch-induced activation of Raf-1 kinase and MAP kinases
by approximate to 50% and 60%, respectively, and attenuated stretch-in
duced increase in phenylalanine incorporation into proteins. In contra
st, HOE 694 did not inhibit angiotensin II-and endothelin-l-induced Ra
f-1 kinase and MAP kinase activation. These results suggest that among
many mechanosensitive ion channels and exchangers, the Na+-H+ exchang
er plays a critical role in mechanical stress-induced cardiomyocyte hy
pertrophy.