ROLE OF ION CHANNELS AND EXCHANGERS IN MECHANICAL STRETCH-INDUCED CARDIOMYOCYTE HYPERTROPHY

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.