HETEROGENEITY AND UNDERLYING MECHANISM FOR INOTROPIC ACTION OF ENDOTHELIN-1 IN RAT VENTRICULAR MYOCYTES

1. To clarify the mechanisms underlying the positive inotropic action of endothelin-1 (ET-1), we investigated the effect of ET-1 on twitch c ell shortening and the Ca2+ transient in rat isolated ventricular myoc ytes loaded with a fluorescent Ca2+ indicator indo-1. 2 There was a ce ll-to-cell heterogeneity in response to ET-1. ET-1 (100 nM) increased twitch cell shortening in only 6 of 14 cells (44%) and the increase in twitch cell shortening was always accompanied by an increase in the a mplitude of the Ca2+ transient. 3 The ETA- and ETB-receptors antagonis t TAK-044 (100 nM) almost reversed both the ET-1-induced increases in twitch cell shortening and in the Ca2+ transient. In the ET-1 non-resp onding cells, the amplitude of the Ca2+ transient never increased. 4 I ntracellular pH slightly increased (similar to 0.08 unit) after 30 min perfusion of ET-1 in rat ventricular myocytes. However, ET-1 did not change the myofilament responsiveness to Ca2+, which was assessed by ( 1) the relationship between the Ca2+ transient amplitude and twitch ce ll shortening, and by (2) the Ca2+ transient-cell shortening phase pla ne diagram during negative staircase.5 We concluded that there was a c ell-to-cell heterogeneity in the positive inotropic effect of ET-1, an d that the ET-receptor-mediated positive inotropic effect was mainly d ue to an increase in the Ca2+ transient amplitude rather than to an in crease in myofilament responsiveness to Ca2+.