Heterogeneity and underlying mechanism for inotropic action of endothelin-1 in rat ventricular myocytes

Abstract

1. To clarify the mechanisms underlying the positive inotropic action of endothelin-1 (ET-1), we investigated the effect of ET-1 on twitch cell shortening and the Ca²⁺ transient in rat isolated ventricular myocytes loaded with a fluorescent Ca²⁺ indicator indo-1.

2. There was a cell-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 amplitude of the Ca²⁺ transient.

3. The ET_A- and ET_B-receptors antagonist 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-responding cells, the amplitude of the Ca²⁺ transient never increased.

4. Intracellular pH slightly increased (∼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 cell shortening, and by (2) the Ca²⁺ transient-cell shortening phase plane diagram during negative staircase.

5. We concluded that there was a cell-to-cell heterogeneity in the positive inotropic effect of ET-1, and that the ET-receptor-mediated positive inotropic effect was mainly due to an increase in the Ca²⁺ transient amplitude rather than to an increase in myofilament responsiveness to Ca²⁺.

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