Negative inotropic effect of endothelin-1 in the mouse right ventricle

Effects of endothelin-1 on the contraction and cytosolic Ca2+ concentrations [Ca2+](i)) of the mouse right ventricle were investigated. Endothelin-1 (1-300 nM) elicited a negative inotropic effect in a concentration-dependent manner. The endothelin-1-induced negative inotropy was antagonized by a selective endothelin ETA receptor antagonist, BQ-123 (cyclo [Asp-Pro-Val-Leu-Trp-]; 3, 10 mu M). Endothelin-1 reduced the peak amplitudes of both the [Ca2+](i) transient and contraction without changing inward Ca2+ current. The relationship between peak amplitude of [Ca2+](i) and peak force generated by changing the extracellular Ca2+ concentration ([Ca2+](o)) was not affected by endothelin-1. In addition, the trajectory of the [Ca2+](i)-contraction phase plane diagram obtained at 2 mM [Ca2+](o) in the absence of endothelin-1 was superimposable on that obtained at 4 mM [Ca2+](o) in the presence of endothelin-1 (300 nM). Endothelin-1 (300 nM) translocated protein kinase C from cytosol to membrane, suggesting activation of protein kinase C. Further, a selective protein kinase C inhibitor, bisindolylmaleimide I (10 mu M), inhibited the endothelin-1-induced negative inotropy. These results suggest that endothelin-1 elicits negative inotropy by reducing the amplitude of the [Ca2+](i) transient without changing inward Ca2+ current through the activation of the endothelin ET, receptor followed by protein kinase C activation in the mouse right ventricle. (C) 2000 Elsevier Science B.V. All rights reserved.