Negative inotropic effect of endothelin-1 in the mouse right ventricle.
Effects of endothelin-1 on the contraction and cytosolic Ca(2+) concentrations (¿Ca(2+)(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 ET(A) receptor antagonist, BQ-123 (cyclo ¿Asp-Pro-Val-Leu-Trp-; 3, 10 microM). Endothelin-1 reduced the peak amplitudes of both the ¿Ca(2+)(i) transient and contraction without changing inward Ca(2+) current. The relationship between peak amplitude of ¿Ca(2+)(i) and peak force generated by changing the extracellular Ca(2+) concentration (¿Ca(2+)(o)) was not affected by endothelin-1. In addition, the trajectory of the ¿Ca(2+)(i)-contraction phase plane diagram obtained at 2 mM ¿Ca(2+)(o) in the absence of endothelin-1 was superimposable on that obtained at 4 mM ¿Ca(2+)(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 microM), inhibited the endothelin-1-induced negative inotropy. These results suggest that endothelin-1 elicits negative inotropy by reducing the amplitude of the ¿Ca(2+)(i) transient without changing inward Ca(2+) current through the activation of the endothelin ET(A) receptor followed by protein kinase C activation in the mouse right ventricle.
Izumi
M
M
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, 113-8657, Tokyo, Japan. izu@jvm2.vm.a.u-tokyo.ac.jp
Miyamoto
S
S
Hori
M
M
Ozaki
H
H
Karaki
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology
D019332:Endothelin-1; D007211:Indoles; D008301:Maleimides; D010456:Peptides, Cyclic; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium