Endothelin-1 does not alter Ca2+ responsiveness in saponin-skinned ferret papillary muscles.
Endothelin is a potent vasoconstrictor and a positive inotropic agent in myocardium. Endothelin has been reported to increase myocardial contractility with little or no increase in intracellular Ca2+, thus apparently enhancing myofilament responsiveness to Ca2+. We investigated the effects of endothelin on tension development and Ca2+ responsiveness in both intact and saponin-skinned ferret right ventricular papillary muscles. Isolated ferret papillary muscles were stimulated for 2 h in the presence or absence of endothelin (100 nM). The muscles were then chemically skinned with saponin and exposed to relaxing and contracting solutions containing varying amounts of Ca2+, and the developed force of contraction was measured. The [Ca2+] required for half-maximal activation (pCa50) was determined by fitting force versus Ca2+ data to the Hill equation. In isometrically contracting muscles, endothelin (100 nM) caused a mean percent increase in developed tension of 34.7% +/- 11.3% (mean +/- S.E.). In muscles that were exposed to endothelin for 2 h and then skinned, neither the pCa50 nor the maximal Ca(2+)-activated force (Fmax) were significantly different from control skinned papillary muscles. After skinning, when endothelin (100 nM) was added to the Ca2+ buffers, both pCa50 and Fmax were significantly decreased. When papillary muscles were pretreated with phorbol 12-myristate 13-acetate (PMA) and then skinned, there was a significant increase in the pCa50. These results indicate that endothelin acts directly on the myofilaments to impair force development by directly decreasing the Ca2+ responsiveness of myofilaments.(ABSTRACT TRUNCATED AT 250 WORDS)
Paik
G Y
GY
Charles A. Dana Research Institute, Harvard Medical School, Boston, Massachusetts.
Wang
J
J
Perreault
C L
CL
Morgan
J P
JP
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003198:Computer Simulation; D004075:Diglycerides / Q000378:metabolism; D004594:Electrophysiology; D016232:Endothelins / Q000494:pharmacology*; D005289:Ferrets; D006352:Heart Ventricles / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004075:Diglycerides; D016232:Endothelins; D010716:Phosphatidylinositols; D012503:Saponins; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium