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)