Endothelin-1 enhances cross-bridge function of ferret myocardium: role of second messengers.
To investigate postreceptor pathways of endothelin and the site of action responsible for enhancing myocardial contractility, studies were performed on ferret papillary muscles loaded with the Ca2+ indicator aequorin. Endothelin-1 (ET) and the alpha 1-adrenoceptor agonist, phenylephrine (PE) produced similar dose-dependent increases in tension development and peak intracellular Ca2+ concentration ([Ca2+]i); moreover, pretreatment with PE eliminated effects of ET, suggesting similar postreceptor pathways. Because alpha 1-adrenoceptor activation is thought to cause the hydrolysis of phosphatidylinositol and generate D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and 1,2-diacylglycerol (DAG), the protein kinase C (PKC) activator 4 beta-phorbol 12-myristate 13-acetate (PMA) was used to determine whether activation of PKC was responsible for the myocardial actions of ET. In contrast to ET, PMA decreased tension development and peak [Ca2+]i, and pretreatment with PMA attenuated the myocardial action of ET; however, intracellular Ins(1,4,5)P3 levels were greatly increased by ET stimulation, suggesting that rather than DAG, Ins(1,4,5)P3 might be the second messenger for the actions of ET. To determine whether ET produced actions on the contractile elements, thereby enhancing myocardial contractility, 2,3-butanedione monoxime (BDM) was used to interfere with the interaction of myosin and actin. Pretreatment with 6 mM BDM did not alter the half-maximum effective concentration (EC50) of the [Ca2+]o-tension relation, but, in contrast, shifted the ET dose-response curve to the right, and increased the EC50 by approximately 1.0 log unit. In addition, ET partially reversed the downward shift of the peak [Ca2+]i-peak tension curve induced by BDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
J
J
Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts 02215.
Flemal
K
K
Morgan
J P
JP
D000818:Animals; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005289:Ferrets; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology; D015290:Second Messenger Systems; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016232:Endothelins; D011942:Receptors, Adrenergic, alpha; D017466:Receptors, Endothelin; C004717:diacetylmonoxime; D015544:Inositol 1,4,5-Trisphosphate; D003931:Diacetyl; D013755:Tetradecanoylphorbol Acetate