Ca2+ sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium.
Effects of the Ca2+ sensitizer N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride (Org-30029) on the myocardial contractile depression induced by acidosis and 2,3-butanedione monoxime (BDM) were investigated in aequorin-loaded canine ventricular myocardium. The peak Ca2+ transient-peak force relation during administration of Org-30029 (10(-4) to 10(-3) M) was shifted to the left and upward compared with the relation for elevation of the extracellular Ca2+ concentration ([Ca2+]o) (2.5-12.5 mM). Acidosis (pH 6.6) depressed the force with a small increase in the peak Ca2+ transient. BDM (3 mM) depressed the force with no change in the peak and duration of the Ca2+ transient, indicating that BDM may inhibit selectively the cross-bridge interaction. During acidosis or in the presence of BDM, elevation of [Ca2+]o increased the peak Ca2+ transient to the same extent as that in the control, but the force was inhibited. In contrast, Org-30029 increased the force to a level equivalent to the control with a slight change in the peak Ca2+ transient. In addition, during acidosis, Org-30029 (10(-3) M) increased the force in association with a slight decrease in the peak Ca2+ transient. Thus Org-30029 can reverse the myocardial contractile depression induced by a decrease in the Ca2+ sensitivity of myofilaments, as occurs in pathophysiological situations such as acidosis in cardiac ischemia. Org-30029 may exert the Ca(2+)-sensitizing effect by an increase in the affinity of troponin C for Ca2+ and by a direct action on the cross-bridge interaction.
Watanabe
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A
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Tomoike
H
H
Endoh
M
M
D000138:Acidosis / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009930:Organic Chemicals; D009994:Osmolar Concentration
D002316:Cardiotonic Agents; D009930:Organic Chemicals; C062763:ORG 30029; C004717:diacetylmonoxime; D003931:Diacetyl; D002118:Calcium