Ca2+ sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium.

Abstract

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.

• Authors: A Watanabe, H Tomoike, M Endoh
• Journal: The American journal of physiology (Am J Physiol) Vol. 271 Issue 5 Pt 2 Pg. H1829-39 (Nov 1996) ISSN: 0002-9513 [Print] United States
• PMID: 8945898 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Organic Chemicals
• ORG 30029
• diacetylmonoxime
• Diacetyl
• Calcium

Topics

• Acidosis (metabolism, physiopathology)
• Animals
• Calcium (metabolism)
• Cardiotonic Agents (pharmacology)
• Diacetyl (analogs & derivatives, pharmacology)
• Dogs
• Extracellular Space (metabolism)
• Female
• In Vitro Techniques
• Male
• Myocardial Contraction (drug effects)
• Myocardium (metabolism)
• Organic Chemicals
• Osmolar Concentration