org-30029 and Heart-Failure

The present study was aimed at investigating the effect of two Ca++ sensitizers, EMD 57033 (without significant phosphodiesterase inhibition) and ORG 30029 (with phosphodiesterase inhibition), in myocardium from nonfailing and failing human hearts. In nonfailing myocardium both EMD 57033 and ORG 30029 increased force of contraction by 280 +/- 27% and 94 +/- 13%, respectively (n = 6); the time to 80% relaxation (t80%) by 278 +/- 45% and 155 +/- 21%; and diastolic force by 28 +/- 8% and 12 +/- 3%, respectively. In trabeculae from failing myocardium, the increase in active force was similar to that in nonfailing trabeculae (EMD, 305 +/- 30%; ORG, 88 +/- 12% (n = 6)). However, the increase in t80% (EMD, 378 +/- 56%; ORG, 230 +/- 26%) and diastolic force (65 +/- 12%; 24 +/- 5%) was more pronounced in failing myocardium. EMD had no effect on the peak of the [Ca++]i transient; however, it prolonged the time course of the [Ca++]i transient in both nonfailing and failing myocardial fibers. ORG increased the peak of the Ca++ transient and prolonged the time course in preparations from both nonfailing and failing hearts. Both EMD and ORG shifted the [Ca++]-force relationship toward lower [Ca++] (EMD > ORG). The Ca++ sensitizers EMD 57033 and ORG 30029 increased active force development in nonfailing and failing human myocardium, but both impaired relaxation in failing myocardium to a greater extent than in nonfailing human myocardium in a concentration-dependent fashion.

Topics: Adult; Calcium; Cardiotonic Agents; Diastole; Dose-Response Relationship, Drug; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Contraction; Organic Chemicals; Quinolines; Thiadiazines

The action of a novel cardiotonic agent N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximide hydrochloride (Org 30029) on intracellular aequorin light transients and isometric contractions was investigated in isolated canine ventricular trabeculae. The positive inotropic effect of Org 30029 (30 microM-3 mM) was consistently associated with prolongation of the duration of contraction and an increase in the amplitude of the intracellular Ca2+ transients. The maximum inotropic response to Org 30029 was approximately 150% of the maximum response to isoproterenol, whereas the maximum increase in the amplitude of Ca2+ transients produced by Org 30029 was only 20% of the isoproterenol-induced maximum. The duration of isometric contractions was prolonged by Org 30029, with no change in the duration of the light transients. The concentration-response curve for the positive inotropic effect of Org 30029 was shifted by carbamylcholine chloride (carbachol, 3 microM) to the right and downward, but the maximum response to Org 30029 was greater than that to isoproterenol even in the presence of carbachol. Carbachol abolished the increase in light transients and cAMP accumulation induced by Org 30029 (1 mM), whereas it only partially attenuated the positive inotropic effect of Org 30029. In the presence of carbachol (3 microM), Org 30029 increased the force of contraction in a concentration-dependent manner without augmenting the aequorin light transients. These results are compatible with the hypothesis that Org 30029 increases cardiac contractility by increasing myofilament Ca2+ responsiveness.

Topics: Actin Cytoskeleton; Aequorin; Animals; Calcium; Carbachol; Cardiotonic Agents; Chordae Tendineae; Dogs; Dose-Response Relationship, Drug; Female; Heart Failure; Isoproterenol; Male; Myocardial Contraction; Organic Chemicals