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The aim of this study was to compare the positive inotropic effects of 3 different agents with 3 different mechanisms of actions-levosimendan, rolipram, and dobutamine-on human atrial trabecular muscles. Samples of right atrial appendage (1 cm, 500-1000 mg) were removed and immersed in preoxygenated and modified Tyrode solution. In oxygenated Tyrode solution, preparations were used to investigate the concentration-effect relationship of levosimendan, dobutamine, and rolipram on percentage developed tension (DT), from 10 to 10 M, each concentration for 15 minutes. All 3 agents produced concentration-dependent increments in DT. We found that levosimendan was the most efficacious positive inotropic agent on isolated human atrial trabeculae. Both the sensitivity (pD2) and maximum response (Emax) of human atrial trabeculae to levosimendan (6.711 +/- 0.26 and 23.2 +/- 2.2 mN, respectively) were significantly greater than those of dobutamine (6.663 +/- 0.19 and 17.6 +/- 2.8 mN) and rolipram (6.497 +/- 0.18 and 15.0 +/- 1.0 mN). pD2 and Emax values for dobutamine were significantly higher than those for rolipram. It was suggested that because of its potential to enhance cardiac performance without predisposition to calcium-induced arrhythmias, levosimendan might be more useful as a positive inotropic agent in clinical practice.

Background: Dobutamina Studio Italiano Multicentrico (Do.S.I.M.) is a prospective, randomized, multicenter interuniversity Italian study aimed at assessing the effects of dobutamine on spontaneous variability of ventricular arrhythmias in sinus rhythm NYHA class III-IV patients with congestive heart failure (CHF)., Methods: Out of 74 pre-hoc estimated CHF patients, 68 (92%) were randomized electively to either being washed out of all active drugs except diuretics (group A) or to continue with the standard regimen including digitalis, diuretics and ACE-inhibitors (group B, standard therapy). In 63 patients, complete Holter data were obtained and are reported here. After 72 hours, in both groups, 48-hour Holter monitoring (Holter 1) was performed. The spontaneous variability of ventricular arrhythmias was assessed by calculating the natural logarithm of the sum of hourly incidences (during 48 consecutive hours) of index events such as the mean heart rate or the various forms of total and either sustained or non-sustained ventricular arrhythmias. The results were then grouped for the first and second 24-hour Holter periods. All patients were submitted to 10 microg/kg/min infusion of dobutamine for 72 hours and 48-hour Holter monitoring (Holter 2) was repeated 24 hours before the end of dobutamine infusion. The incidence of arrhythmia and the distribution of laboratory and echocardiographic variables was also studied in group A and B patients. The data of the two groups along with the intrapatient +/- 95% confidence intervals were pooled, both on and off dobutamine., Results: There was no significant difference between Holter 1 and Holter 2 in the rates of index events in 63 patients with regard to pro-arrhythmic effects. Pro-arrhythmic effects were seen during dobutamine infusion in 21% of cases, an effect which subsided (to 5%) when dobutamine was discontinued. Interestingly, the positive inotropic effects of dobutamine (based on ejection fraction changes) were parallel (22%) to the pro-arrhythmic changes, although they persisted long after dobutamine discontinuation (18%). The pro-arrhythmic effects of dobutamine, both during (5%) as well as after (1%) drug infusion, were unrelated to heart rate changes. The prevalence and incidence of non-sustained ventricular tachycardia due to dobutamine were 47 and 29% respectively., Conclusions: In sinus rhythm patients with severe CHF, dobutamine had chronotropic effects and increased a depressed ejection fraction without significantly increasing arrhythmogenicity.