Haemodynamic interactions between the novel calcium sensitiser levosimendan and isosorbide-5-mononitrate in healthy subjects.
OBJECTIVE
The new calcium sensitiser levosimendan also possesses vasodilatory effects due to potassium-channel opening. The aim of the present study was to assess the possible haemodynamic interactions between levosimendan and isosorbide-5-mononitrate in young healthy men.


METHODS
The study was crossover, placebo controlled, double blind, randomised, and it comprised of four study days with one medication--levosimendan, isosorbide-5-mononitrate, levosimendan plus isosorbide-5-mononitrate or placebo--given on each. Levosimendan was administered i.v. as an initial bolus dose of 12 microg/kg over 10 min, followed by a continuous infusion of 0.2 microg/kg/min for a total time of 2 h. Isosorbide-5-mononitrate (20 mg) was given orally as a single dose. Leg blood flow and venous capacity (venous occlusion plethysmography), cardiac output (impedance cardiography), skin blood flow (laser-Doppler flowmetry), blood pressure and heart rate were recorded at baseline, and 20 min, 1 h, 2 h, 4 h and 6 h after the start of the infusion. An orthostatic test was performed at baseline and at 2 h 15 min. Twelve healthy, male subjects were included. Their mean age was 24 years (range 20-34 years).


RESULTS
Levosimendan increased leg blood flow by 32%, and no additive effect of the combination of levosimendan and isosorbide-5-mononitrate was observed. The effects of levosimendan on heart rate and blood pressure were minimal and in close conformity with previous studies. In general, there were no additive effects of the combination compared with each drug alone at rest. The only additive effect was seen in the orthostatic response. Heart rate increased by 40 beats min(-1) with the combination (95% confidence interval compared with placebo 11-24 beats min(-1)), by 30 beats min(-1) with levosimendan (2-15 beats min(-1)), by 28 beats min(-1) with isosorbide-5-mononitrate (1-15 beats min(-1)), and by 22 beats min(-1) with placebo. Furthermore, three subjects were unable to stand upright for the stipulated time with the combination, and the orthostatic test had to be discontinued prematurely. There were no changes in the conduction intervals in the electrocardiogram on any of the treatments. The combination had no influence on the occurrence of headache compared with isosorbide-5-mononitrate alone.


CONCLUSIONS
No major additive haemodynamic effects of the combination of levosimendan and isosorbide-5-mononitrate compared with each drug alone could be observed at rest. However, during an orthostatic test, the circulatory response was significantly potentiated with the combination, and three of the subjects were unable to stand upright for the stipulated time.
Sundberg
S
S
Orion Pharma, Orion Research Centre, Espoo, Finland.
Lehtonen
L
L
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D018592:Cross-Over Studies; D003971:Diastole; D004311:Double-Blind Method; D004347:Drug Interactions; D004906:Erythrocyte Count / Q000187:drug effects; D006261:Headache / Q000139:chemically induced; D006339:Heart Rate / Q000187:drug effects; D006400:Hematocrit; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006835:Hydrazones / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D007548:Isosorbide Dinitrate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D007866:Leg / Q000098:blood supply; D008297:Male; D011187:Posture; D011724:Pyridazines / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D000077464:Simendan; D016683:Supine Position; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology*
D006835:Hydrazones; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan; D003404:Creatinine; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate