Functional and antiischaemic effects of the phosphodiesterase inhibitor levosimendan in isolated rabbit hearts.
Several phosphodiesterase inhibitors have been reported to possess antiischaemic properties by improving myocardial oxygen demand/supply balance. Levosimendan is a new phosphodiesterase inhibitor with calcium-sensitizing properties. We investigated the functional and antiischaemic properties of levosimendan in isolated electrically-driven rabbit hearts (Langendorff, constant perfusion pressure: 70 cm H2O, Tyrode solution, Ca++ 1.8 mmol/l, 37 degrees, 200 beats/min.). Acute regional myocardial ischaemia was induced by ligature of a circumflex artery branch and quantified from epicardial NADH-fluorescence photography.


RESULTS
The left ventricular pressure was similarly enhanced by levosimendan 10(-7) M or 5 x 10(-6) M (+15%) (P < 0.05). The global coronary flow was increased more markedly by levosimendan 5 x 10(-6) M (+35-50%) compared to 10(-7) M (+25%) (P < 0.05). The relative coronary flow (= global coronary flow/pressure-rate-product) was significantly enhanced only by levosimendan 5 x 10(-6) M (+20-35%) (P < 0.05), but not by levosimendan 10(-7) M (+10-15%) (P > 0.05). Epicardial NADH-fluorescence area and intensity were significantly diminished by levosimendan (-20%) (P < 0.05), and there was no significant difference between myocardial ischaemia reduction by levosimendan 10(-7) M and 5 x 10(-6) M (P > 0.05).


CONCLUSIONS
Levosimendan is an inotrope with coronary dilator activity, showing antiischaemic effects in isolated rabbit hearts. These may be caused by (1) phosphodiesterase-inhibition and improvement of myocardial perfusion and/or (2) by oxygen-sparing effects, related to calcium sensitization of myofilaments, particularly at lower concentrations associated with a lower coronary dilator activity.
Rump
A F
AF
Institute of Pharmacology, University of Köln, Germany.
Acar
D
D
Rösen
R
R
Klaus
W
W
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004558:Electric Stimulation; D005453:Fluorescence; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D009243:NAD / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D000077464:Simendan; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D014665:Vasodilator Agents; D009243:NAD; D000077464:Simendan