CORONARY VASORELAXANT EFFECT OF LEVOSIMENDAN, A NEW INODILATOR WITH CALCIUM-SENSITIZING PROPERTIES

We examined the action of levosimendan, a new Ca2+-sensitizing inodila tor, on isolated porcine coronary arteries. Vessel rings were studied in isometric myographs. Arterial cyclic adenosine monophosphate (cAMP) levels were determined by radioimmunoassay. Levosimendan (10(-7)-10(- 3) M) completely relaxed arteries preconstricted by prostaglandin F-2 alpha (PGF(2 alpha)) with a pD(2) (-logEC(50)) value of 3.99 +/- 0.05 (n = 6-9 in all experiments). Pretreatment with levosimendan also pre vented contraction induced by PGF(2 alpha.) The vasorelaxation produce d by levosimendan (10(-7)-10(-3) M) was not attenuated by removal of t he endothelium. Levosimendan (10(-7)-10(-3) M) relaxed contractions in duced by 30 mM K+ as well as 80 mM K+, whereas the K+ channel opener l evcromakalim selectively relaxed contraction induced by 30 mM K+. Neit her the cyclooxygenase inhibitor indomethacin nor the beta-adrenocepto r blocker propranolol influenced levosimendan-induced vasorelaxation. The Ca2+-entry blocker isradipine failed to relax arteries precontract ed by endothelin-l in Ca2+-free/EGTA medium. However, levosimendan (10 (-7)-3 x 10(-3) M) completely relaxed endothelin-1-induced contraction s in this medium. Levosimendan potentiated the relaxant effect of a cA MP-stimulating drug, isoprenaline, but also that of nitroglycerin and isradipine. At a maximal effective concentration, it increased arteria l tissue contents of CAMP twofold. In conclusion, levosimendan produce s coronary vasorelaxation by a mechanism that seems to be endothelium independent and not mediated by K+ channel opening, Ca2+-entry blockad e, release of cyclooxygenase products, or beta-adrenoceptor stimulatio n. Accumulation of cAMP may possibly participate in vasorelaxation at high concentrations of levosimendan, but a cAMP-independent mechanism seems to be involved at lower concentrations.