Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization.
Levosimendan is a pyridazinone-dinitrile derivative belonging to a new class of cardiac inotropic drugs, Ca++ sensitizers. Levosimendan is also a vasodilator both in vitro and in vivo, but its mechanism is not well understood. The cardiac target protein of levosimendan, troponin C, is a Ca++-binding EF-hand protein. This raises the possibility that levosimendan may also interact with smooth muscle EF-hand proteins, such as, calmodulin, the regulatory myosin light chains, or S100 proteins. We investigated the effects of levosimendan on [Ca++]i, and force in porcine coronary arteries, with receptor-mediated (U46619) or KCl stimulation. At high levels of stimulation, levosimendan decreased force without changing or increasing [Ca++]i, measured with the Ca++-sensitive fluorescent probe fura-2 in the intact artery. With lower levels of U46619, levosimendan (1 microM) lowered force by 70% and reduced [Ca++]i by 38%. The relationship between force and [Ca++]i for KCl stimulation are significantly rightward shifted, indicating Ca++ desensitization by levosimendan. In contrast, the phosphodiesterase III inhibitor, milrinone, does not shift the force-Ca++ relations but elicits relaxation via lowering [Ca++]i. There was little change in pHi, indicating that the Ca++ desensitization by levosimendan was not attributable to decreasing pHi. Levosimendan relaxes coronary arteries and lowers [Ca++]i by mechanisms different than milrinone. Our results indicate a lowering of [Ca++]i by levosimendan consistent with opening of potassium channels and a relaxation that is independent of [Ca++]i. Our evidence points to a novel mechanism that might involve the direct effect of levosimendan on the smooth muscle contractile or regulatory proteins themselves.
Bowman
P
P
Molecular and Cellular Physiology, University of Cincinnati, Ohio, USA.
Haikala
H
H
Paul
R J
RJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003331:Coronary Vessels; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006835:Hydrazones / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D066298:In Vitro Techniques; D020105:Milrinone / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone; D002118:Calcium