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 clas s of cardiac inotropic drugs, Ca++ sensitizers. Levosimendan is also a vaso dilator both in vitro and in vivo, but its mechanism is not well understood . nle cardiac target protein of levosimendan, troponin C, is a Ca++-binding EF-hand protein. This raises the possibility that levosimendan may also in teract with smooth muscle EF-hand proteins, such as, calmodulin, the regula tory myosin light chains, or S100 proteins. We investigated the effects of levosimendan on [Ca++](i), and force in porcine coronary arteries, with rec eptor-mediated (U46619) or KCl stimulation. At high levels of stimulation, levosimendan decreased force without changing or increasing [Ca++](i), meas ured with the Ca++-sensitive fluorescent probe fura-2 in the intact artery. With lower levels of U46619, levosimendan (1 mu M) lowered force by 70% an d reduced [Ca++](i) by 38%. The relationship between force and [Ca++](i), f or KCI stimulation are significantly rightward shifted, indicating Ca++ des ensitization by levosimendan. In contrast, the phosphodiesterase III inhibi tor, milrinone, does not shift the force-Ca++ relations but elicits relaxat ion via lowering [Ca++](i). There was little change in pH(i), indicating th at the Ca++ desensitization by levosimendan was not attributable to decreas ing pH(i). Levosimendan relaxes coronary arteries and lowers [Ca++](i) by m echanisms different than milrinone. Our results indicate a lowering of [Ca+](i) by levosimendan consistent with opening of potassium channels and a r elaxation that is independent of [Ca++](i). Our evidence points to a novel mechanism that might involve the direct effect of levosimendan on the smoot h muscle contractile or regulatory proteins themselves.