Calcium sensitization in perfused beating guinea pig heart by a positive inotropic agent MCI-154.
We investigated the effects of MCI-154, a positive inotropic agent that increases the myofilament response to Ca++, on Ca++ transients, left ventricular (LV) function and phosphodiesterase (PDE) III activity of guinea pig heart, and compared them with the effects of pimobendan and milrinone. In Langendorff guinea pig hearts loaded with a fluorescent Ca++ probe indo-1, LV pressure and Ca++ transient were measured simultaneously. MCI-154 (10(-10)-10(-6) M) increased LV developed pressure, +dP/dt and -dP/dt with a reduction of LV end-diastolic pressure, although it did not affect coronary flow. The positive inotropic activity of MCI-154 was more potent than that of pimobendan and milrinone; EC50 values (concentrations for increasing +dP/dt by 50% from base line) were 4.31, 41.5 and 294 x 10(-9) M, respectively. The positive inotropic effect of MCI-154 was accompanied by the increase in systolic, diastolic and amplitude of indo-1 fluorescence ratio. The relative increase in Ca++ transients against the increase in LV contractility produced by MCI-154, however, was significantly less than that by increasing perfusate [Ca++], pimobendan or milrinone. MCI-154 (3 x 10(-7)-10(-4) M) inhibited the activity of PDE III isolated from guinea pig LV tissues, but the inhibitory effect of MCI-154 was less than pimobendan and milrinone; IC50 values were 10.1, 3.5 and 2.4 x 10(-6) M, respectively. These findings suggest that MCI-154 exerts a positive inotropic effect mainly through Ca(++)-sensitizing action in intact beating whole hearts.
Abe
Y
Y
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
Ishisu
R
R
Onishi
K
K
Sekioka
K
K
Narimatsu
A
A
Nakano
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005453:Fluorescence; D006168:Guinea Pigs; D007211:Indoles; D008297:Male; D020105:Milrinone; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011728:Pyridones; C059587:Indo-1 pentaacetoxymethyl ester; C041648:pimobendan; C052228:MCI 154; D020105:Milrinone; D002118:Calcium