Cardiotonic drugs differentially alter cytosolic [Ca2+] to left ventricular relationships before and after ischemia in isolated guinea pig hearts.

Objective: Cardiotonic agents may differentially alter indices of the cytosolic [Ca2+]/left ventricular pressure (LVP) relationship when given before and after ischemia. We measured and calculated systolic-diastolic [Ca2+], systolic-diastolic LVP, velocity ratios (VRs) d[Ca2+]/dtmax to dLVP/dtmax (VRmax), d[Ca2+]/dtmin to dLVP/dtmin (VRmin), and area ratio (AR, area Ca2+]/area LVP per beat) before and after 30 min global ischemia in guinea pig hearts.

Methods: Hearts were perfused with levosimendan, dobutamine, dopamine, or digoxin. Ca2+ transients were recorded by indo-1 fluorescence via a fiber optic probe placed on the LV free wall. [Ca2+]/LVP loops were acquired by plotting LVP time as a function of [Ca2+] at multiple time points during the cardiac cycle.

Results: Ischemia reperfusion increased [Ca2+] and decreased contractility and relaxation and produced a flatter and broader [Ca2+]/LVP loop. All drugs shifted the [Ca2+]/LVP loop rightward and upward when given before and after ischemia. Dobutamine increased [Ca2+] and contractility more than other drugs. Digoxin increased [Ca2+] the least but increased contractility similar to dopamine and levosimendan. Before ischemia dopamine and digoxin both decreased VRmax and VRmin, whereas dobutamine increased VRmin, but not VRmax, and levosimendan had no effect on VR. VRmax and VRmin were markedly elevated after ischemia, but again decreased with dopamine and digoxin; dobutamine again increased VRmin, but not VRmax, and levosimendan decreased both VRmax and VRmin. Before ischemia dopamine and digoxin both decreased AR, dobutamine increased AR, and levosimendan had no effect; after ischemia AR was markedly elevated but dopamine and digoxin decreased AR, dobutamine increased AR, and levosimendan decreased AR.

Conclusion: Although each drug enhanced contractility and relaxation both before and after ischemia by increasing cytosolic [Ca2+] and Ca2+ flux, dopamine and digoxin improved, and dobutamine worsened responsiveness to Ca2+, i.e., velocity ratio and area ratio, whereas levosimendan had no net effect before ischemia but improved responsiveness after ischemia.