Anti-ischemic and membrane stabilizing activity of calmodulin inhibitors

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Abstract
In the control perfused working rat hearts subjected to 25 min global ischemia, reperfusion resulted in a 50% recovery of the hemodynamic functions. A concentration-dependent improvement of this recovery and a reduction of the postischemic lactate dehydrogenase (LDH) release was caused by calmidazolium (CMZ), trifluoperazine (TFP), and chlorpromazine (CPZ) added prior to ischemia. The drugs were not effective when added only to the reperfusate. The concentrations of CMZ, TFP, and CPZ producing the half-maximal effects were 2.5×10−9 M, 1.5×10−7 M and 3×10−7 M, respectively. Prolongation of the ischemic period caused a progressive deterioration of the functional recovery of the hearts while the total postischemic LDH release showed, at the same time, an initial gradual rise followed by a later decay. In untreated hearts the duration of ischemia resulting in 50% loss of hemodynamic function and in a maximal LDH release was 25 min. TFP (10−6 M) and CMZ (10−7 M) prolonged these times by 4–7 min and 5–10 min, respectively. TFP, CPZ, and CMZ protected the erythrocytes from osmotic hemolysis. The maximum anti-hemolytic activity was produced by 3×10−6 M CMZ, 3×10−5 M TFP, and 10−4 CPZ. The concentration-dependency of this effect was not affected by low concentrations of sodium dodecyl sulphate (SDS). Neither TFP nor CMZ prevented the hemolysis produced by 10−3 M SDS. It is concluded that the delay in the development of the ischemic injury produced by TFP and CMZ is due to the effects of these drugs as calmodulin antagonists rather than as membrane stabilizers.