Phenothiazine protection in calcium overload-induced heart failure: a possible role for calmodulin

Abstract

The effect of several phenothiazines on the extent of cellular damage resulting from the calcium paradox was examined. Hearts treated with trifluoperazine, a potent calmodulin inhibitor, exhibited less cellular damage than untreated myocardium as reflected by light microscopy, high-energy phosphate content and the loss of protein and creatine phosphokinase into the perfusate. A dose response of this effect revealed a maximal response at about 1 microM trifluoperazine, a concentration which lies well within the range generally attributed to calmodulin inhibition. Several other lines of evidence were also obtained suggesting a possible role for calmodulin in calcium-overload induced necrosis. First, the phenothiazines had little influence on membrane changes believed responsible for altered calcium permeability. Second, trifluoperazine was without major effect unless included in the reperfusion buffer, indicating that the drug is only effective during the phase associated with calcium overload. Finally, less protection was afforded hearts exposed to phenothiazines such as chlorpromazine and promethazine, which are weaker inhibitors of calmodulin, than those treated with the potent inhibitor trifluoperazine. While other interpretations are possible, these studies are consistent with a role for calmodulin in calcium overload-induced heart failure.

Effect of calmodulin antagonists on hypoxia and reoxygenation damage in isolated rabbit hearts

“…Thus, a new class of agents -calmodulin antagonists -have become useful in assessing the role of calcium in intracellular processes (4,16,32,42). Recently, trifluoperazine (TFP), one of these antagonists (41), was reported to reduce myocardial damage associated with the Ca-paradox (32,33). It raised the possibility that a calmodulin dependent process may be involved in the development of cellular damage of the myocardium (32,33).…”

“…Recently, trifluoperazine (TFP), one of these antagonists (41), was reported to reduce myocardial damage associated with the Ca-paradox (32,33). It raised the possibility that a calmodulin dependent process may be involved in the development of cellular damage of the myocardium (32,33). *) This study was supported by the grant W.10.8.4.13.05 347 To verify this hypothesis further we have examined the effects of TFP and compound R 24571 on hearts subjected to hypoxia and reoxygenation.…”

Moderation of myocardial ischemia reperfusion injury by calcium channel and calmodulin receptor inhibition

“…In spite of that, TFP has been found to protect myocardial cells against damage resulting from the Ca 2+ paradox [24]. Previous studies [10] as well as our own [12] have shown the cardioprotective effects of TFP against myocardial ischemic and reperfusion injury when applied in the face of an ischemic insult.…”

The possible role of phospholipase A2 in cardiac membrane destabilization under calcium overload conditions

“…It is also likely that most of the stabilizing potency of TFP rises from its antiphospholipase activity (1,37). The phenothiazines have been previously shown to protect the heart against disturbances in phospholipid metabolism as well as against reperfusion calcium-mediated damage (35).…”

“…Due to the presence of calmodulin in the myocardium, its certain activation during calcium overload (35) and the ability to alter many aspects of intracellular metabolism involving stimulation of membrane-associated PLA2 the above proposal seems rather reasonable.…”