In the nonrecirculating isolated perfused rat heart it has recently been described that basal myocardial protein degradation is suppressed by 30% within 5 min of maximal β-adrenergic receptor occupancy under 5 × 10 −7 m isoproterenol ( Lockwood, 1985, Biochem. J. 231, 299–308). This adrenergic-controlled proteolytic process presumably contributes to the well-known normal coordination of myocardial protein mass with functional demand. It is presently reported that elevated intracellular calcium is among the messengers that somehow suppress protein degradation. Acute elevation of extracellular calcium to a maximal concentration of 9.0 m m mimicked the simultaneous effects of isoproterenol on increasing inotropy and decreasing protein degradation, although this concentration was eventually lethal. Conversely, infusion of trifluoperazine (TFP), a calmodulin-blocking antipsychotic drug, caused stimulation of protein degradation above basal levels within 5 min. The stimulation of degradation by 30–60% was transient at 5 × 10 −7 m and returned to the control level in 5–10 min. However, TFP produced massive irreversible release of amino acid peptides and proteins at 10 −5 m within 30 min, followed by grossly observable cell structural disruption and cell separation. The degradative stimulation caused by TFP was potentiated by lowering the normal 2.5-m m extracellular Ca 2+ concentration to 1.25 m m. Trifluoperazine at 10 −5 m caused longitudinal separation of myofibrils by disrupting lateral attachments between adjacent Z lines, leading to a loss of lateral myofibrillar registry followed by myofibrillar degeneration. Spot desmosomes were disrupted, leading to lateral cell separation; however, the fascia adherens region of the intercalated disks remained intact and cells maintained end-to-end attachment. Perfusion under the low extracellular Ca 2+ concentration of 0.1 m m for 0.5 hr caused separation of the fascia adherens region and spot desmosomes of the intercalated disks as well as disruption of cytoplasmic myofibrils and other changes. Although the structural disorganization caused by perfusion with low (0.1 m m) Ca 2+ were similar to those caused by TFP, cells also lost end to end attachment under low Ca 2+. Amitriptyline (10 −5 m), thioridazine (10 −5 m), and calmidazolium (10 −6 m) stimulated protein degradation and caused structural damage. It is speculated that the above Ca 2+-related phenomena describe the mechanism of the well-known toxic cardiomyopathy resulting from overdoses of some of the antipsychotic-antidepressant drugs. The antipsychotic agent, haloperidol, which has been reported to be noncardiotoxic and weakly inhibitory toward calmodulin, did not stimulate protein degradation, nor did it cause structural disruption even at a grossly supratherapeutic 8 × 10 −6 m concentration that completely suppressed contractile activity.