Polyamines mediate uncontrolled calcium entry and cell damage in rat heart in the calcium paradox.

Abstract

Brief perfusion of heart with calcium-free medium renders myocardial cells calcium-sensitive so that readmission of calcium results in uncontrolled Ca2+ entry and acute massive cell injury (calcium paradox). We investigated the hypothesis that polyamines may be involved in the mediation of abnormal Ca2+ influx and cell damage in the calcium paradox. The isolated perfused rat heart was used for these studies. Calcium-free perfusion promptly (< 5 min) decreased the levels of polyamines and the activity of their rate-regulating synthetic enzyme, ornithine decarboxylase (ODC), and calcium reperfusion abruptly (< 15-180 s) increased these components. a-Difluoromethylornithine (DFMO), a specific suicide inhibitor of ODC, suppressed the calcium reperfusion-induced increase in polyamines and the concomitant increase in myocardial cellular 4"Ca influx, loss of contractility, release of cytosolic enzymes, myoglobin, and protein, and structural lesions. Putrescine, the product of ODC activity, nullified DFMO inhibition and restored the calcium reperfusion-induced increment in polyamines and the full expression of the calcium paradox. Putrescine itself enhanced the reperfusion-evoked release of myoglobin and protein in the absence of DFMO. Hypothermia blocked the changes in heart ODC and polyamines induced-by calcium-free perfusion and calcium reperfusion and prevented the calcium paradox. These results indicate that rapid Ca2+-directed changes in ODC activity and polyamine levels are essential for triggering excessive transsarcolemmal transport of Ca2" and explosive myocardial cell injury in the calcium paradox.

Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission

“…How neuronal activity induces ODC1 is not clearly understood but in peripheral tissue there is evidence of a physiological coupling between polyamine levels and intracellular calcium (Ca 2+ ) concentrations (Chang, 1991; Koenig et al, 1987; Langdon et al, 1984). In a pioneer study of a phenomenon called the calcium paradox, Koening et al linked Ca 2+ and polyamines with excitability and pathological consequences of maladaptive homeostatic mechanisms in the heart (Koenig et al, 1987).…”

“…In a pioneer study of a phenomenon called the calcium paradox, Koening et al linked Ca 2+ and polyamines with excitability and pathological consequences of maladaptive homeostatic mechanisms in the heart (Koenig et al, 1987). Koening et al (1987) demonstrated that changes in ODC1 activity and polyamine concentrations followed changes in intracellular Ca 2+ concentration ([Ca 2+ ]) with a time delay of approximately 15 seconds.…”

“…Koening et al (1987) demonstrated that changes in ODC1 activity and polyamine concentrations followed changes in intracellular Ca 2+ concentration ([Ca 2+ ]) with a time delay of approximately 15 seconds. These series of experiments showed that ODC1 and polyamines are part of an activity feedback mechanisms involving intracellular [Ca 2+ ], and that abnormal polyamine-mediated compensation may trigger pathological excitability, intracellular [Ca 2+ ] overload, and cell death (Koenig et al, 1987). Similarly, in neurons, a reduction in extracellular [Ca 2+ ] from 2 to 1 mM produces hyperexcitability and seizure-like activity (Isaev et al, 2012).…”

Reperfusion paradox: A novel mode of glial cell injury

“…Of these, reperfusion injury, or that which occurs during reperfusion of previously ischemic tissue, has not yet been defined. Although normally characterized in the intact heart (Koenig et al, 1987;Uemura et al, 1985), little evidence exists for such a phenomenon in single cells of a number of excitable tissues (Li et al, 1988;Young, 1986). Conceptually, however, the term "calcium paradox" injury has been 01992 Wiley-Liss, Inc. associated with deleterious reperfusion phenomena in both the myocardium and central nervous system (Young, 1986).…”

Regulation of the Phosphoinositide Cascade by Polyamines in Brain

“…Interest has focused on spermine and spermidine as potential neuromodulators of the NMDA receptor complex in brain; specifically, the binding of (+)-5-[3H]methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate ([3H]MK-801), N-(1-[2-thienyl]cyclohexyl)-3,4-[ 3H]piperidine ([3H]TCP), and [3H]glycine to the NMDA receptor complex was enhanced by polyamines (Ransom and Stec, 1988), and the effect was blocked by arcaine, agmatine, diethylenetriamine, and 1,8-octanediamine, structurally related analogues of spermine and spermidine (Reynolds, 1990;Sacaan and Johnson, 1990;Williams et al, 1990). Furthermore, spermine and spermidine are considered to be intracellular messengers that increase free cytosolic Ca 2+ levels by stimulating Ca 2+ influx and mobilizing Ca 2+ from intracellular sites in both brain (Igbal and Koenig, 1985 ;Bondy and Walker, 1986) and other tissues (Koenig et al, 1983(Koenig et al, , 1987 .…”