Summary
We observed changes in the performance of isolated right ventricle strips taken from rats when calcium was repleted following various periods of calcium depletion in order to study certain phenomena, such as the calcium paradox, in this preparation. Furthermore, to assess the possible role of calmodulin in this myocardial damage, the effects of known calmodulin inhibitors such as trifluoperazine and chlorpromazine on the contractility and resting tension were studied by means of the calcium repletion after a calcium-depleted period of 12 min. The temperature was kept at 37°C, and the muscle strips were stimulated electrically at a rate of 0.25 Hz. When there was a calcium-depleted period of longer than 8 min, a marked increase in resting tension was observed and reached maximum at 2 to 4 min. The recovery of peak developed tension and peak positive or negative dT/dt worsened as the duration of the calcium depletion was longer. These findings indicate the massive intracellular calcium influx by the calcium reintroduction and the myocardial damage induced by the calcium overload as observed in isolated whole hearts. Treatment with trifluoperazine (1–5 μM) and chlorpromazine (1–5 μM) did not inhibit a rise in resting tension significantly after the calcium repletion, except for 5 μM of both drugs at 6 min. Trifluoperazine significantly improved the recovery of the contractility (developed tension and dT/dt), whereas the protective effect of chlorpromazine was not obtained. These results suggest that the depression of calmodulin activity is beneficial in the prevention of myocardial damage produced by calcium repletion, although there is a difference in the effect of the calmodulin inhibitors, trifluoperazine and chlorpromazine.
Similar content being viewed by others
References
Alto LE, Dhalla NS (1979) Myocardial cation contents during induction of calcium paradox. Am J Physiol 237:H713-H719
Chien KR, Pfau RG, Farber JL (1979) Ischemic myocardial cell injury: prevention by chlorpromazine of an accelerated phospholipid degradation and associated membrane dysfunction. Am J Pathol 97:505–530
Fleckenstein A, Janke J, Döring HJ, Leder O (1974) Myocardial fiber necrosis due to intracellular Ca overload: a new principle in cardiac pathophysiology. In: Myocardial Biology; Dhalla NS (ed). University Park Press, Baltimore, 563–580. (Recent advances in studies on cardiac structure and metabolism; vol 4)
Frank JS, Rich TL, Beydler S, Kreman M (1982) Calcium depletion in rabbit myocardium: ultrastructure of the sarcolemma and correlation with the calcium paradox. Circ Res 51:117–130
Franson RC, Pang DC, Towle DW, Weglicki WB (1978) Phospholipase A activity of highly enriched preparations of cardiac sarcolemma from hamster and dog. J Mol Cell Cardiol 10:921–930
Hülsmann WC (1983) On the mechanism of the calcium paradox: the release of hydrolytic enzymes. Eur Heart J 4 (Suppl H): 57–61
Katz AM, Messineo FC (1981) Lipid-membrane interactions and the pathogenesis of ischemic damage in the myocardium. Circ Res 48:1–16
Kunze H, Nahas N, Traynor JR, Wurl M (1976) Effects of local anaesthetics on phospholipases. Biochem Biophys Acta 441:93–102
Lamers JMJ, Ruigrok TJC (1983) Diminished Na+/K+ and Ca2+ pump activities in the Ca2+-depleted heart: possible role in the development of Ca2+ overload during the Ca2+ paradox. Eur Heart J 4 (Suppl H):73–79
Lagerstrand G, Mattisson A, Poupa O (1983) Studies on the calcium paradox phenomenon in cardiac muscle strips of poikilotherms. Comp Biochem Physiol 76A:601–613
Levin RM, Weiss B (1976) Mechanism by which psychotropic drugs inhibit adenosine cyclic 3′, 5′-monophosphate phosphodiesterase of brain. Mol Pharmacol 12:581–589
Levin RM, Weiss B (1977) Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. Mol Pharmacol 13:690–697
Lomský M, Ekroth R, Poupa O (1983) The calcium paradox and its protection by hypothermia in human myocardium. Eur Heart J 4 (Suppl H):139–142
Mori T, Takai Y, Minakuchi R, Yu B, Nishizuka Y (1980) Inhibitory action of chlorpromazine, dibucaine, and other phospholipid-interacting drugs on calcium-activated, phospholipid-dependent protein kinase. J Biol Chem 255:8378–8380
Nayler WG, Elz JS, Perry SE, Daly MJ (1983) The biochemistry of uncontrolled calcium entry. Eur Heart J 4 (Suppl H):29–41
Nayler WG, Poole-Wilson PA, Williams A (1979) Hypoxia and calcium. J Mol Cell Cardiol 11:683–706
Okumura K, Ogawa K, Satake T (1983) Pretreatment with chlorpromazine prevents phospholipid degradation and creatine kinase depletion in isoproterenol-induced myocardial damage in rats. J Cardiovasc Pharmacol 5:983–988
Paradise NF, Visscher MB (1975) K+ and Mg2+ net fluxes in relation to zero [Ca2+] perfusion and subsequent cardiac contracture (38739). Proc Soc Exp Biol Med 149:40–45
Shen AC, Jennings RB (1972) Myocardial calcium and magnesium in acute ischemic injury. Am J Pathol 67:417–440
Schaffer SW, Burton KP, Jones HP, Oei HH (1983) Phenothiazine protection in calcium overloadinduced heart failure: a possible role for calmodulin. Am J Physiol 244:H328-H334
Shaikh NA, Downar E (1981) Time course of changes in porcine myocardial phospholipid levels during ischemia: a reassessment of the lysolipid hypothesis. Circ Res 49:316–325
Signal RK, Matsukubo MP, Dhalla NS (1979) Calcium-related changes in the ultrastructure of mammalian myocardium. Br J Exp Pathol 60:96–106
Weiss B, Prozialeck M, Cimino M, Barnette MS, Wallace TL (1980) Pharmacological regulation of calmodulin. Ann NY Acad Sci 356:319–345
Walsh MP, Le Peuch CJ, Vallet B, Cavadore JC, Demaille JG (1980) Cardiac calmodulin and its role in the regulation of metabolism and contraction. J Mol Cell Cardiol 12:1091–1101
Zimmerman ANE, Hülsmann WC (1966) Paradoxical influence of calcium ions on the permeability of the cell membranes of the isolated rat heart. Nature 211:646–647
Zimmerman ANE, Daems W, Hülsmann WC, Snijder J, Wisse E, Durrer D (1967) Morphological changes of heart muscle caused by successive perfusion with calcium-free and calcium-containing solutions (calcium paradox). Cardiovasc Res 1:201–209
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Okumura, K., Ogawa, K. & Satake, T. Effects of trifluoperazine and chlorpromazine on calciumrepleted injury in isolated ventricle strips. Basic Res Cardiol 80, 556–563 (1985). https://doi.org/10.1007/BF01907919
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01907919