2,3,7,8-tetrachlorodibenzo-p-dioxin increases cardiac myocyte intracellular calcium and progressively impairs ventricular contractile responses to isoproterenol and to calcium in chick embryo hearts

L Canga, L Paroli, TJ Blanck, RB Silver and AB Rifkind

Department of Pharmacology, Cornell University Medical College, New York, New York 10021.

Binding by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor leads to transcriptional activation of several genes and a toxicity syndrome that includes tumor promotion, wasting, hormonal and immune system dysfunction, and death. Recent findings indicate that TCDD may also affect cardiac function. Here, we used the chick embryo, a TCDD-sensitive species, to further characterize the effects of TCDD on ventricular muscle contraction and on cardiac myocyte [Ca2+]i assessed with fura 2. The results show that TCDD causes an evolving sequence of contractile defects, independent of changes in diet, first impairing cAMP-modulated contraction (after 48 hr) and later (by seven days) decreasing responses to [Ca2+]o. Phenobarbital, even at high doses, failed to affect the inotropic response to isoproterenol, supporting the specificity of the ventricular contractile effects of TCDD. TCDD treatment also depressed inotropic responses to theophylline and forskolin, indicating that it has a post-beta-adrenergic receptor effect on cAMP action. In contrast to its depression of responses to beta-adrenergic stimuli and to [Ca2+]o, TCDD did not affect initial tensions of ventricular muscle stimulated at 1 Hz or the force- frequency response up to 1 Hz, indicating that TCDD-treated ventricles can respond normally at slow rates of stimulation. TCDD treatment depressed lusitropic (relaxation) responses to isoproterenol and to increasing [Ca2+]o indicating that it impairs the ability of the sarcoplasmic reticulum to sequester Ca2+. Fura 2-based measurements showed that [Ca2+]i was nearly doubled after TCDD treatment. The increase in [Ca2+]i is consistent with the decrease in the contractile response to [Ca2+]o, amelioration of the response to isoproterenol by subphysiologic concentrations of [Ca2+]o, and intermittent lack of response to electrical stimulation in high K+ observed in ventricles from TCDD-treated embryos. TCDD treatment also depressed the initial increase in [Ca2+]i by isoproterenol, consistent with the decreased contractile response to isoproterenol. The findings show that TCDD causes well defined, progressive impairment of avian ventricular responses to inotropic stimuli, providing new evidence that the heart is a target of TCDD action and that TCDD disturbs intracellular calcium processing.

Volume 44, Issue 6, pp. 1142-1151, 12/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				D. S. Antkiewicz, R. E. Peterson, and W. Heideman Blocking Expression of AHR2 and ARNT1 in Zebrafish Larvae Protects Against Cardiac Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicol. Sci., November 1, 2006; 94(1): 175 - 182. [Abstract] [Full Text] [PDF]

				S. A. Carney, J. Chen, C. G. Burns, K. M. Xiong, R. E. Peterson, and W. Heideman Aryl Hydrocarbon Receptor Activation Produces Heart-Specific Transcriptional and Toxic Responses in Developing Zebrafish Mol. Pharmacol., August 1, 2006; 70(2): 549 - 561. [Abstract] [Full Text] [PDF]

				D. S. Antkiewicz, C. G. Burns, S. A. Carney, R. E. Peterson, and W. Heideman Heart Malformation Is an Early Response to TCDD in Embryonic Zebrafish Toxicol. Sci., April 1, 2005; 84(2): 368 - 377. [Abstract] [Full Text] [PDF]

				R. J. Sommer, A. J. Hume, J. M. Ciak, J. J. VanNostrand, M. Friggens, and M. K. Walker Early Developmental 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure Decreases Chick Embryo Heart Chronotropic Response to Isoproterenol but Not to Agents Affecting Signals Downstream of the Beta-Adrenergic Receptor Toxicol. Sci., February 1, 2005; 83(2): 363 - 371. [Abstract] [Full Text] [PDF]