Heart as a target organ in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity: decreased beta-adrenergic responsiveness and evidence of increased intracellular calcium.
The heart has not been regarded as a major target organ of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity notwithstanding that lethal cardiac dysfunction can occur in the absence of histopathological changes. To assess possible TCDD cardiotoxicity, we studied the effect of TCDD five days after treatment (10 micrograms/kg of body weight; single dose given i.p. in corn oil) on the contractility of guinea pig right ventricular papillary muscle. Controls were treated with corn oil. TCDD treatment significantly decreased beta-adrenergic responsiveness. In papillary muscles from TCDD-treated guinea pigs, the positive inotropic effect of isoproterenol (0.03-0.3 microM) was decreased by a mean of 65% (P less than 0.001), and the enhancement in the velocity of relaxation was 60% less than in the controls (P less than 0.05). On the other hand, TCDD treatment did not alter the positive inotropic effect of lower concentrations of isoproterenol (0.1-10 nM). After TCDD, responsiveness to low-frequency stimulation (0.1 and 0.25 Hz) was enhanced, responsiveness to increases in extracellular Ca2+ concentration was attenuated, and isoproterenol-elicited aftercontractions in K+-depolarized preparations were increased in magnitude. Collectively, the latter findings suggest that in addition to decreasing beta-adrenergic responsiveness, TCDD increases the intracellular Ca2+ concentration in papillary muscle. Finally, slow Ca2+ channels were not blocked after TCDD treatment, inasmuch as isoproterenol restored contractility equally effectively in K+-depolarized TCDD-treated and control papillary muscles. Our findings indicate that TCDD causes a specific pattern of cardiac dysfunction in a mammalian species, selectively augmenting or decreasing different cardiac responses. The cardiac changes are consistent with reported membrane effects of TCDD; further, they suggest that the heart may be a major target organ for TCDD toxicity.
Canga
L
L
Department of Pharmacology, Cornell University Medical College, New York, NY 10021.
Levi
R
R
Rifkind
A B
AB
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000032:analysis*; D004147:Dioxins / Q000633:toxicity*; D006168:Guinea Pigs; D007424:Intracellular Fluid / Q000032:analysis; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000032:analysis / Q000187:drug effects*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011188:Potassium / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D011188:Potassium; D002118:Calcium