The heart has not been regarde4 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 jug/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 fi-adrenergic responsiveness. In papillary muscles from TCDD-treated guinea pigs, the positive inotropic effect of isoproterenol (0.03-0.3 1AM) was decreased by a mean of 65% (P < 0.001), and the enhancement in the velocity of relaxation was 60% less than in the controls (P < 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 I3-adrenergic responsiveness, TCDD increases the intracellular Ca2+ concentration in papMary muscle. Finally, slow Ca2+ channels were not blocked after TCDD treatment, inasmuch as isoproterenol restored contractility equally effectively in K+ -depolarized TCDDtreated 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. 2,3,7, is the prototype of a group of chemically related, highly toxic environmental chemicals. Binding by TCDD and other toxic polyhalogenated biphenyls to specific cytosolic and nuclear receptors leads to induction of a group of enzymes, the best-characterized of which are specific isozymes of cytochrome P-450. These chemicals also elicit a symptom complex characterized by weight loss, thymic involution, tumor promotion, edema, increased mortality, and in some species,

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1 The reactivity to methoxamine (Met) of atria isolated from the hearts of normal and from acutely streptozotocin-diabetic rats has been studied. 2 Met (1 x 10-6M) increased the tension of both normal and diabetic atria, but in diabetic atria, the dose-response curve to Met was shifted to the left and the efficacy of Met was enhanced. 3 Inhibitors of ca-adrenoceptors blocked, in a competitive manner, the positive inotropic effect induced by Met in both types of atrial preparations. 4 Inhibitors of the cyclo-oxygenase pathway for arachidonic acid metabolism blocked the atrial response to Met in non-diabetic as well as in diabetic atria. The inhibition of prostacyclin synthetase prevented the effect of Met in normal atria, while blockers of thromboxane generation inhibited it in diabetic ones. 5 Agents that inhibit the activity of lipoxygenase(s) significantly reduced the positive inotropic action induced by Met in diabetic atria but failed to modify it in non-diabetic preparations. 6 These results show that diabetic atria are more sensitive to Met than normal atria. In diabetes the response to ca-adrenoceptor stimulation could be mediated by oxidative products generated via thromboxane synthetase and lipoxygenase(s) activities; whereas in normal preparations the action of Met may involve the release of prostacyclin.

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The effects of a wide range of Prostacyclin (PGI2) concentrations on the Isometric Developed Tension (IDT) of isolated left auricles driven at different frequencies (0.8, 1.6 or 3.3 Hz) were explored. A comparison of the positive inotropism of PGI2, norepinephrine (NE), tyramine and phenylephrine (Phenyl) indicated that PGI2, NE and tyramine enhanced peak tension significantly less at slow (0.8 and 1.6 Hz) than at higher rates (3.3 Hz); whereas Phenyl augmented equally the IDT at all of these three driving frequencies. The positive inotropism evoked by PGI2 was inhibited by (-)-propranolol and also by a treatment with 6-OHDA. Cocaine, normetanephrine and U-0521, augmented the positive inotropic influence of PGI2 on atria paced at a slow rate (0.8 Hz) but not at a faster one (3.3 Hz). These results suggest that the action of PGI2 on atrial contractions is apparently indirect and mediated by the release of tissue catecholamines. In addition the effect of PGI2 and NE at slow and fast rates appears associated with a different relative relevance of the processes which terminate the action of added sympathomimetic agonists, namely, neuronal or extraneuronal uptake as well as metabolization via COMT. These mechanisms seen to be more prominent at slower driving frequencies and could explain the diminished effect of PGI2 and NE on slowly paced atria.