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The effects of a wide range of PGE1 and PGE2 concentrations on the isometric developed tension of isolated rat atria beating spontaneously or paced at a fixed rate, were explored. PGE1 only produced a negative inotropic effect (NIE), whereas PGE2 elicited a biphasic inotropic action; negative at low concentrations and positive (PIE) at higher ones. Phenoxybenzamine and phentolamine failed to modify either the NIE or the PIE, but subthreshold exogenous norepinephrine abolished the NIE, suggesting a presynaptic inhibitory effect of PGEs on the adrenergic neurotransmitter release. Auricles pretreated with subthreshold norepinephrine react with a PIE to PGE1, but not to PGE2. On the contrary in the presence of subthreshold methoxamine the PIE of PGE2 was increased whereas the action of PGE1 was not modified.

Contractile responses to exogenous sodium arachidonate (NaA) were studied in auricles from normal and acutely diabetic (streptozotocin-treated) rats. NaA induced a concentration-dependent positive inotropic effect in atria from normal and diabetic rats but the magnitude of the contractile influence of the fatty acid was different in both types of auricles, i.e. diabetic atria had a greater responsiveness to NaA than normal preparations. Blockers of arachidonic acid (AA) metabolism via cyclo-oxygenase (indomethacin and acetylsalicylic acid), abolished the stimulatory influence of NaA in normal and in diabetic auricles. Moreover, incubation with tranylcipromine, a prostacyclin synthetase inhibitor, reduced the inotropic effect of NaA in normal atria, but failed to modify it in the diabetic atria. On the other hand, inhibitors of thromboxane (TX) synthetase (imidazole and L-8027) diminished the effect of NaA in diabetic preparations without altering the contractile responses in the controls. In the presence of lipoxygenase blocking agents (nordihydroguaiaretic acid and dithizone), the influence of NaA was reduced at normal values only in the atria from diabetic rats. Both atrial preparations (normal and diabetic) converted ([1-14C]arachidonic acid (AA) into PGI2 (assessed as 6-oxo-PGF1 alpha) and TXB2. Moreover, normal atria generated more PGI2 than TXB2 whereas TXB2 production was greater than that of PGI2 in diabetic atria. The foregoing results suggest that in non-diabetic atria the effect of exogenous NaA may be attributed to metabolites generated by the sequential action of cyclo-oxygenase and prostacyclin synthetase. On the other hand, the contractile action of exogenous NaA in diabetic atria may be ascribed to thromboxanes and lipoxygenase(s) metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of chagasic sera, containing an antibody (EVI antibody) which reacts with the plasma membrane of working myocardial cells, on "toxic" and "non-toxic" actions of ouabain upon isolated self beating or paced rat atria suspended in different media, were explored. Although ouabain produced a dose-dependent positive inotropic influence on atria suspended in Krebs-Ringer-bicarbonate (KRB) and in KRB plus normal human serum (KRB + NHS) it did not elicit any significant positive inotropic effect on atria beating in KRB plus EVI positive human chagasic serum (EVI(+)S). Additionally, EVI(+)S dose-response curves of classical signs of digitalis cardiac toxicity shifted to the left. The threshold concentration of ouabain required to elicit the onset of "toxic" effects was higher in control preparations (kept in KRB or KRB + NHS) than in EVI(+)S exposed preparations. (-)-Propranolol attenuated the overall toxic action of ouabain in EVI(+)S and facilitated its positive inotropic influence. In control media, the beta-adrenoceptor blocker failed to modify either the "non-toxic" or the "toxic" effect of ouabain. On the other hand, with control atria, subthreshold exogenous norepinephrine inhibited the positive inotropism of ouabain. The data suggest that an adrenergic mechanism is involved in the action of ouabain on cardiac tissue immersed in an EVI(+)S-containing solution. The foregoing results may explain the severe "toxic" effects observed with cardioactive glycosides when they are used in patients with Chagas' heart disease, even at low doses.