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The 2-n-propyl- and 2-n-butyl-3-dimethylamino-5,6-methylenedioxyindene hydrochlorides (MDIs) were previously shown to be calcium antagonists with an intracellular site of action. The present investigation was designed to explore the antiarrhythmic properties of the MDIs using the pathophysiological model of the ouabain-toxic dog. Cardiac arrhythmias in dogs were induced by intravenous administration of a loading dose of 55–60 μg/kg of ouabain, followed by a continuous infusion of a maintenance dose of 0.072 μg/kg per minute of the cardiac glycoside. Intravenous doses of 5–30 mg/kg of either of the MDIs administered to arrhythmic dogs resulted in a dose-dependent conversion to sinus rhythm which was preceded by a dose-dependent drop in diastolic blood pressure. Systolic pressure was unaltered, and the effects of the MDIs on heart rate were variable but generally unimpressive and not dose related. Pretreatment of dogs with single (30 mg/kg) or multiple (six injections of 10 mg/kg each) doses of the MDIs prior to ouabain administration afforded a significant protection of the animals against ouabain-induced arrhythmias, with the "time-to-onset" of arrhythmias being 4.5 to 8 times longer in the presence of the MDI pretreatments as compared with non-protected dogs. These findings indicate that the MDIs possess significant antiarrhythmic properties against ouabain-induced arrhythmias, and may lower blood pressure by direct arteriolar dilation without significant effects on cardiac chronotropy or inotropy.

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Short-term (96-h) tests on Xenopus laevis embryos are advocated for rapid screening of teratogens, as an alternative to the use of mammals. The objective of the present investigation was to determine whether extending the short-term tests beyond 96 h would detect the teratogenicity of chemicals that would otherwise be missed by the short-term tests. Lead teratogenicity was examined in Xenopus, using lead concentrations of 0.02, 0.05, 0.1, 0.5, 1.0, and 3.0 mg/L, which bracket the U.S. Environmental Protection Agency (EPA) maximum allowable concentration of 0.05 mg/L in water. Short-term exposure times were 72 or 96 h, starting on d 1, 2, or 3 postfertilization, while long-term exposure covered d 1 through metamorphosis. Short-term exposure resulted in neural tube defects (when exposure included d 1 and/or d 2) and tail curvatures, but only at the higher lead concentrations (1 and 3 mg/L). Lower lead concentrations produced no malformations upon short-term exposure, and this corresponded with the absence of tissue lead uptake. On the other hand, long-term exposure to lead (> 3 wk) resulted in the delayed appearance of lordoscoliosis at low lead concentrations (0.02-0.1 mg/L). The delayed appearance of lordoscoliosis corresponded roughly with the attainment of stable lead tissue levels, and this malformation persisted after metamorphosis. Thus, short-term observation tests alone may fail to detect the teratogenicity of low concentrations of environmental chemicals, and may result in the setting of inappropriately liberal exposure standards.