Freshly isolated hearts of fetal mice of gestational ages ranging between 12 and 22 days (term) were exposed to several concentrations of a variety of chronotropic agents. Acetylcholine (10-4 to 10-2 M) caused marked bradycardia in all hearts, even after only 12 to 14 days' gestation (i.e., even before cardiac innervation had occurred), and the intensity of the response increased steadily with age throughout gestation. Responsiveness to norepinephrine was present but minimal at 12-14 days, so that mean atrial rate rose by < 10% with a maximal concentration of the drug (10-5 M); responsiveness became more marked by 15 to 16 days (just after the time atrial innervation is thought to begin) and still greater effects appeared just before term. Glucagon had no effect in hearts of < 17 days' gestational age, but caused tachycardia thereafter, indicating that cardiac responsiveness to glucagon differentiates later than does responsiveness to norepinephrine. Responses to theophylline in 12 to 14 day hearts exceeded those to norepinephrine, indicating that the drug can affect heart rate independently of its ability to cause release of endogenous catecholamines. In contrast, tyramine caused no response until 21 to 22 days, well after the time the beta receptor has differentiated and after innervation is fairly well developed, suggesting that the drug's primary sympathomimetic effect is indirect rather than direct. Dibutyryl cyclic AMP did not cause tachycardia at any fetal age. It was concluded that maturation of responsiveness of the mouse heart to cardioactive drugs develops in specific patterns for different agents. The identification of differential patterns of maturation for various drugs may provide valuable means for characterizing the differentiation of specific receptors and for investigating possible mechanisms of action of the drugs.
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