A propensity for bradycardia in preterm human infants suggested that the heart rate response to cholinergic stimulation may vary during development. Isolated, intact fetal mouse hearts (FMH) in organ culture were used as a model to explore developmental differences in chronotropic response to cholinergic stimulation. FMH's of gestational ages (GA) from 13–22 days, maintained for 36 hr in culture, were exposed to acetylcholine (AcH) with and without prior addition of physostigmine. Heart rate decreased markedly with 10--4 and 10--8 M AcH (84 ± 3 and 48 ± 4%) in 13–14 day hearts, but the decrease was progressively blunted with increasing age and was only 7 ± 3 and 3 ± 2 % at 21–22 days GA. Physostigmine markedly enhanced the cholinergic response in older hearts with 54 ± 4 and 32 ± 5% decreases in heart rate with the two doses of AcH at 21–22 days. However, it did not alter the response in younger hearts.
The data suggest that the chronotropic response to AcH progressively diminishes with advancing GA and the extent of intrinsic cholinesterase activity at different GA's is, in part, responsible for the decrease.
Increasing cholinesterase activity during gestation may, in part, protect more mature fetal hearts from severe bradycardia. Likewise, “unprotected” AcH receptors may account for the pronounced bradycardia in less mature hearts. If unprotected AcH receptors are important to the bradycardic response, does this play any role in vivo? One possibility is that the fetal heart's capacity to synthesize AcH and acetylcholinesterase may not develop synchronously. Such nonparallel enzyme system development might occur as a normal developmental sequence, exposed abnormally by premature birth or conversely, may be induced by abnormalities during gestation (e.g., chronic hypoxemia, intrauterine malnutrition). This general scheme is not unprecedented in that asynchronous development of interrelated enzymes systems deleterious to the prematurely born have already been well documented in the liver and lung. This hypothesis is currently being investigated.