Developmental Factors Contributing to the Susceptibility to Bradycardia in Isolated, Cultured Fetal Mouse Hearts

Abstract

Summarvtle and attention behavioral responses (3,21,34,35,42). 2) The A propensity for bradycardia in preterm human infants suggested that the heart rate response to cholinergic stimulation may ;ary 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 lo-' and lo-' 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 f 2 % at 21-22 days GA. Physostigmine markedly enhanced the cholinergic response in older hearts with 54 f 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 i n 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. SpeculationIncreasing cholinesterase activity during gestation may, in part, protect more mature fetal hearts from severe bradycardia. Likekise, "unprotected" AcH receptors may account for the pronounced bradvcardia 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 develop ment 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.The widespread use of heart rate monitoring in fetal and neonatal intensive care has revealed a rather high incidence of bradyarrhythmias in the newborn infant (8,21,25,38,41,42). In fact, detection of bradycardia has become a major factor in determining the therapeutic threshold of certain fetal and neonatal afflictions (13,17).Clinical and laboratory investigations as well as simple clinical observations have suggested: 1) Bradycardia (usually sinus) occurs spontaneously and.in response to a wide variety of stimuli such as increased CNS pressure, umbilical cord compression, hypoxemia, apnea, nasopharyngeal and laryngeal stimulation, defecation, star-incidence and/or the severity ofbradycardia may be increased in the premature infant (18,26,27,34).As a group, immature fetuses and neonates are certainly subject to more bradycardia-evoking stimuli. However, the occurrence and severity of this ...

Studies on the mechanisms of action of MR33317

“…In addition, one might study based on such findings, whether or not MR33317 increases the negative inotropic effect of acetylcholine in the human heart. This is expected from previous reports wherein the negative inotropic or chronotropic effects of acetylcholine in the heart were potentiated by physostigmine, or other acetylcholinesterase inhibitors (Maurer 1979;Korth and Kühlkamp 1987;Kakinuma et al 2009).…”

Hemodynamic vulnerability to acute hypoxia in day 10.5–16.5 murine embryos

“…2), suggesting that the minimum EHR may be determined by autonomous cardiomyocyte ion channel profiles 37,40 . It is interesting that the EHR reported in cultured mouse embryos never surpasses the minimum EHR we noted during acute hypoxia at corresponding days 76–79 . This is probably because of the reduced efficiency of oxygen delivery in vitro versus the placental circulation and the absence of circulating chronotropic factors, such as epinephrine and norepinephrine 80–82 .…”

Arrhythmias in the developing heart

“…). In humans, sensitivity to bradycardia in premature infants suggests that the heart rate response to cholinergic stimulation may change during development (Maurer ). This hypothesis was tested on isolated intact foetal mouse hearts (ED13–ED22).…”