Adrenergic modulation of cardiac development in the rat: effects of prenatal exposure to propranolol via continuous maternal infusion.

During early postnatal development, catecholamines are thought to modulate cardiac cell replication and differentiation, and to program future beta-adrenergic sensitivity. To determine if the sensitive period for these events extends to prenatal ages, pregnant rats were infused with propranolol continuously via osmotic minipumps from gestational day 7 through parturition and the offspring were examined for markers of cardiac cellular development (basal ornithine decarboxylase activity and levels of DNA and protein) and for reactivity to acute beta-adrenergic challenge (heart rate responses and stimulation of ornithine decarboxylase). During the propranolol infusion, fetal cardiac responses to terbutaline, a beta-adrenergic agonist, were completely blocked; after discontinuation of beta-blockade at birth, responses became normal and remained unaffected into young adulthood. Biochemical markers indicated a delay in cellular development caused by propranolol: basal ornithine decarboxylase activity was elevated in the fetus and DNA was subnormal for the first week after birth. Cardiac growth was maintained in the face of DNA deficits by cell enlargement (elevated protein/DNA) which persisted through weaning. By young adulthood, all markers were within normal limits. These data suggest that fetal catecholamines, acting on beta-receptors, do play an initial role in cardiac cellular development, but that the critical period for programming of beta-adrenergic responsiveness occurs later in maturation.

Duke Scholars

Author Theodore Alan Slotkin Pharmacology & Cancer Biology