THE ACTIONS OF CARDIOACTIVE DRUGS 
ON DEVELOPING MYOCARDIUM 
William F. Friedman* 
Clinicians have long recognized age related differ- 
ences in cardiac pharmacology. These phenomena may 
reflect altered drug matabolism or disposition in the im- 
mature organism and/or an altered sensitivity of fetal 
and neonatal myocardium per se. The latter possibility 
was examined by studying the responsiveness to car- 
dioactive drugs of heart muscle isolated from a total 
of 50 fetal, newborn, and adult sheep. Fetal and adult 
cardiac muscle was equally responsive to isoproterenol 
and acetylcholine. Fetal heart was supersensitive to the 
positive inotropic effects of norepinephrine. At all ages 
acidosis attenuated the augmentation of contractility 
produced by norepinephrine. Propranolol exerted a more 
profound negative inotropic action on fetal than adult 
heart although the effectiveness of beta adrenergic re- 
ceptor blockade by propranolol was equal in fetal and 
adult myocardium. Cardiac NE concentrations were sig- 
nificantly lower in the fetal than the newborn lamb 
(P<0.001), and highest in the adult (P<0.002). The 
activities of intraneural enzymes involved in NE bio- 
synthesis and degradation, tyrosine hydroxylase and 
monoamine oxidase, respectively, were lowest in fetal 
heart, higher in the newborn, and highest in the adult 
(P<0.001), whereas the activity of catecholo-o-methyl 
transferase, an extraneural degradative enzyme, was 
highest in the fetus. Histochemical studies showed 
sparse catecholamine-containing neurons in fetal my- 
ocardium and a progressive increase of these nerves 
with age. In contrast, the extent of parasjmipathetic in- 
nervation of the fetal and adult hearts appeared similar. 
Thus, biochemical, pharmacological, and histochemical 
techniques describe differential development of para- 
sympathetic and sympathetic innervation in the mam- 
malian heart, and allow an explanation for age-depend- 
ent differences in autonomic responsiveness to the 
adrenergic, but not the cholinergic, neurotransmitter. 
It is apparent that a marked age-dependency of the 
myocardial responses to many cardioactive drugs exists 
that must be considered in any clinical evaluation of 
cardiac pharmacology in the perinatal period. 
* Associate Professor of Pediatrics and Medicine Chief of Pediatric 
Cardiology University of California, San Diego School of Medicine 
La Jolla, California. 
Recipient of Research Career Development Award #5 K04 
HE41737 from the National Heart and Lung Institute. 
*♦ Study Supported by U.S. Public Health Service Grant HE 
12373. 
INTRODUCTION** 
Although it is common pediatric knowledge 
that altered responsiveness to drugs may be a 
function of the age of the recipient, to date, car- 
diovascular pharmacology in the perinatal pe- 
riod has been based almost entirely on empirical 
observations and extrapolations from known ef- 
fects in adult patients. If age related differences 
exist in cardiac pharmacology, they could, of 
course, reflect altered drug metabolism or dispo- 
sition in the immature organism. Certainly, too, 
the developing myocardium may differ from the 
adult in its sensitivity to cardioactive stimuli 
and it is to this question that the present inves- 
tigations were directed. In order to study the 
myocardial responsiveness to drugs, atrial and 
ventricular heart muscle was isolated from fetal 
and neonatal lambs and adult sheep and studied 
in a myograph under identical conditions. The 
dose-effect relationships to norepinephrine, iso- 
proterenol, propranolol and acetylcholine were 
analyzed, and form the basis for this report. In 
addition, biochemical and histochemical meth- 
ods were employed in efforts to understand the 
observed age-related differences in pharmaco- 
logic responsiveness. Let us first examine cer- 
tain aspects of developmental autonomic phar- 
macology. 
PHARMACOLOGICAL STUDIES 
Thus far, physiologic and pharmacologic 
studies undertaken to assess the maturation of 
the autonomic control of the circulation have 
been concerned largely with the ability of young 
animals to respond to various physiologic stim- 
uli, such as hypoxemia, acidosis, and carotid 
sinus hypotension, or to the injection of 
catacholamines.^"^ Although the autonomic 
nervous system plays an important role in car- 
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