736 
PHARMACOLOGY 
diocirculatory control in the mature mammal, 
the precise mechanisms and degree of neural 
control of the circulation of the fetus and new- 
born is not clear. There remains a lack of quan- 
tification of the development of the separate 
factors constituting an integrated circulatory 
response — the afferent, central, and efferent 
components of a vascular reflex, the responsive- 
ness of the peripheral vasculature, and the di- 
rect inotropic and chronotropic effects on the 
myocardium of the sympathetic and parasym- 
pathetic neurotransmitters. The studies de- 
scribed in the present report v^^ere designed to 
define more clearly the myocardial responsive- 
ness to the sympathetic and parasympathetic 
neurotransmitters . 
In the past, a variety of technical difficulties 
have surrounded efforts to analyze myocardial 
contractility in the fetal or neonatal heart in 
situ. Thus, there is an absence of meaningful 
comparisons of fetal, neonatal and adult cardiac 
tissue to the sympathetic neurotransmitter, nor- 
epinephrine, and to the parasympathetic neu- 
rotransmitter, acetylcholine. We believe we 
have obviated many of these technical difficul- 
ties in our laboratory by isolating myocardium 
from fetal and newborn lambs and adult sheep, 
and studying its pharmacological responsive- 
ness to the adrenergic and cholinergic neuro- 
transmitters in a myograph under identical con- 
ditions. Other pharmacologic stimuli have also 
been employed to further understand age-re- 
lated differences in responsiveness. In our stud- 
ies, a single right ventricular papillary muscle 
or moderator band was removed rapidly from 
the heart of either a fetal lamb in the last 15 
days of gestation by hysterotomy under local 
anesthesia, or from a newborn lamb or an adult 
sheep, and suspended in a myograph in oxygen- 
ated Ringer's solution at 30 °C, pH 7.4, and 
stimulated at 12 contractions/minute. The mus- 
cle was stretched to the apex of its length-active 
tension curve, and the changes in isometric ten- 
sion were recorded after addition to the bathing 
medium of the appropriate pharmacologic stim- 
ulus. In appropriate experiments, atrial tissue 
rather than ventricular myocardium was stud- 
ied in a similar manner. 
Norepinephrine 
Figure la shows the average dose response 
curves of fetal and adult ventricular myocar- 
dium to norepinephrine. It is quite clear that 
fetal cardiac tissue has a much lower threshold 
to the inotropic effects of norepinephrine, the 
sympathetic neurotransmitter, and is also about 
three-fold more sensitive to norepinephrine 
throughout the dose response curve when com- 
pared to the adult. Figure lb shows a similar 
but not as marked contrast in sensitivity to nor- 
epinephrine when ventricular myocardium from 
newborn lambs younger than three days of age 
was compared to that obtained from lambs rang- 
ing in age from 3 days to 3 weeks. 
Supersensitivity to norepinephrine would be 
expected if the fetal and early newborn myocar- 
dium lacked a complete development of sympa- 
thetic innervation, or if sympathetic nerves 
within these young hearts had a reduced capac- 
ity to take up and bind catecholamines. Uptake 
and binding represent an important mechanism 
for the inactivation of norepinephrine, and it 
would be anticipated that a reduction in the 
heart's ability to utilize this mechanism of inac- 
tivation would permit a higher concentration of 
the neurotransmitter to reach and activate the 
heart's beta receptors, and thereby render the 
tissues supersensitive. In order to more com- 
pletely evaluate this hypothesis, the phamaco- 
logic responsiveness of fetal and adult ventricu- 
lar muscle to isoproterenol was determined. 
Isoproterenol 
Isoproterenol is a direct acting beta adre- 
nergic agonist that is not taken up and stored in 
sympathetic nerves. In contrast to the findings 
with norepinephrine, equal responsiveness of 
fetal and adult myocardium was observed (Fig- 
ure 2) . This finding indicates that beta receptor 
sensitivity to catacholamines is similar in adult 
and fetal myocardium, and supports the hypoth- 
esis that sympathetic innervation is incomplete 
or functionally immature in the heart of the 
fetus or early newborn. 
Acetylcholine 
Vagal stimulation or administration of the 
parasympathetic neurotransmitter, acetycho- 
