740 
PHARMACOLOGY 
VENTRICULAR MYOCARDIUM 
10-10 10-9 10-8 10-7 10-6 10-5 10-4 
ISOPROTERENOL (Molar cone ) 
Figure 6. — Average dose response curve to isoproter- 
enol in the absence and presence of different concen- 
trations of propranolol. The beta blocking effect was 
comparable at both ages. The numbers in brackets 
are the numbers of muscles studied. Vertical bars: 
S.E.M. 
norepinephrine are localized almost exclusively 
in intracellular storage sites within the termi- 
nations of the sympathetic nerves.^ Norepi- 
nephrine was determined spectrophotofluoro- 
metrically by the trihydoxy indole method after 
alumina absorption.^ Figure 8 compares the 
cardiac norepinephrine stores in lambs and 
sheep at different stages of development. My- 
ocardial concentrations of norepinephrine in the 
fetus within several weeks of term was signifi- 
cantly lower than in the newborn lamb less than 
3 days old, and there was no difference between 
older newborns and adult sheep. Similar results 
were observed when other mammalian species 
were studied. Thus, a gradual increase with ad- 
vancing age was observed in the myocardial 
norepinephrine stores of the rabbit (Figure 9) 
and substantial age-related differences were also 
observed in swine (Figure 10). 
The rate of formation of norepinephrine is 
determined by tyrosine hydroxylase. This intra- 
neuronal enzyme catalyzes the first transforma- 
tion in catacholamine biosynthesis.^" Its activ- 
ity was determined by measuring the formation 
of tritiated water from 3,5-ditritiotyrosine.i^ 
In the lamb and sheep tyrosine hydoxylase ac- 
tivity was lowest in the fetus, somewhat higher 
in the neonate, and highest in the adult (Figure 
11). A significant correlation existed between 
tyrosine hydroxylase activity and the cardiac 
stores of norepinephrine at all of the age levels 
studied. It was of particular interest that the 
adrenal glands of these same animals showed 
equal activities of tyrosine hydroxylase and 
abundant catacholamine stores at all ages (Fig- 
ure 12). These findings suggest that the low 
myocardial activity of the enzyme is related to 
delayed development of sympathetic innerva- 
tion rather than to a generalized immaturity of 
enzyme synthesis. 
Monoamine oxidase is a catabolic enzyme 
that catalyzes the oxidative deamination of nor- 
epinephrine, and the enzym.e is located in part 
within sympathetic nerves. When this enzyme's 
activity was determined by measuring the 
deaminated 14C metabolites of 14C- 
tryptamine^^, we observed a reduced activity in 
the fetal heart when compared to the adult 
(Figure 13). 
ATRIAL MYOCARDIUM 
^ 40 - peius (10) V,^ 
S • — • Adult (10) U 
^ 50- f 
<i 
cn\ I I 1 1 1 ' 
lO-'O 10-9 10-8 10-7 10-6 10-5 10-4 
PROPRANOLOL (molar cone) 
Figure 7.— Average curves obtained from studying 
spontaneously beating SA node-right atrial prepara- 
tions showing no age-related differences in the nega- 
tive chronotropic response to propranolol. Numbers 
in brackets are the numbers of atria studied. Vertical 
bars: S.E.M. 
