WILLIAM F. FRIEDMAN 
739 
Mature Fetal Lamb 
• — • pH 7.4 (95% O2 
-5%C02) 
0—^ NE 10'^ M 
* pH 7.1 (90% O2- 
10% CO2J 
A---A NE 10'^ M 
Figure 4. — A typical experiment in which force velocity 
curves were constructed from isotonic, afterloaded 
contractions of right ventricular myocardium isolated 
from a fetal lamb in the last week of gestation. The 
pH was reduced from 7.4 to 7.1 by increasing the 
carbon dioxide tension of the bathing medium. Aci- 
dosis depressed both velocity of shortening and ten- 
sion development, and although norepinephrine aug- 
mented both velocity and force, the levels achieved 
were not comparable to those when the muscle was 
bathed at a normal pH. 
Figure 6 shows dose-response curves of fetal 
and adult heart muscles to isoproterenol con- 
structed in the absence of beta blocker (the 
curves labeled control) and in the presence of 
two different molar concentrations of proprano- 
lol (3 X 10-8 and 3 X lO-^). As would be 
expected, propranolol reduced the response to 
isoproterenol in a dose-related manner and dis- 
placed the curves to the right. Thus, in the pres- 
ence of beta blocker, a higher concentration of 
isoproterenol was required to achieve a given 
increase in tension. Note, however, that the de- 
gree of blockade was the same for the fetus and 
the adult. 
Interestingly, in contrast to the age-depend- 
ent differences that existed in the inotropic ac- 
tions of propranolol, we did not uncover a dif- 
ference in the chronotropic actions of the beta 
blocker. A spontaneously beating SA node-right 
atrial preparation was employed to study the 
effects on intrinsic heart rate. In Figure 7 the 
absolute change in the frequency of contraction 
is plotted against the concentration of propran- 
olol. Both the fetus and adult were slowed to the 
same extent. 
BIOCHEMICAL STUDIES 
These studies were undertaken to more com- 
pletely understand the mechanism of the age- 
dependent differential sensitivity to norepi- 
nephrine described above. In order to describe 
the development of the heart's ability to synthe- 
size, store and metabolize catacholamines, we 
have measured the myocardial norepinephrine 
stores and the critical enzymes in norepi- 
nephrine biosynthesis and degradatioon. 
The cardiac concentration of norepinephrine 
in fatal, neonatal and adult animals may be em- 
ployed as an index of the magnitude of sympa- 
thetic innervation because the heart's stores of 
VENTRICULAR MYOCARDIUM 
PROPRANOLOL (Molar cone) 
Figure 5. — Average propranolol dose response curves 
showing a more marked negative inotropic action on 
the fetal heart. The numbers in brackets are the 
numbers of muscles studied. Vertical bars: S.E.M. 
