710 
PHARMACOLOGY 
cardiac beta adrenergic blocking actions of a 
drug upon the heart may be studied exclusive 
of the effects of beta blockade upon the peri- 
pheral vascular system. 
The experimental design of the study appears 
in Figure 1. In the control state the initial heart 
rate and the chronotropic response to an iso- 
proterenol challenge was determined. Similarly, 
the left ventricular dp/dt during atrial pacing 
was measured and the left ventricular dp/dt 
response to an isoproterenol challenge during 
atrial pacing was measured. 
Initially for each beta blocker investigated, 
the dose of drug necessary to completely inhibit 
the positive chronotropic and inotropic response 
to an isoproterenol challenge was determined. 
This dose of beta blocker was considered 100% 
blockade. Five serial dilutions were then made 
EXPERIMENTAL DESIGN 
CONTROL 
HR 
paced 
LV dp/dt 
CHRONOTROPIC INOTROPIC 
Figure 1. — Experimental design of study. In the control 
state initial heart rate and the chronotropic response 
to an isoproterenol challenge was determined. Simi- 
larly the left ventricular dp/dt during atrial pacing 
was measured and the left ventricular dp/dt response 
to an isoproterenol challenge during atrial pacing 
was measured. 
so that the first concentration utilized was 31/8 % 
of the total blocking dose. 
After injection of the lowest concentration of 
drug, heart rate was measured, as was the 
heart rate response to an isoproterenol chal- 
lenge. At each concentration of beta blocker in- 
jected the heart rate changes due to beta blocker 
alone and the attenuation of isoproterenol re- 
sponse could then be determined. Pacing was 
then instituted and left ventricular dp/dt was 
measured as was the left ventricular dp/dt re- 
sponse to isoproterenol. The intrinsic left ven- 
tricular dp/dt response to beta blockade and the 
attenuation of isoproterenol response could then 
be determined. 
These studies were then repeated at increas- 
ing concentrations of beta blocker. No animal 
received more than 1 beta blocking agent and 
six animals received each beta blocking drug. 
Measurements of heart rate and dp/dt were 
made one minute after injection of drug into 
the inferior vena cava. 
RESULTS 
A representative tracing appears on Figure 2. 
Left ventricular dp/dt appears on the top. 
Aortic pressure (AP) and left ventricular pres- 
sure (LVP) are measured in mm.Hg. Left ven- 
tricular diastolic pressure is measured in cm. 
H2O. The time is recorded on the abscissa. 
The data in Figure 3 and the three to follow 
represent six animal experiments for each drug. 
The dose of drug administered, in mg/kg intra- 
venously, appears on the bottom of the figure. 
Equi-potency was judged by the dose necessary 
to completely block the chronotropic and ino- 
tropic response to isoproterenol. A single star 
denotes the level of significance from control 
of a paired Student's T test at the 0.05 level and 
a double star denotes significance at the 0.01 
level. The intrinsic chronotropic changes of 
beta blockade are plotted on this slide. On the 
ordinate is the percent change from control 
and on the abscissa is the dose of drug and the 
percent of total blocking dose. 
Sotalol> Propranolol > AY 21011 = to Alpre- 
nolol caused a dose dependent negative chrono- 
tropic response. The change in heart rate com- 
