712 
PHARMACOLOGY 
HEART RATE RESPONSE 
100 
90 
80 
70 
60 
PER CENT 
CHANGE 
FROM 50 
CONTROL 
40 
30 
20 
10 
a Ns 
-• ALPRENOLOL (A) 
-O PROPRANOLOL ( P) 
AY 21011 (AY) 
-A MJ 1999 (S) 
it: p = 0.05 
p = 0.01 
3.125% 6 25% 12 5% 25% 50% 100% 
% OF BLOCKING DOSE 
(A) 0.0015 0.003 0.006 0.012 0.024 0.048 
(P) 0.003 0.006 0.012 0.024 0.048 0.096 
(AY) 0.00625 0.0125 0.025 0.05 0,1 0.2 
(S) 0.025 0.05 0.1 0.2 0.4 0.8 
mg/kg, i.v. 
Figure 3. — Heart rate response to increasing doses 
of drug. Sotalol>Propranolol>AY21011 = Alprenolo] 
caused a dose dependent negative chronotropic 
response. 
propranolol 28% and with Practolol 38%. Based 
on these data, further clinical trials utilizing 
newer more specific beta adrenergic blocking 
agents for the control of angina pectoris appear 
to be warranted. 
SUMMARY 
1. In an open chest canine preparation, the 
chronotropic and inotropic effects of Pro- 
pranolol (P), MJ-1999 (Sotalol) (S), 
AY21011 (Practolol) (AY) , and Alprenolol 
(A) were studied. 
2. AY21011 (Practolol) blocked the chrono- 
tropic and inotropic responses to isoprotere- 
nol most effectively, followed closely by pro- 
pranolol. 
3. All four agents displayed equivalent intrinsic 
negative inotropic activity. 
4. Sotalol had the greatest intrinsic negative 
chronotropic effect followed by propranolol. 
5. The differing chronotropic and inotropic ef- 
HEART RATE RESPONSE 
TO ISOPROTERENOL CHALLENGE 
minants of oxygen need are heart rate, velocity 
of contraction and developed tension. Developed 
tension is in part related to end diastolic vol- 
ume due to the dependence of wall tension upon 
the radius of the left ventricle. The effectiveness 
of propranolol in anginal states seems to be re- 
lated to its ability to inhibit the myocardial re- 
sponses to exercise induced catechol stimulation. 
Nevertheless, based on this investigation AY 
21011 (Practolol) deserves further study as a 
possible anti-anginal agent. Its ability at low 
concentrations to block both the chronotropic 
and inotropic properties of isoproterenol might 
mean a diminution in myocardial oxygen re- 
quirements by decreasing two of the major de- 
terminants of oxygen consumption; heart rate 
and velocity of contraction. Support for this 
hypothesis has come from a parallel study of 
these agents in the exercise laboratory. In a 
group of patients with established ischemic 
heart disease, studied over a 1-2 year period, 
the average increase in physical performance 
with placebo was 3% ; with Sotalol 21%, with 
100 
90 
80 
70 
60 
PER CENT 
CHANGE 
FROM 50 
CONTROL 
■• ALPRENOLOL (A) 
•O PROPRANOLOL ( P) 
•A AY 21011 (AY) 
A MJ 1999 (S) 
* p = 0.05 
p = 0.01 
40 
30 
20 
10 
3.125% 6.25% 12.5% 25% 50% 
% OF BLOCKING DOSE 
(A) 0.0015 0.003 0.006 
(P) 0.003 0.006 0.012 
(AY) 0.00G25 0.0125 0.025 
(S) 0.025 0.05 0.1 
0.012 0.024 0.048 
0.024 0.048 0.096 
0.05 0.1 0.2 
0.2 0.4 0.8 
mg/kg, i.v. 
Figure 4. — The effect of beta adrenergic blockade upon 
the chronotropic action of isoproterenol. AY21011 
blocked the chronotropic response to isoproterenol 
most effectively followed by propranolol, alprenolol 
and sotalol. 
