PHARMACOLOGIC ACTIONS OF NEWER 
BETA BLOCKING AGENTS 
Lawrence S. Cohen," George F. Vastagh" and Jere H. Mitchell" 
ABSTRACT 
Cardiac beta-adrenergic receptor blockade decreases 
chronotropic and inotropic responses. In an open chest 
canine preparation in which aortic pressure, cardiac 
output, and heart rate could be controlled, the chrono- 
tropic and inotropic effects of Propranolol (P), MJ- 
1999 (Sotalol) (S), AY21011 (Practolol) (AY), and 
Alprenolol (A) were studied before and after isopro- 
terenol challenge (I). Equiactive doses of these agents 
were compared based on initial studies which determined 
the ability to block an I. 
In unpaced studies S>P>AY=A caused a dose de- 
pendent negative chronotropic effect. After I, AY>P> 
A>S progressively blocked the positive chronotropic 
effect as the amount of blocker was increased. 
In paced studies all 4 agents lowered left ventricular 
dp/dt equivalently. After I, AY>P=S = A progressively 
blocked the inotropic effect. 
These data show that AY blocked the chronotropic 
and inotropic responses to I most effectively while 
having less intrinsic negative chronotropic activity. S 
had the greatest intrinsic negative chronotropic re- 
sponse and blocked the chronotropic response to I least. 
All 4 agents displayed equivalent intrinsic negative 
inotropic activity. 
INTRODUCTION 
In 1958 Powell and Slater introduced the first 
of the clinically useful beta adrenergic blocking 
agents, dichloroisoproterenol. Although this 
agent had potent beta blocking activity, it also 
possessed an intrinsic sympathomimetic action. 
Pronethalol, introduced in 1962, had little or 
no intrinsic sympathomimetic activity but was 
found to have a tumorigenic effect in mice. 
Propranolol, a more recent beta blocking agent, 
has been investigated intensively and has been 
utilized clinically in a variety of cardiac disor- 
ders, particularly angina pectoris. One of the 
limitations in the use of propranolol has been a 
* Yale Univei-sity School of Medicine, New Haven, Connecticut. 
*♦ The University of Texas (Southwestern) Medical School at 
Dallas, Dallas, Texas. 
direct myocardial depressant action separate 
from its beta adrenergic blocking action. Re- 
cently several newer beta blocking agents, re- 
portedly with more cardiospecificity, have been 
introduced. MJ-1999 (Sotalol), Alprenolol (Ap- 
tine) and AY 21011 (Practolol) are three such 
agents. The object of this investigation was to 
compare the relative negative chronotropic and 
inotropic properties of Propranolol, Sotalol, Al- 
prenolol and Practolol and to determine if there 
was any difference in their ability to induce 
beta adrenergic blockade to the chronotropic 
and inotropic properties of isoproterenol. 
MATERIALS AND METHODS 
In an open chest canine preparation, the 
brachiocephalic, left subclavican and upper in- 
tercostal arteries were ligated and the descend- 
ing aorta cannulated. The left ventricle pumped 
blood into a blood-primed extra corporeal cir- 
cuit from which blood was returned to the de- 
scending aorta and carotid arteries. The extra 
corporeal system included a bottle of adjustable 
height which held aortic pressure constant, a 
rotor pump which returned a constant flow to 
the dog, and a heat exchange unit which main- 
tained a constant blood temperature. An elec- 
trode was sutured to the right atrium and con- 
nected to a Grass impulse generator for control 
of heart rate. Pressures were recorded from 3 
Statham P23Db strain gauge transducers; one 
attached to a wide-bore cannula which was 
placed into the left ventricular cavity through 
an apical dimple, one into the arch of the aorta 
through a carotid artery, and one into the tub- 
ing carrying blood from the extra corporeal 
pump into the body. An R-C electronic circuit 
continuously differentiated the signal from a 
Dallons-Telco catheter tip manometer in the 
left ventricular cavity. In this preparation, the 
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