JOSEPH V. LEVY 
arations to certain prostaglandins. One can only 
conclude that species, strain and tissue type are 
possible major determinants in the responsive- 
ness of cardiac tissue to this important class of 
substances. Only extensive trials in man will 
ansv^^er the question of whether or not agents 
such as PGEi or PGE2 have a significant ino- 
tropic effect in man. The in vitro data to date 
appear not to be consistent enough to confi- 
dently predict the effect in humans. 
This kind of problem is further illustrated by 
the diversity of inotropic responses reported for 
glucagon in various test systems, including in- 
tact man (Table V). At the least, the data to 
date indicate that the canine preparations are 
exquisitely sensitive to the positive inotropic ef- 
fects of glucagon. Man does not appear to be 
either consistent in his response, or quantita- 
tively similar in reactivity. Undoubtedly the 
presence or absence of disease states and pre- 
sumed associated biochemical derangement 
(e.g., adenyl cyclase) may influence the ulti- 
mate reactivity to this substance. 
The many traps and pitfalls associated with 
the evaluation of hormones is further exempli- 
fied by the diversity of responses reported for 
the direct cardiac stimulant actions of aldoster- 
one. Table VI summarizes some results obtained 
by various investigators. The fact that the use 
of any given preparation (e.g., cat papillary) 
yielded different results certainly suggests that 
other possible technical factors besides species, 
strain or tissue type are involved in determin- 
ing the action of this steroid on the heart. The 
implication of these findings to human cardiac 
Table V. — Species Differences in Inotropic Responses 
to Glucagon 
Tissue 
Species 
Effect 
Investigator** 
Left Atrium 
Human 
0; ± 
Levy 
Papillary . 
Human 
0 
Prasad 
L. Papillary 
-- - Human 
Parmley et al. 
L. Papillary 
Human 
+ 
Strauer 
L. Papillary 
Cat 
+ + + 
Parmley et al. 
L. Papillary 
Dog 
+ + + + 
Parmley et al. 
L. Vent.* 
Sheep 
0 
Scholkens 
L. Vent.* 
.- - Human 
Various 
* In vivo 
** See References 
+ = positive inotropism 
0 = no significant effect 
± = variable inotropic response 
751 
Table VI. — Does Aldosterone Produce a Positive 
Inotropic Effect? 
Tissue/organ Response Investigator* 
Rat Heart + Ballard et al. 
Cat Papillary + Lefer et al. 
Cat Papillary + Tanz 
Monkey Papillary + Nayler 
Rabbit L. Atria 0 Levy 
Frog Vent 0 Hajdu 
Rat Papillary 0 Tanz 
Rat Trab. Carneae 0 Ullrick 
Rat Trab. Carneae 0 Tanz 
* See References 
+ = positive inotropism 
0 = no effect 
disease states or therapy remains to be deter- 
mined. 
The fact that any given preparation may 
yield substantive differences in response to a 
given agent reinforces the need to understand 
the multitude of factors that can influence tis- 
sue responses in vitro. Table VII lists some of 
the better known and appreciated elements. The 
more we know about how any given test sub- 
stance (e.g., norepinephrine) is influenced by 
the factors listed, the more complete and precise 
our knowledge will be on how and where it acts 
to produce its effects. The less we know about 
interactions of these factors with the test sub- 
stance, the less confident we can be about the 
true biological effects on that given tissue or 
test system. Unfortunately for most agents, we 
are woefully ignorant of how these factors op- 
erate to influence the actions on the tissues we 
are studying. 
ISOLATED HUMAN CARDIAC TISSUE 
The use of human cardiac tissue for drug 
studies is not a recent phenomenon. What has 
Table VII. — Factors Influencing Response of Tissues 
in Vitro 
1. Spontaneous changes in sensitivity or responsiveness of tissue. 
2. Desensitization, tachyphylaxis or tolerance as result of prior 
exposure to agent. 
3. Net response based on resultant of actions of agent on several 
receptor sites in tissue. 
4. Release of tissue mediators or factors (e.g., norepinephrine, 
acetylcholine) . 
5. Enzymatic degradation of agent. 
6. Removal of agent from receptor site by active transport or 
uptake to other site. 
7. Equilibration conditions (exposure time) . 
8. Removal of agent from medium (diffusion, absorption, uptake. 
