| Summary: | Thesis (M.A.)--Boston University === Under conditions of general body stress, the adrenal medulla is called upon to secrete its hormone,
epinephrine. As a result of the influences of this
hormone , a variety of changes in the resting physiology
of the organism are incurred, which usually aid the individual in meeting the stressful challenge. One of the first changes which is known to occur as a result of
the action of endogenous or exogenous epinephrine is a
generalized hyperglycemia. Although this fundamental
observation has been known for half a century, a complete
understanding of the mechanism of action is still
lacking . In the fasting animal, it could logically
result from an increased liver glycogenolysis and/or a
decreased glucose uptake by the tissues. A review of
the literature has shown that whereas all workers are
agreed on an increased liver glycogenolysis as a result
of epinephrine activity, they are far from agreement on
the latter phase, the glucose uptake. The results of
this study indicate that much of the confusion is due
to a misuse of terms, for it has been demonstrated that,
at least in vitro , the glucose uptake of muscle tissue
increases, while the amount of glucose utilized decreases
following epinephrine. The extra glucose is stored in
the form of hexosemonophosphate.
There have recently been made available a number
of compounds belonging to the aryl-2-haloalkylamine
series, of which Dibenamine is a type compound, which
have the ability to inhibit many of the actions of
exogenous or endogenous epinephrine. For this reason,
they are known as adrenergic blocking drugs. It was of
interest to study a number of these compounds to determine
their ability to inhibit epinephrine-induced
hyperglycemia . A standard intravenous dose of 4 gamlnu/ kg.
was used as the challenging dose of epinephrine on the
basis of a dose-response curve and the previous report
that it was within physiologic range. The following
compounds were tested. They are listed by the aryl
portion of' the molecules: 2-orthobenzyl phenoxyethyl;
l-phenyl-2-N-methylbenzyl; 9-fluorenyl; 1-naphthylmethyl;
methylthionaphthalene; 2-biphenylyloxy; benzhydryl ; and
one dihydrogenated derivative of ergot, dihydroergocornine .
It is suggested that the effectiveness of 2-haloalkylamines
in diminishing or blocking epinephrine-induced hyperglycemia
in rabbits is roughly related to their potency as measured
by antagonism of the other effects of epinephrine. The
basis of this suggestion is that the most potent drugs
block or diminish the blood sugar rise in a dose of
2 mg./kg., while the less potent homologues require a
dose of 5 mg. /kg . t o obtain the same effect. The least
potent of these agents did not reduce the hyperglycemia
even in a dose of 10 ms ./kg. In addition , the methyl
homololgue of one of the adrenergic blocking drugs is
known to have a markedly reduced epinephrine antagonism,
and did not have any effect on the hyperglycemia . Likewise, when the halogen is replaced by an hydroxyl radical,
and the resulting agent loses its epinephrine reversal
action, it also loses its ability to block epinephrine induced
hyperglycemia. A reviewer of the literature, together
with the data obtained, seems to indicate that it
is a general property of the adrenergic blocking drugs
to inhibit the hyperglycemic effect of epinephrine in the rabbit. Also, it is to be expected that larger
doses of blocking drug are required to inhibit
epinephrine-induced hyperglycemia than epinephrine-induced hypertension. The hypertensive action of epinephrine is due to an algebraic summation of a
pressor and depressor phase . Hence, a slight inhibition
of the pressor response becomes magnified by the
depressor action. However, in the glycemic effect of
epinephrine, only a hyperglycemic phase is present, and
would require larger doses of blocking drug to induce
an equivalent diminution to that found in the blood
pressure response.
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