Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 18 Pituitary Function
Activation of the immune system by infections results
in the enhanced production of the cytokine interleukin-1
(IL-1 β ), which has the ability to stimulate CRH secretion
from the hypothalamus and thus activates the hypothalamus-pituitary-adrenal
axis. The biosynthesis and release
of IL-6 has been found in the folliculostellate cells of the
AL. IL-6 also stimulates the HPA-axis, at both the hypothalamic
and the pituitary level ( Sweep et al. , 1991 ).
Endogenous corticosteroids inhibit ACTH release predominantly
at hypothalamic sites. Synthetic steroids such as
dexamethasone may act primarily at the pituitary level ( de
Kloet et al. , 1974 ). In a review on corticosteroid-mediated
feedback, Keller-Wood and Dallman (1984) suggested
three different time schedules: a fast feedback that acts
on the corticotropic cell but may not be related to nuclear
receptor binding, an intermediate feedback that probably
acts by inhibition of CRH release, and a slow feedback
that acts by a decrease in mRNA encoding POMC in the
pituitary gland. The delay in inhibiting ACTH production
may be caused by the high stability of the mRNA encoding
POMC and not by the absence of direct inhibition of the
transcription. Dexamethasone inhibits gene transcription
in vivo within 30 min in the rat ( Fremeau et al. , 1986 ). In
the dog, the intermediate-delayed feedback is determined
by the mean change in corticosteroid concentration over
time ( Keller-Wood, 1989 ). Acute lowering of plasma cortisol
in the horse by inhibition of synthesis in the adrenal
gland resulted in an increased ratio of ACTH:CRH in pituitary
venous blood before CRH concentrations started to
rise ( Alexander et al. , 1993, 1996 ), indicating that the first
effect is the opposite of the fast feedback and is mediated
by increased sensitivity of the corticotrope.
d . Secretion by the IL
The release of POMC-derived peptides by the IL is under
direct neural control. The rat and the mouse have been the
mammals in which most studies on the regulation and processing
of POMC in the IL have been carried out thus far.
In the rat, the release of POMC-derived peptides is regulated
predominantly via tonic dopaminergic inhibition and β -
adrenergic stimulation ( Berkenbosch et al. , 1981 ; Tilders et
al. , 1985 ), although GABAergic innervation of the IL has also
been demonstrated ( Oertel et al. , 1982 ). In addition, Proulx-
Ferland et al. , (1982) demonstrated that CRH is a potent
stimulator of α -MSH secretion by the IL. In line with the
absence of a glucocorticoid receptor in the IL ( Antakly et al. ,
1985 ), the α -MSH response to CRH could not be suppressed
by dexamethasone administration. The expression of the
glucocorticoid receptor in the IL is suppressed by dopamine
(Antakly et al. , 1987 ), whereas the CRH receptor content
of the rat IL is stimulated by dopamine ( Shiver et al. , 1992 ).
In the dog, in vitro studies ( Mol et al. , 1987 ) and in vivo
and immunohistochemical observations ( Middleton et al. ,
1987b ) have revealed the IL to be resistant to glucocorticoid
suppression. There is also evidence from in vivo studies
that dopaminergic pathways play a regulatory role in canine
IL function ( Kemppainen and Sartin, 1986 ). However, in
other respects the situation in the dog is different from that
in the rat with regard not only to the heterogeneous cytology
(see Section I.A.5) but also to some of the regulation
characteristics. Despite the fact that CRH-immunoreactive
fibers have been identified in the canine neurointermediate
lobe ( Stolp et al. , 1987 ) and although in vitro CRH stimulates
ACTH release from the neurointermediate lobe ( Mol
et al. , 1987 ), there is no convincing evidence that CRH can
stimulate release of ACTH from the IL in vivo (Kemppainen
and Sartin, 1986, 1987 ; Middleton et al. , 1987a ), whereas
no ( Kemppainen and Sartin, 1986) or a very small ( Rijnberk
et al. , 1987 ) α -MSH response to CRH stimulation has been
observed. Kooistra et al. , (1997a) showed that α-MSH is
secreted in a pulsatile manner in the dog. In contrast, with a
significant increase of plasma α -MSH concentrations after
administration of the dopamine antagonist haloperidol, even
after pretreatment with dexamethasone to inhibit the contribution
of the AL, there were small increases in the plasma
concentrations of ACTH and cortisol, which suggests that
the canine IL contributes to circulating ACTH concentrations
( Kooistra et al. , 1997a ).
The cat has an actively secreting IL, which is reflected
in high plasma concentrations of α -MSH and β -endorphin,
POMC-derived peptides secreted predominantly by melanotropes
( Peterson et al. , 1994 ). In the cat as well as in the
dog, no stimulation of α -MSH occurs after CRH administration
( Willemse and Mol, 1994 ). However, cats undergoing
handling and skin testing without anesthesia show
significant increases in plasma α -MSH concentrations
( Willemse et al. , 1993 ). In vitro experiments revealed the
sensitivity of feline IL MSH release to dopaminergic inhibition
( Willemse and Mol, 1994 ).
In fetal and newborn lamb and in adult sheep ( Newman
et al. , 1987 ), the administration of a dopamine-receptor
antagonist results in α -MSH release. Elimination of the
inhibitory hypothalamic control in sheep by hypothalamuspituitary
disconnection results in increased α -MSH release
( Clarke et al. , 1986 ). The dopamine inhibition of ACTH
secretion in the hyperadrenocorticoid horse ( Wilson et al. ,
1982 ) suggests that in the normal horse the IL is under
dopaminergic control. In the rabbit the dopaminergic control
of the IL is absent ( Schimchowitsch et al. , 1986 ).
e . Action
The predominant action of ACTH is stimulation of steroidogenesis
and corticosteroid release from the adrenals
(see Chapter 19 on adrenal function). ACTH also exerts a
growth-stimulating effect on the adrenal cortex. Moreover,
non-ACTH portions of POMC—that is, N-terminal POMC
peptides—are involved in adrenocortical growth ( Lowry
et al. , 1987 ). In pharmacological dosages, ACTH may promote
lipolysis in fat cells and amino acid uptake in muscle.
The role of intact ACTH produced in hypothalamic neurons