DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

MOPGAL and then to VMA, with VMA being the major end
product of NE and epinephrine metabolism. Another route for the
formation of VMA is conversion of NE and epinephrine into
normetanephrine and metaneprhine, respectively, by COMT followed
by deamination to MOPGAL and ultimately VMA. This is now
thought to be only a minor pathway, as indicated by the size of the
arrows on Figure 8–7.
In contrast to sympathetic neurons, adrenal medullary chromaffin
cells contain both MAO and COMT. In chromaffin cells, the COMT
is mainly present as the membrane-bound form of the enzyme in contrast
to the form found in the cytoplasm of extra-neuronal tissue. This
isoform of COMT has a higher affinity for catecholamines than does
the soluble form found in most other tissues (e.g., liver and kidney). In
adrenal medullary chromaffin cells, leakage of NE and epinephrine
from storage vesicles leads to substantial intracellular production of
the O-methylated metabolites normetanephrine and metanephrine. It
is estimated that in humans, over 90% of circulating metanephrine and
25-40% of circulating normetanephrine are derived from catecholamines
metabolized within adrenal chromaffin cells.
The sequence of cellular uptake and metabolism of catecholamines
in extraneuronal tissues contributes very little (~25%)
to the total metabolism of endogenously produced NE in sympathetic
neurons or the adrenal medulla. However, extraneuronal
metabolism is an important mechanism for the clearance of circulating
and exogenously administered catecholamines.
Classification of Adrenergic Receptors. Crucial to
understanding the remarkably diverse effects of the catecholamines
and related sympathomimetic agents is an
understanding of the classification and properties of the
different types of adrenergic receptors (or adrenoceptors).
Elucidation of the characteristics of these receptors
and the biochemical and physiological pathways
they regulate has increased our understanding of the
seemingly contradictory and variable effects of catecholamines
on various organ systems. Although structurally
related (discussed later), different receptors
regulate distinct physiological processes by controlling
the synthesis or release of a variety of second messengers
(Table 8–6).
Based on studies of the abilities of epinephrine,
norepinephrine, and other related agonists to regulate
various physiological processes, Ahlquist first proposed
the existence of more than one adrenergic receptor. It
was known that these drugs could cause either contraction
or relaxation of smooth muscle depending on the
site, the dose, and the agent chosen. For example, NE
was known to have potent excitatory effects on smooth
muscle and correspondingly low activity as an
inhibitor; isoproterenol displayed the opposite pattern
of activity. Epinephrine could both excite and inhibit
smooth muscle. Thus, Ahlquist proposed the designations
α and β for receptors on smooth muscle where
catecholamines produce excitatory and inhibitory
responses, respectively. An exception is the gut,
which generally is relaxed by activation of either α
or β receptors. The rank order of potency of agonists is
isoproterenol > epinephrine ≥ norepinephrine for
β adrenergic receptors and epinephrine ≥ norepinephrine
>> isoproterenol for α adrenergic receptors (Table 8–3).
This initial classification was corroborated by the finding
that certain antagonists produce selective blockade
of the effects of adrenergic nerve impulses and sympathomimetic
agents at α receptors (e.g., phenoxybenzamine),
whereas others produce selective β receptor
blockade (e.g., propranolol).
β Receptors later were subdivided into β 1
(e.g.,
those in the myocardium) and β 2
(smooth muscle and
most other sites) because epinephrine and norepinephrine
essentially are equipotent at the former sites, whereas epinephrine
is 10-50 times more potent than norepinephrine
at the latter. Antagonists that discriminate between β 1
and
β 2
receptors were subsequently developed (Chapter 12).
A human gene that encodes a third β receptor (designated
β 3
) has been isolated (Emorine et al., 1989). Since
the β 3
receptor is about tenfold more sensitive to norepinephrine
than to epinephrine and is relatively resistant
to blockade by antagonists such as propranolol, it may
mediate responses to catecholamine at sites with “atypical”
pharmacological characteristics (e.g., adipose tissue).
Although the adipocytes are a major site of β 3
adrenergic receptors, all three β adrenergic receptors
are present in both white adipose tissue and brown adipose
tissue. Animals treated with β 3
receptor agonists
exhibit a vigorous thermogenic response as well as
lipolysis (Robidoux et al., 2004). Polymorphisms in the
β 3
receptor gene may be related to risk of obesity or
type 2 diabetes in some populations (Arner and
Hoffstedt, 1999). Also, there has been interest in the
possibility that β 3
receptor–selective agonists may be
beneficial in treating these disorders (Weyer et al.,
1999). The existence of a fourth type of βAR, β 4
AR,
has been proposed. Despite intense efforts, β 4
AR, like
α 1L
AR, has not been cloned. Current thinking is that
the β 4
AR represents an affinity state of β 1
AR rather
than a descrete receptor (Hieble, 2007).
There is also heterogeneity among α adrenergic
receptors. The initial distinction was based on functional
and anatomic considerations when it was realized
that NE and other α-adrenergic receptors could
profoundly inhibit the release of norepinephrine from
neurons (Westfall, 1977) (Figure 8–6). Indeed, when
sympathetic nerves are stimulated in the presence of
certain α receptor antagonists, the amount of NE liberated
by each nerve impulse increases markedly. This
201
CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS