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

Table 8–7
Representative Agents Acting at Peripheral Cholinergic and Adrenergic Neuroeffector Junctions (Continued)
MECHANISM OF ACTION SYSTEM AGENTS EFFECT
α 2
Yohimbine Selective α 2
receptor blockade
β 1
, β 2
Propranolol Nonselective β receptor blockade
β 1
Metoprolol, atenolol Selective β 1
receptor blockade
(cardiomyocytes; renal j-g cells)
β 2
— Selective β 2
receptor blockade
(smooth muscle)
9. Inhibition of enzymatic Cholinergic AChE inhibitors Cholinomimetic (muscarinic sites)
breakdown of transmitter Edrophonium, Depolarization blockade (nicotinic
neostigmine,
sites)
pyridostigmine
Adrenergic Nonselective MAO inhibitors Little direct effect on NE or
Pargyline, nialamide sympathetic response; potentiation
of tyramine
Selective MAO-B inhibitor Adjunct in Parkinson disease
Selegeline
Peripheral COMT inhibitor Adjunct in Parkinson disease
Entacapone
COMT inhibitor
Tolcapone
a
At least five subtypes of muscarinic receptors exist. Agonists show little selectivity for subtypes whereas several antagonists show partial subtype
selectivity (see Table 8–3).
b
Two subtypes of muscle acetylcholine nicotinic receptors and several subtypes of neuronal receptors have been identified (seeTable 8–2).
ACh, acetylcholine; AChE, acetylcholine esterase; COMT, catechol-O-methyl transferase; MAO, monoamine oxidase; NE, norepinephrine;
j-g cells, renin-secreting cells in the juxta-glomerular complex of the kidney.
of PKA by cyclic AMP and the importance of compartmentation of
components of the cyclic AMP pathway are discussed in Chapter 3.
A representation of the general structure of adrenergic receptors is
shown in Figure 8–8.
α Adrenergic Receptors. The deduced amino acid
sequences from the three α 1
receptor genes (α 1A
, α 1B
,
and α 1D
) and three α 2
receptor genes (α 2A
, α 2B
, and α 2C
)
conform to the well-established GPCR paradigm
(Bylund, 1992; Zhong and Minneman, 1999). The general
structural features of α receptors and their relation
to the functions of ligand binding and G protein activation
appear to agree with those set forth in Chapter 3
and earlier in this chapter for the β receptors. Within
the membrane-spanning domains, the three α 1
adrenergic
receptors share ~75% identity in amino acid
residues, as do the three α 2
receptors, but the α 1
and α 2
subtypes are no more similar than are the α and β subtypes
(~30-40%).
α 2
Adrenergic Receptors. As shown in Table 8–6, α 2
receptors couple to a variety of effectors (Aantaa et al.,
1995; Bylund, 1992; Tan and Limbird, 2005).
Inhibition of adenylyl cyclase activity was the first
effect observed, but in some systems the enzyme
actually is stimulated by α 2
adrenergic receptors,
either by G i
βγ subunits or by weak direct stimulation
of G s
. The physiological significance of these
latter processes is not currently clear. α 2
Receptors
activate G protein–gated K + channels, resulting in
membrane hyperpolarization. In some cases (e.g.,
cholinergic neurons in the myenteric plexus) this
may be Ca 2+ -dependent, whereas in others (e.g.,
muscarinic ACh receptors in atrial myocytes) it
results from direct interaction of βγ subunits with K +
channels. α 2
Receptors also can inhibit voltage-gated
Ca 2+ channels; this is mediated by G o
. Other secondmessenger
systems linked to α 2
receptor activation
include acceleration of Na + /H + exchange, stimulation
of PLC β2
activity and arachidonic acid mobilization,
increased phosphoinositide hydrolysis, and increased
intracellular availability of Ca 2+ . The latter is
involved in the smooth muscle–contracting effect of