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

stimulation of the viscera during surgical interventions can
reflexly increase the vagal stimulation of the heart.
The intravenous injection of a small dose of ACh
produces a transient fall in blood pressure owing to generalized
vasodilation (mediated by vascular endothelial
NO), which is usually accompanied by reflex tachycardia.
A considerably larger dose is required to see direct
effects of ACh on the heart, such as eliciting bradycardia
or AV nodal conduction block. The generalized
vasodilation produced by exogenously administered
ACh is due to the stimulation of muscarinic receptors,
primarily of the M 3
subtype (Khurana et al., 2004;
Lamping et al., 2004), located on vascular endothelial
cells despite the apparent lack of cholinergic innervation.
Occupation of the receptors by agonist activates
the G q
–PLC–IP 3
pathway, leading to Ca 2+ -calmodulin–
dependent activation of endothelial NO synthase and
production of NO (endothelium-derived relaxing factor)
(Moncada and Higgs, 1995), which diffuses to
adjacent vascular smooth muscle cells and causes them
to relax (Furchgott, 1999; Ignarro et al., 1999)
(Chapters 3 and 8). If the endothelium is damaged, as
occurs under various pathophysiological conditions,
ACh acts predominantly on M 3
receptors located on
vascular smooth muscle cells, causing vasoconstriction.
Although endogenous ACh does not have a significant role in
the physiological regulation of peripheral vascular tone, there is evidence
that baroreceptor or chemoreceptor reflexes or direct stimulation
of the vagus can elicit parasympathetic coronary vasodilation
mediated by ACh and the consequent production of NO by the
endothelium (Feigl, 1998). However, neither parasympathetic
vasodilator nor sympathetic vasoconstrictor tone plays a major role
in the regulation of coronary blood flow relative to the effects of
local oxygen tension, activation of K ATP
channels, and autoregulatory
metabolic factors such as adenosine (Berne and Levy, 2001).
ACh affects cardiac function directly and also indirectly
through inhibition of the adrenergic stimulation of the heart. Cardiac
effects of ACh are mediated primarily by M 2
muscarinic receptors
(Stengel et al., 2000), which couple to G i
/G o
. The direct effects
include an increase in the ACh-activated K + current (I K-ACh
) due to
activation of K-ACh channels, a decrease in the L-type Ca 2+ current
(I Ca-L
) due to inhibition of L-type Ca 2+ channels, and a decrease in
the cardiac pacemaker current (I f
) due to inhibition of HCN (pacemaker)
channels (DiFrancesco and Tromba, 1987). The indirect
effects include a G i
-mediated decrease in cyclic AMP, which opposes
and counteracts the β 1
adrenergic/G s
–mediated increase in cyclic
AMP, and an inhibition of the release of norepinephrine from sympathetic
nerve terminals. The inhibition of norepinephrine release is
mediated by presynaptic M 2
and M 3
receptors, which are stimulated
by ACh released from adjacent parasympathetic postganglionic
nerve terminals (Trendelenburg et al., 2005). There are also presynaptic
M 2
receptors that inhibit ACh release from parasympathetic
postganglionic nerve terminals in the human heart (Oberhauser
et al., 2001).
In the SA node, each normal cardiac impulse is initiated by the
spontaneous depolarization of the pacemaker cells (Chapter 29). At
a critical level (the threshold potential), this depolarization initiates
an action potential. ACh slows the heart rate primarily by decreasing
the rate of spontaneous depolarization; attainment of the threshold
potential and the succeeding events in the cardiac cycle are
therefore delayed. Until recently it was widely accepted that
β adrenergic and muscarinic cholinergic effects on heart rate resulted
from regulation of the cardiac pacemaker current (I f
). Unexpected
findings made through genetic deletion of HCN4 and pharmacological
inhibition of I f
have generated an alternative, albeit controversial,
theory involving a pacemaking function for an intracellular Ca 2+
“clock” (Lakatta and DiFrancesco, 2009) that might mediate effects
of ACh on heart rate (Lyashkov et al., 2009).
In the atria, ACh causes hyperpolarization and a decreased
action potential duration by increasing I K-ACh
. ACh also inhibits
cyclic AMP formation and norepinephrine release, decreasing atrial
contractility. The rate of impulse conduction is either unaffected or
may increase in response to ACh; the increase probably is due to the
activation of additional Na + channels in response to ACh-induced
hyperpolarization. In contrast, in the AV node (which has Ca 2+ channel-dependent
action potentials; see Chapter 29), ACh slows conduction
and increases the refractory period by inhibiting I Ca-L
; the
decrement in AV conduction is responsible for the complete heart
block that may be observed when large quantities of cholinergic agonists
are administered systemically. With an increase in parasympathetic
(vagal) tone, such as is produced by the digitalis glycosides,
the increased refractory period of the AV node can contribute to the
reduction in the frequency with which aberrant atrial impulses are
transmitted to the ventricles and thereby decrease the ventricular rate
during atrial flutter or fibrillation.
Cholinergic (vagal) innervation of the His-Purkinje system
and ventricular myocardium is sparse (Kent et al., 1974; Levy and
Schwartz, 1994) and the effects of ACh are smaller than those
observed in the atria and nodal tissues. In the ventricles, ACh,
whether released by vagal stimulation or applied directly, has a
small negative inotropic effect; this inhibition is most apparent
when there is concomitant adrenergic stimulation or underlying
sympathetic tone (Brodde and Michel, 1999; Levy and Schwartz,
1994; Lewis et al., 2001). Automaticity of Purkinje fibers is suppressed,
and the threshold for ventricular fibrillation is increased
(Kent and Epstein, 1976).
Respiratory Tract. The parasympathetic nervous system
plays a major role in regulating bronchomotor tone.
A diverse set of stimuli cause reflex increases in
parasympathetic activity that contributes to bronchoconstriction.
The effects of ACh on the respiratory
system include not only bronchoconstriction but also
increased tracheobronchial secretion and stimulation of
the chemoreceptors of the carotid and aortic bodies.
These effects are mediated primarily by M 3
muscarinic
receptors (Fisher et al., 2004).
Urinary Tract. Parasympathetic sacral innervation
causes detrusor muscle contraction, increased voiding
pressure, and ureteral peristalsis. These responses are
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CHAPTER 9
MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS