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100 SECTION II Autonomic Drugs

The sensory fibers in the nonadrenergic, noncholinergic sys- contributing to mean arterial pressure (eg, a drug-induced increase
tems are probably better termed “sensory-efferent” or “sensory- in peripheral vascular resistance) evoke powerful homeostatic sec-
local effector” fibers because, when activated by a sensory input, ondary responses that tend to compensate for the directly evoked
they are capable of releasing transmitter peptides from the sensory change. The homeostatic response may be sufficient to reduce the
ending itself, from local axon branches, and from collaterals that change in mean arterial pressure and to reverse the drug’s effects
terminate in the autonomic ganglia. These peptides are potent on heart rate. A slow infusion of norepinephrine provides a useful
agonists in many autonomic effector tissues. example. This agent produces direct effects on both vascular and
cardiac muscle. It is a powerful vasoconstrictor and, by increasing
peripheral vascular resistance, increases mean arterial pressure. In
FUNCTIONAL ORGANIZATION OF the absence of reflex control—in a patient who has had a heart
AUTONOMIC ACTIVITY transplant, for example—the drug’s effect on the heart is also
stimulatory; that is, it increases heart rate and contractile force.
Autonomic function is integrated and regulated at many levels, However, in a subject with intact reflexes, the negative feedback
from the CNS to the effector cells. Most regulation uses nega- response to increased mean arterial pressure causes decreased
tive feedback, but several other mechanisms have been identified. sympathetic outflow to the heart and a powerful increase in
Negative feedback is particularly important in the responses of the parasympathetic (vagus nerve) discharge at the cardiac pacemaker.
ANS to the administration of autonomic drugs. This response is mediated by increased firing by the baroreceptor
nerves of the carotid sinus and the aortic arch. Increased barore-
Central Integration ceptor activity causes the decreased central sympathetic outflow
and increased vagal outflow. As a result, the net effect of ordinary
At the highest level—midbrain and medulla—the two divisions of pressor doses of norepinephrine in a normal subject is to produce
the ANS and the endocrine system are integrated with each other, a marked increase in peripheral vascular resistance, an increase in
with sensory input, and with information from higher CNS cen- mean arterial pressure, and often, a slowing of heart rate. Brady-
ters, including the cerebral cortex. These interactions are such that cardia, the reflex compensatory response elicited by this agent, is
early investigators called the parasympathetic system a tropho- the exact opposite of the drug’s direct action; yet it is completely
tropic one (ie, leading to growth) used to “rest and digest” and predictable if the integration of cardiovascular function by the
the sympathetic system an ergotropic one (ie, leading to energy ANS is understood.
expenditure), which is activated for “fight or flight.” Although
such terms offer little insight into the mechanisms involved, they B. Presynaptic Regulation
do provide simple descriptions applicable to many of the actions The principle of negative feedback control is also found at the
of the systems (Table 6–3). For example, slowing of the heart and presynaptic level of autonomic function. Important presynaptic
stimulation of digestive activity are typical energy-conserving and feedback inhibitory control mechanisms have been shown to exist
energy-storing actions of the parasympathetic system. In contrast, at most nerve endings. A well-documented mechanism involves
cardiac stimulation, increased blood sugar, and cutaneous vaso- the α receptor located on noradrenergic nerve terminals. This
2
constriction are responses produced by sympathetic discharge that receptor is activated by norepinephrine and similar molecules;
are suited to fighting or surviving attack. activation diminishes further release of norepinephrine from these
At a more subtle level of interactions in the brain stem, nerve endings (Table 6–4). The mechanism of this G protein–
medulla, and spinal cord, there are important cooperative interac- mediated effect involves inhibition of the inward calcium current
tions between the parasympathetic and sympathetic systems. For that causes vesicular fusion and transmitter release. Conversely, a
some organs, sensory fibers associated with the parasympathetic presynaptic β receptor appears to facilitate the release of norepi-
system exert reflex control over motor outflow in the sympathetic nephrine from some adrenergic neurons. Presynaptic receptors
system. Thus, the sensory carotid sinus baroreceptor fibers in the that respond to the primary transmitter substance released by the
glossopharyngeal nerve have a major influence on sympathetic nerve ending are called autoreceptors. Autoreceptors are usually
outflow from the vasomotor center. This example is described in inhibitory, but in addition to the excitatory β receptors on norad-
greater detail in the following text. Similarly, parasympathetic sen- renergic fibers, many cholinergic fibers, especially somatic motor
sory fibers in the wall of the urinary bladder significantly influence fibers, have excitatory nicotinic autoreceptors.
sympathetic inhibitory outflow to that organ. Within the ENS, Control of transmitter release is not limited to modulation by
sensory fibers from the wall of the gut synapse on both pregan- the transmitter itself. Nerve terminals also carry regulatory recep-
glionic and postganglionic motor neurons that control intestinal tors that respond to many other substances. Such heteroreceptors
smooth muscle and secretory cells (Figure 6–2). may be activated by substances released from other nerve termi-
nals that synapse with the nerve ending. For example, some vagal
A. Integration of Cardiovascular Function fibers in the myocardium synapse on sympathetic noradrenergic
Autonomic reflexes are particularly important in understand- nerve terminals and inhibit norepinephrine release. Alternatively,
ing cardiovascular responses to autonomic drugs. As indicated the ligands for these receptors may diffuse to the receptors from
in Figure 6–7, the primary controlled variable in cardiovascular the blood or from nearby tissues. Some of the transmitters and
function is mean arterial pressure. Changes in any variable receptors identified to date are listed in Table 6–4. Presynaptic