FUNCTIONAL ORGANIZATION OF AUTONOMIC ACTIVITY
Autonomic function is integrated and regulated at many levels, from the CNS to the effector cells. Most regulation uses negative feedback, but several other mechanisms have been identified. Negative feedback is particularly important in the responses of the ANS to the administration of autonomic drugs.
At the highest level—midbrain and medulla—the two divisions of the ANS and the endocrine system are integrated with each other, with sensory input, and with information from higher CNS centers, including the cerebral cortex. These interactions are such that early investigators called the parasympathetic system a trophotropic one (ie, leading to growth) used to “rest and digest” and the sympathetic system an ergotropic one (ie, leading to energy expenditure), which is activated for “fight or flight.” Although such terms offer little insight into the mechanisms involved, they do provide simple descrip-tions applicable to many of the actions of the systems (Table 6–3). For example, slowing of the heart and stimulation of digestive activity are typical energy-conserving and storing actions of the parasympathetic system. In contrast, cardiac stimulation, increased blood sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting or surviving attack.
At a more subtle level of interactions in the brain stem, medulla, and spinal cord, there are important cooperative interactions between the parasympathetic and sympathetic systems. For some organs, sensoryfibers associated with the parasympathetic system exert reflex control over motor outflow in the sympathetic system. Thus, the sensory carotid sinus baroreceptor fibers in the glossopharyngeal nerve have a major influence on sympathetic outflow from the vasomotor center. This example is described in greater detail in the following text. Similarly, parasympathetic sensory fibers in the wall of the urinary blad-der significantly influence sympathetic inhibitory outflow to that organ. Within the ENS, sensory fibers from the wall of the gut synapse on both preganglionic and postganglionic motor cells that control intesti-nal smooth muscle and secretory cells (Figure 6–2).
Autonomic reflexes are particularly important in understanding cardiovascular responses to autonomic drugs. As indicated in Figure 6–7, the primary controlled variable in cardiovascular func-tion is mean arterial pressure. Changes in any variable contribut-ing to mean arterial pressure (eg, a drug-induced increase in peripheral vascular resistance) evoke powerful homeostatic second-ary responses that tend to compensate for the directly evoked
change. The homeostatic response may be sufficient to reduce the change in mean arterial pressure and to reverse the drug’s effects on heart rate. A slow infusion of norepinephrine provides a useful 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 the absence of reflex control—in a patient who has had a heart trans-plant, for example—the drug’s effect on the heart is also stimulatory; that is, it increases heart rate and contractile force. However, in a subject with intact reflexes, the negative feedback response to increased mean arterial pressure causes decreased sympathetic out-flow to the heart and a powerful increase in parasympathetic (vagus nerve) discharge at the cardiac pacemaker. This response is mediated by increased firing by the baroreceptor nerves of the carotid sinus and the aortic arch. Increased baroreceptor activity causes the changes mentioned in central sympathetic and vagal outflow. As a result, the net effect of ordinary pressor doses of norepinephrine in a normalsubject is to produce a marked increase in peripheral vascular resis-tance, an increase in mean arterial pressure, and a consistent slowingof heart rate. Bradycardia, the reflex compensatory response elicited by this agent, is the exact opposite of the drug’s direct action; yet it is completely predictable if the integration of cardiovascular function by the ANS is understood.
The principle of negative feedback control is also found at the presynaptic level of autonomic function. Important presynaptic feedback inhibitory control mechanisms have been shown to exist at most nerve endings. A well-documented mechanism involves the α2 receptor located on noradrenergic nerve terminals. This receptor is activated by norepinephrine and similar molecules; activation diminishes further release of norepinephrine from these nerve endings (Table 6–4). The mechanism of this G protein-mediated effect involves inhibition of the inward calcium current that causes vesicular fusion and transmitter release. Conversely, a presynaptic β receptor appears to facilitate the release of norepi-nephrine from some adrenergic neurons. Presynaptic receptorsthat respond to the primary transmitter substance released by the nerve ending are called autoreceptors. Autoreceptors are usually inhibitory, but in addition to the excitatory β receptors on nor-adrenergic fibers, many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors.
Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory recep-tors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve termi-nals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6–4. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers.
Postsynaptic regulation can be considered from two perspectives: modulation by previous activity at the primary receptor (which may up- or down-regulate receptor number or desensitize receptors;), and modulation by other simultaneous events.
The first mechanism has been well documented in several receptor-effector systems. Up-regulation and down-regulation are known to occur in response to decreased or increased activation, respectively, of the receptors. An extreme form of up-regulation occurs after denervation of some tissues, resulting in denervationsupersensitivity of the tissue to activators of that receptor type. Inskeletal muscle, for example, nicotinic receptors are normally restricted to the end-plate regions underlying somatic motor nerve terminals. Surgical denervation results in marked proliferation of nicotinic cholinoceptors over all parts of the fiber, including areas not previously associated with any motor nerve junctions. A phar-macologic supersensitivity related to denervation supersensitivity occurs in autonomic effector tissues after administration of drugs that deplete transmitter stores and prevent activation of the post-synaptic receptors for a sufficient period of time. For example, prolonged administration of large doses of reserpine, a norepi-nephrine depleter, can cause increased sensitivity of the smooth muscle and cardiac muscle effector cells served by the depleted sympathetic fibers.
The second mechanism involves modulation of the primary transmitter-receptor event by events evoked by the same or other transmitters acting on different postsynaptic receptors. Ganglionic transmission is a good example of this phenomenon (Figure 6–8). The postganglionic cells are activated (depolarized) as a result of binding of an appropriate ligand to a neuronal nicotinic (NN) ace-tylcholine receptor. The resulting fast excitatory postsynapticpotential (EPSP) evokes a propagated action potential if thresholdis reached. This event is often followed by a small and slowly devel-oping but longer-lasting hyperpolarizing afterpotential—a slow inhibitory postsynaptic potential (IPSP). This hyperpolarizationinvolves opening of potassium channels by M2 cholinoceptors. The IPSP is followed by a small, slow excitatory postsynaptic potential caused by closure of potassium channels linked to M1 cholinocep-tors. Finally, a late, very slow EPSP may be evoked by peptides released from other fibers. These slow potentials serve to modulate the responsiveness of the postsynaptic cell to subsequent primary excitatory presynaptic nerve activity.