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, sensory fibers 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 bladder 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 neurons that control intestinal smooth muscle and secretory cells (Figure 6–2).
A. Integration of Cardiovascular Function
Autonomic reflexes are particularly important in understanding cardiovascular responses to autonomic drugs. As indicated in Figure 6–7, the primary controlled variable in cardiovascular function is mean arterial pressure. Changes in any variable contributing to mean arterial pressure (eg, a drug-induced increase in peripheral vascular resistance) evoke powerful homeostatic secondary 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 transplant, 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 outflow 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 decreased central sympathetic outflow and increased vagal outflow. As a result, the net effect of ordinary pressor doses of norepinephrine in a normal subject is to produce a marked increase in peripheral vascular resistance, an increase in mean arterial pressure, and often, a slowing of 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.
B. Presynaptic Regulation
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 norepinephrine from some adrenergic neurons. Presynaptic receptors that 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 noradrenergic fibers, many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors.