The fight-or-flight reaction is a sympathetic response that is centrally controlled in the cortex and hypothalamus
Emotional responses vary greatly among people. A severe emotional reaction can resemble the fight-or-flight response in animals (see p. 345). This defense reaction causes a generalized increase in skeletal muscle tone and increased sensory attention.
Fight-or-flight behavior is an extreme example of an integrated acute stress response that originates entirely within the central nervous system (CNS), without involvement of peripheral sensors or reflexes. The response is due to the activation of sensory centers in the cortex (Fig. 25-4), which activate a part of the limbic system called the amygdala (see p. 349). The amygdala in turn activates the locus coeruleus (see p. 312), which is in the pons, as well as hypothalamic nuclei. Noradrenergic neurons in the locus coeruleus project to nearly every part of the CNS (see Fig. 13-7A), including the hypothalamic paraventricular nucleus (PVN), which produces both an endocrine and an ANS response. The endocrine response of the PVN involves (1) release of arginine vasopressin (AVP) by magnocellular neurons in the PVN (see Fig. 40-8), thereby reducing urine output (see pp. 817–818); and (2) release of corticotropin-releasing hormone (CRH; see p. 1023) by parvocellular neurons in the PVN, activating the hypothalamic-pituitary-adrenal axis and thereby releasing cortisol, which is important for the metabolic response to stress. The ANS response of the PVN involves projections to (1) autonomic nuclei in the brainstem (dorsal motor nucleus of the vagus, rostral ventrolateral medulla, and nucleus tractus solitarii [NTS]) that are part of the medullary cardiovascular center (see p. 537), and (2) direct projections to the spinal intermediolateral column (see Fig. 25-4).
FIGURE 25-4 Fight-or-flight response.
The overall fight-or-flight response involves the following:
1. Skeletal muscle blood flow. In animals—but perhaps not in humans—activation of postganglionic sympathetic cholinergic neurons (see p. 342–343) directly causes a rapid increase in blood flow to skeletal muscle (see p. 539). In humans as well as in other mammals, flow also increases secondarily more slowly and less dramatically because the adrenal medulla releases epinephrine, which acts on β2 adrenoceptors on skeletal muscle blood vessels. The result is dilation and an increase in blood flow. In a full-blown fight-or-flight reaction, muscle exercise generates metabolites that further increase skeletal muscle blood flow (see pp. 563–564). Of course, humans may not exercise skeletal muscle in responding to internal stress (e.g., anxiety or panic).
2. Cutaneous blood flow. The sympathetic response causes little change in blood flow to skin unless it stimulates sweating. The neural pathway involves sympathetic cholinergic neurons (see pp. 342–343), which release acetylcholine and perhaps vasodilatory neurotransmitters (e.g., calcitonin gene–related peptide, vasoactive intestinal peptide). The acetylcholine causes the secretion of sweat and possibly also the local formation of kinins (see pp. 553–554). These kinins increase capillary permeability and presumably also dilate arterioles but constrict venules (i.e., increasing the midcapillary pressure). The result would be an increased filtration of fluid from the skin capillaries into the interstitium, causing dermal swelling.
3. Adrenal medulla. Preganglionic sympathetic neurons stimulate the chromaffin cells to release epinephrine, which causes vasodilation in muscle (through β2 adrenoceptors) and vasoconstriction in the kidney and splanchnic beds (through α1 adrenoceptors).
4. Renal and splanchnic blood flow. In virtually all vascular beds, increased sympathetic output causes vasoconstriction and thereby decreases blood flow. The systemic release of epinephrine also vasoconstricts these vascular beds rich in α1 adrenoceptors.
5. Veins. Most veins constrict in response to sympathetic output.
6. The heart. Increased sympathetic output and decreased vagal output cause a rise in heart rate and contractility, so that cardiac output increases.
7. Blood volume. High plasma levels of AVP reduce urine output and maintain blood volume.
8. Mean arterial pressure. Depending on the balance of vasodilation and vasoconstriction, the overall result of vascular resistance changes may be either a decrease or an increase in total peripheral resistance. Nevertheless, because cardiac output increases, the net result of an increased cardiac output and a resistance change is an increase in arterial pressure.
The common faint reflects mainly a parasympathetic response caused by sudden emotional stress
About one fifth of humans experience one or more episodes of fainting during adolescence. This type of fainting is known as vasodepressor syncope or vasovagal syncope (VVS). About 40% of syncope cases seen in outpatient settings are vasovagal in nature. VVS can occur in response to a sudden emotional stress, phlebotomy, the sight of blood, or acute pain. Fainting usually starts when the individual is standing or sitting, rarely when the individual is recumbent. The loss of consciousness is due to a transient fall in perfusion pressure to the brain. The “playing dead” reaction in animals is the equivalent of VVS in humans.
VVS originates with activation of specific areas in the cerebral cortex. Indeed, stimulation of areas in the anterior cingulate gyrus can trigger a faint. Although the exact trigger is not known, VVS has been attributed to activation of the Bezold-Jarisch reflex. This reflex—originally described as the cardiorespiratory response to the intravenous injection of Veratrum alkaloids—causes bradycardia, hypotension, and apnea. In experimental animals, stimulation of arterial baroreceptors (see p. 534) or ventricular baroreceptors (see p. 547) by any of a host of chemicals—Veratrum alkaloids, nicotine, capsaicin, histamine, serotonin, and snake and insect venoms—can also trigger the Bezold-Jarisch reflex. In patients, coronary injection of contrast material or of thrombolytic agents can cause VVS, presumably by stimulating ventricular receptors. It is possible that these chemical stimuli activate the same stretch-sensitive TRPC channels of arterial baroreceptors (see pp. 534–535) that are usually activated by high blood pressure. In humans, triggers clearly distinct from those known to initiate a Bezold-Jarisch reflex can also elicit VVS. Whatever the actual trigger, vagal afferents carry signals to higher CNS centers, which act through autonomic nuclei in the medulla to cause a massive stimulation of the parasympathetic system and abolition of sympathetic tone.
VVS involves changes in several parameters (Fig. 25-5):
1. Total peripheral resistance. A massive vasodilation results from the removal of sympathetic tone from the resistance vessels of the skeletal muscle, splanchnic, renal, and cerebral circulations. The resulting fall in blood pressure fails to activate a normal baroreceptor response.
2. Cardiac output. Intense vagal output to the heart causes bradycardia and decreased stroke volume, resulting in a marked decrease in cardiac output. Because atropine, a muscarinic receptor blocker, does not reliably prevent syncope, decreased sympathetic tone to the heart may also play a role in causing bradycardia.
3. Arterial pressure. The combination of a sudden decrease in both total peripheral resistance and cardiac output causes a profound fall in mean arterial pressure.
4. Cerebral blood flow. The fall in mean arterial pressure causes global cerebral ischemia. If the decreased cerebral blood flow persists for only a few seconds, the result is dizziness or faintness. If it lasts for ~10 seconds, the subject loses consciousness. The stress underlying the common faint also may provoke hyperventilation, which lowers arterial (see p. 680). The resulting constriction of cerebral blood vessels (see p. 559) further impairs cerebral blood flow, which increases the likelihood of a faint.
5. Other manifestations of altered ANS activity. Pallor of the skin and sweating (beads of perspiration) are signs that often appear before the loss of consciousness. Intense vagal stimulation of the gastrointestinal tract may cause epigastric pain that is interpreted as nausea. Mydriasis (pupillary dilation) as well as visual blurring can also result from parasympathetic stimulation. N25-5
FIGURE 25-5 Vasovagal syncope.
Ocular Symptoms and Signs Associated with Fainting
Contributed by Emile Boulpaep
On pages 579–580, the text points out that fainting may be associated with mydriasis (dilation of the pupil) and blurred vision. In addition, fainting may also be associated with dimmed vision.
The mydriasis that may occur during the loss of consciousness is not the direct consequence of the strong parasympathetic stimulation that underlies the fainting episode. Stimulation of the autonomic (parasympathetic) portion of cranial nerve III (see pp. 338–339, Fig. 14-4) would lead to contraction of the sphincter muscle in the iris, and therefore would lead to miosis (pupillary constriction). How then does mydriasis arise? It is likely that the brain ischemia that leads to the altered mental status of the faint also causes a palsy of the preganglionic fibers that originate in the oculomotor (Edinger-Westphal) nucleus (see Fig. 14-5), resulting in a relaxation of the iris's sphincter muscle and therefore mydriasis. Note that the dilator muscle of the iris is innervated by postganglionic sympathetic fibers emanating from the superior cervical ganglion. Evidently, the brain hypoperfusion that triggers the faint has a lesser effect on the sympathetic system that causes dilation of the pupil.
Blurred vision before or after the loss of consciousness may be a direct consequence of strong parasympathetic stimulation. The ciliary zonule fibers are elastic elements that tend to stretch the lens of the eye in a radial direction and thus to flatten the lens. The ciliary muscle that encircles the lens is composed of smooth-muscle fibers that are arranged both radially and circularly. The main effect of contraction of the ciliary muscle is to relax the radial tension exerted by elastic zonule fibers, thereby allowing the lens to become more curved. A higher curvature of the front surface of the lens increases its focal power (see Equation 15-1). It is possible that very strong parasympathetic stimulation could cause blurring by the following sequence of events: Preganglionic fibers in the oculomotor (Edinger-Westphal) nucleus synapse in the ciliary ganglion on postganglionic parasympathetic fibers that innervate the smooth-muscle fibers of the ciliary muscle. Parasympathetic activation of this system would cause the lens to accommodate for objects very close to the eye. Therefore, the patient would experience blurred vision for any object further removed from the eye.
Dimming of vision may be part of the prodrome of fainting, presumably due to a loss of adequate retinal perfusion.
Fainting is more likely to occur in a warm room (see pp. 576–577), after a volume loss (e.g., dehydration or hemorrhage), or after standing up or other maneuvers that tend to lower mean arterial pressure. You might think that these stresses would trigger baroreceptor responses that increase cardiac output and vascular resistance, thereby making fainting less likely. However, the same integrated pattern of brain activity that orchestrates VVS also appears to suppress the expected baroreceptor reflexes that would otherwise counteract the syncope. N25-6
Suppression of the Classical Baroreceptor Response in Vagovagal Syncope
Contributed by Emile Boulpaep
In rare cases, certain chemicals can cause vasovagal syncope.
One hypothesis is that certain chemicals that stimulate TRPC channels of baroreceptors can activate the baroreceptors maximally, as if blood pressure had risen markedly. According to this view, vasovagal syncope is the appropriate response: decreased cardiac output and decreased peripheral resistance. Even though blood pressure falls, vessels collapse, and stretch on the walls of the blood vessels wanes, the baroreceptors would still behave as if they were maximally stimulated.
After regaining consciousness, the patient often notices oliguria (reduced urine output), caused by high plasma levels of AVP (also known as antidiuretic hormone; see pp. 817–819). Elevated levels of AVP can result in part from the reduced atrial stretch that occurs during periods of decreased venous return (see pp. 546–547). The pallor and nausea that persist after fainting may also result from the high levels of circulating AVP.