Stimulation of the sympathetic nervous system produces which of the following responses?

Sympathetic division

The sympathetic nervous system generates and transmits yang energy by eliciting the fight or flight reflex and motivating the body's responses to various stressors. It mostly involves the physiological functioning of the heart and skeletal muscles.

Involves mostly the hormones epinephrine and norepinephrine.

Tonifies:

Heart rate (increases).

Smooth muscle sphincters (constricts).

Coronary blood flow through vasodilation.

Fight or flight response.

Sedates:

Eye pupils (dilates).

Lung bronchioles (dilates).

Urinary bladder.

Digestion.

Peristalsis.

Unselective beta-blockers (e.g., propranolol)

The sympathetic nervous system (SNS) is an anatomical and functional network of nerves, the adrenal medulla, and their respective neurotransmitters and receptors. Catecholamines, including epinephrine and norepinephrine, act on effector tissues through alpha- and beta-adrenergic receptors, which are widely expressed in both normal and neoplastic tissues including PDAC cell lines [195]. Catecholamines are stress molecules, produced by the SNS and linked to PDAC growth via beta-adrenergic signaling demonstrated via in vitro [196,197] and in vivo studies [198]. It is known from epidemiologic studies that stress can promote tumor growth [199] and that PDAC patients have the highest level of psychological stress of all investigated types of cancer [200]. In addition, cancer mortality is significantly increased by high levels of psychological stress [201]. On the other hand, it is suggested that beta-blocker treatment of patients suffering from colorectal cancer [199], breast cancer [202], ovarian cancer [203], melanoma [204], and PDAC [205,206] may lead to improved survival. Moreover, systemic stress has been shown to accelerate growth of cancer cells grown in immunocompromised mice, including ovarian cancer and prostate cancer [207]. A recent preclinical study demonstrated that stress-dependent sympathetic signaling can induce PDAC in preneoplastic lesions (i.e., PanINs) and thus cancer development in a susceptible host could be inhibited by ADRB2 antagonists. ADRB2 signaling likely promotes tumorigenesis through effects on both the epithelial and the stromal compartment [208]. Although the effects of stress in promoting cancer have been linked in the past to suppression of the immune response [209] or to recruitment of M2 macrophages [210,211], it could be shown recently that many of the effects of circulating catecholamines are indeed direct, with stimulation of ADRB2-dependent pancreatic epithelial growth [21].

As aforementioned, at an in vitro level, the positive effects of beta blockade on PDAC rely on ADRB2 inhibition. However, ADRB1-selective beta-blockers (SBBs) are more commonly prescribed than nonselective beta-blockers (NSBB), and populations with greater SBB use are unlikely to demonstrate a benefit from their beta-blocker use. Nevertheless, there are several studies that have investigated the impact of beta-blocker use on cancer survival. Among the 2394 patients in a very recent study [206], only 21 NSBB are in their medication. However, patients who used beta-blockers (selective and nonselective) (n = 522) had a lower cancer-specific mortality rate than nonusers (NBB). No clear rate differences were observed by beta-blocker receptor selectivity owing to very few patients on NSBB. A SEER-Medicare analysis also showed improved survival in patients with PDAC on beta-blocker therapy [205].

The role of ADRB2 in PDAC progression was also supported by a retrospective clinical study from our group, which demonstrated a significantly improved OS in patients on NSBB, although the analysis was limited by the uncertain duration and dosage of beta-blockers. Beta-1–selective drugs provided no clinical advantage in this analysis [212], consistent with in vitro data showing that ADRB1 blockers did not suppress proliferation of Kras mutant pancreatic cells.

Taken together, as there is mounting evidence of the potential impact of beta-blockers on the outcomes of patients with cancer, a prospective clinical trial is warranted to identify those patients who would benefit most from beta-blocker use and to identify the best beta-blocker for a specific tumor type based on adrenergic receptor expression. Tumor cell expression of ADRB2 could be used as a biomarker for selecting those patients who would benefit from a specific beta-blocker. Beta-blockers could then be used as an adjuvant therapy during surgical recovery and chemotherapy to decrease tumor angiogenesis, tumor growth, delays in wound healing, and metastasis [209]. Beta-blockers also may reduce cancer-related psychological distress in patients newly diagnosed with cancer [213]. Therefore, beta-blockers have the potential to impact not only cancer biology and immunology but also the psychological well-being of patients with cancer.

In this regard, the PROSPER trial (Pancreatic Resection with perioperative Off-label Study of Propranolol and Etodolac—a phase II Randomized trial) studies a combination therapy of propranolol (NSBB) and etodolac in the perioperative setting in PDAC. It is hypothesized that this combination might attenuate psychological, surgical, and inflammatory stress responses that facilitate metastasis of the tumor [214]. This approach is interesting because it uses that critical period of surgery as a window for cancer directed therapy that is currently largely unexploited. Moreover, it does not interfere with current practice or future implementation of new adjuvant chemotherapy regimens (https://www.anticancerfund.org/en/approval-pancreatic-cancer-trial-perioperative-use-β-blocker-and-anti-inflammatory-drug).

37.4.3.4 Cardiovascular regulation

The sympathetic nervous system is heavily involved in regulation of avian embryonic blood pressure (Altimiras et al., 2009; Crossley and Altimiras, 2012; Swart et al., 2014; Sirsat et al., 2018). Injection with the α-adrenoreceptor antagonist phentolamine causes hypotension from 60% of chicken incubation, indicating α-adrenergic tone on the vasculature (Girard, 1973; Saint Petery and Van Mierop, 1974; Tazawa et al., 1992a; Crossley and Altimiras 2000; Mueller et al., 2014a). Phentolamine also causes bradycardia, a likely indirect effect of vasodilation, and reduced venous return. β-adrenergic tone on the vasculature is also present from 60% of incubation, as evident by a Pa increase in response to the β-adrenereceptor antagonist propranolol (Girard, 1973; Saint Petery and Van Mierop, 1974; Tazawa et al., 1992a; Crossley and Altimiras 2000). The magnitude of both α- and β-adrenergic tone is maximal at 90% of incubation, just prior to IP (Crossley and Altimiras, 2000). The increase in adrenergic tone is matched to the maximal plasma catecholamine release on day 19. Catecholamine release is also elevated under hypoxic incubation of chicken embryos (Ruijtenbeek et al., 2000; Lindgren et al., 2011). Emu embryos also show signs of increasing α- and β-adrenergic tone on the vasculature matched to increasing levels of catecholamines as incubation proceeds (Crossley et al., 2003), although the onset of these responses differs from chicken embryos.

In addition to regulation via catecholamines, other hormones may also influence baseline cardiovascular function of avian embryos. The most extensively studied in chicken embryos is angiotensin II (ANG II), a strong vasoconstrictor and the active peptide of the renin-angiotensin system (RAS). Components of the RAS, including renin, angiotensin converting enzyme, ANG II, and its receptors, are present early in chicken ontogeny (Nishimura et al., 2003; Savary et al., 2005; Crossley et al., 2010). ANG II levels are elevated in embryos compared to adults, the peptide produces hypertension from at least 60% of incubation (Crossley et al., 2010), and contributes to baseline Pa at 90% of incubation (Mueller et al., 2014a). Despite an increase in Pa, ANG II does not alter MHR as it instead attenuates the embryonic cardiac baroreflex. The baroreflex is an important compensatory mechanism that buffers short-term changes in Pa and is composed of a peripheral limb adjusting vascular resistance and a cardiac limb that changes HR. A functioning baroreflex is present in chicken embryos from 80% of incubation (Altimiras and Crossley, 2000; Elfwing et al., 2011; Mueller et al., 2013a). ANG II decreases the sensitivity of the cardiac baroreflex at 90% of incubation so that reflex changes in HR in response to Pa changes are blunted (Mueller et al., 2013a). ANG II also raises the operating Pa of embryos, and it is via these short-term changes that the hormone partly enacts some of its influence on long term Pa.

Other potentially important moderators of cardiovascular function include nitric oxide (NO) and Endothelin-1 (ET-1), a potent vasodilator and vasoconstrictor, respectively, produced primarily in the endothelium, and natriuretic peptides (NPs), strong vasodilators excreted by heart muscle cells. NO tone is present from at least 70% of incubation and, unlike cholinergic and adrenergic tone, lacks plasticity as it remains unchanged under hypoxic conditions (Iversen et al., 2014). Components necessary for functional ET-1, including mRNA and converting enzymes, are found in chicken embryos from 15% of incubation (Hall et al., 2004; Groenendijk et al., 2008), and ET-1 alters chicken embryo hemodynamics (Groenendijk et al., 2008; Moonen and Villamor, 2011). Likewise, NP is present in the chicken heart and most likely contributes to hemodynamics from at least day 14 (Maksimov and Korostyshevskaya, 2013). Further research from the molecular to whole organism level is required to understand the contribution of these hormones to Pa and HR control, and therefore embryonic cardiovascular regulation.

Neuroendocrine Effects of Alcohol

Alcohol activates the sympathetic nervous system, increasing circulating catecholamines from the adrenal medulla. Hypothalamic–pituitary stimulation results in increased circulating cortisol from the adrenal cortex and can, rarely, cause a pseudo-Cushing's syndrome with typical moon-shaped face, truncal obesity, and muscle weakness. Alcoholics with pseudo-Cushing's show many of the biochemical features of Cushing's syndrome, including failure to suppress cortisol with a 48-h low-dose dexamethasone suppression test. However, they may be distinguished by an insulin stress test. In pseudo-Cushing's, the cortisol rises in response to insulin-induced hypoglycemia, but in true Cushing's there is no response to hypoglycemia.

Ethanol affects hypothalamic osmoreceptors, reducing vasopressin release. This increases salt and water excretion from the kidney, causing polyuria. Significant dehydration may result particularly with consumption of spirits containing high concentrations of ethanol and little water. Loss of hypothalamic neurons (which secrete vasopressin) has also been described in chronic alcoholics, suggesting long-term consequences for fluid balance. Plasma atrial natriuretic peptide, increased by alcohol consumption, may also increase diuresis and resultant dehydration.

Alcoholism also affects the hypothalamic–pituitary–gonadal axis. These effects are further exacerbated by alcoholic liver disease. There are conflicting data regarding the changes observed. Testosterone is either normal or decreased in men, but it may increase in women. Estradiol is increased in men and women, and it increases as hepatic dysfunction deteriorates. Production of sex hormone-binding globulin is also perturbed by alcohol.

The development of female secondary sexual characteristics in men (e.g., gynaecomastia and testicular atrophy) generally only occurs after the development of cirrhosis. In women, the hormonal changes may reduce libido, disrupt menstruation, or even induce premature menopause. Sexual dysfunction is also common in men with reduced libido and impotence. Fertility may also be reduced, with decreased sperm counts and motility.

Sympathoadrenal system

Some preganglionic fibers of the sympathetic nervous system end directly in the adrenal medulla. These fibers stimulate the secretion of adrenaline from the adrenal medulla gland, and therefore they are strictly involved in the fight-or-flight response. Additionally, activation of this receptor also induces renin release, which contributes to the final blood pressure, as well as plasma sodium levels and blood volume. There is evidence that neurohormonal regulation plays a critical role in the pathogenesis and progression of several cardiovascular diseases [19]. Plasma and tissue levels of noradrenaline, adrenaline, angiotensin II, aldosterone, and other mediators are increased in hypertension, heart failure, and some arrhythmias. Their activities correlate with the severity of disease. Therefore, opposing the effect of elevated adrenergic and/or angiotensin, renin–angiotensin–aldosterone signaling is the main objective of several treatment strategies [20–23].

The autonomic nervous system

Evolution equipped mammals with a sophisticated sympathetic nervous system (SNS) that enabled them to respond quickly to a multitude of threats encountered in their immediate environmental surroundings, including exposure to predators as well as dangers associated with natural threats and disasters. In brief, the SNS response, commonly referred to as the “fight-or-flight” response, is characterized by a re-allocation of the body’s energy resources (e.g., oxygen, glucose) to the musculature and other organ systems that need to be activated to support the increased energy demand required for fighting or fleeing, including the heart and vasculature (Andreassi, 2007). Because functioning of other organ systems has a lower priority when confronting threat or danger, energy resources are drawn from the digestive and reproductive systems during SNS activation. The SNS is paired with an active parasympathetic nervous system (PNS) that is designed to reduce the physiological activation of the SNS and return the body’s energy to its resting state where blood flow resumes to the digestive and reproductive systems. Neuroanatomically, SNS activity is linked to the limbic system and brain stem regions of the brain and extends to peripheral destinations directly though neurons comprising an extensive network of cells called the sympathetic ganglia located bilateral to the spinal cord between the neck and tailbone. Two neural networks that, for the most part, function using norepinephrine as a neurotransmitter comprise the SNS: alpha-adrenergic fibers and beta-adrenergic fibers. In the cardiovascular system, both alpha- and beta-adrenergic networks innervate the vasculature and function to constrict and dilate blood vessels respectively. In contrast, beta-adrenergic neurons alone innervate the heart itself and trigger increases in heart rate (HR) and cardiac contractility. The PNS also has direct neural connections to most of the same organ systems innervated by the SNS but largely employs acetylcholine as a neurotransmitter. PNS activity is not routed through the sympathetic ganglia, but instead is connected directly to peripheral organs through several cranial nerves, including the vagal nerve, and the pelvic splanchnic nerves in the sacrum. In the cardiovascular system, the vagal nerve transmits neural signals to the heart, leading to reductions in HR and cardiac contractility, but has no direct influence on arterial vasoconstriction or dilation. In this regard, the SNS and PNS represent distinctive networks of peripheral neurons that alter physiological functioning of the body, much like the accelerator and brake both alter the speed of a motor vehicle (Andreassi, 2007).

Although the direct measurement of ANS activity is challenging to obtain, numerous methods of measuring target organ system activity using surface electrodes that reflect underlying ANS functioning (e.g., HR, skin conductance, skin temperature, pupillometry) are available. For purposes of understanding the mechanisms involved in the association between exposure to stress and subsequent onset of CVD, the most popular indices of measurement are HR, blood pressure (BP), and heart rate variability (HRV). Because both HR and BP are significantly influenced by cardiac activity that is jointly innervated by both the SNS and PNS, it is impossible to determine whether increases in either of these parameters result from increased SNS activity, decreased PNS activity, or some combination of the two. There are certain measures of HRV, however, that are not influenced by SNS activity, and primarily reflect PNS activity (e.g., respiratory sinus arrhythmia, high-frequency HRV detected via spectral analysis). For these measures, elevated HRV reflects more PNS activity.

2.3.8 Nervous system stimulation

A. heterophyllum has the ability to make the sympathetic nervous system highly sensitive to physiological stimuli. It was found that while atisine had a hypotensive effect at every tested dose, the plant extract showed hypertensive properties. Hypertension produced by high doses of aqueous extract was attributed to the excitement of the sympathetic nervous system (Raymond-Hamet, 1954). Nisar et al. (2009) isolated two new diterpenoid alkaloids viz. heterophyllinine A and heterophyllinine B from the roots of A. heterophyllum, which were almost 13 times more selective in inhibiting the enzyme butyrylcholinesterase than acetylcholinesterase. These enzymes are involved in the transmission of nerve impulses.

33.4.1 Catecholamine synthesis and secretion

Catecholamines are widely synthesized throughout the postganglionic sympathetic nervous system which includes the adrenal chromaffin tissue. They are also synthesized in some tissues as, for example, the brain (Yamsaki et al., 2003), but these sites are not thought to contribute substantially to the pool in circulation.

The biosynthetic pathway for the adrenal catecholamines (Ghosh et al., 2001; Mahata et al., 2002; Trifaró, 2002) is outline in Figure 33.11. The rate limiting step in catecholamine biosynthesis is tyrosine hydroxylase. Catecholamines exert a negative feedback on tyrosine hydroxylase. Concerning the description of catecholamine release from the adrenal gland, it is best to use the framework of the catecholamine pathway in the “fight or flight” response to a particular stressor.

The perception of a stressor by the bird impacts on the proximal sympathetic nervous system that is relayed to preganglionic neurons of the spinal cord. The axons of these neurons comprise splanchnic nerves destined for the chromaffin tissue of the adrenal gland. Acetylcholine released from preganglionic sympathetic (splanchnic) nerve terminals interacts with both nicotinic and muscarinic receptors to stimulate phosphorylation of tyrosine hydroxylase, for rapid catecholamine synthesis and release, and upregulates tyrosine hydroxylase synthesis for more long-term stimulation. Phosphorylation lowers the Km of tyrosine hydroxylase for tetrahydrobiopterin, a cofactor necessary for tyrosine hydroxylase activity. VIP and PACAP also stimulate the phosphorylation of tyrosine hydroxylase.

Tyrosine hydroxylase catalyzes the conversion of tyrosine to l-dihydrophenylalanine (l-DOPA). l-DOPA is converted to dopamine by aromatic l-amino acid decarboxylase (l-DOPA decarboxylase). Dopamine is either secreted or undergoes further conversion to NE by dopamine β-hydroxylase with ascorbic acid as a cofactor.

The final step to E is carried out by phenylethanolamine N-methyltransferase (PNMT) in which the S-methyl group of S-adenosyl methionine is transferred to the primary nitrogen group of NE. All of these enzymes have some requirement for innervation and are affected by numerous intra-adrenal peptides. However, PNMT is strictly GR-dependent.

The release of catecholamines into the circulation occurs by the well-studied, stimulus-secretion coupling mechanism. In addition to catecholamines, there are a number of neuropeptides that are co-released (see Section 33.1.2.3). Furthermore, chromogranins and secretogranins are also released. Chromogranins are necessary for sequestration of synthesized catecholamines in secretory granules. The peptides derived from chromogranins have autocrine and paracrine effects on catecholamine release (Trifaró, 2002; Mahata et al., 2010; Tota et al., 2012).

There is no preferential release of E or NE from isolated chicken chromaffin cells in response to acetylcholine analogs (Knight and Baker, 1986). In vivo, however, the secretion of E and NE from the avian adrenal gland is thought to be finely regulated by a number of neural-derived and blood-borne factors and hormones resulting in the differential release of catecholamines (Ghosh et al., 2001). Yet, it is not known precisely how the differential adrenal secretion of E and NE occurs in response to disparate physiological conditions and stressors. Since the preganglionic fibers of splanchnic nerves originate in the spinal cord and since chromaffin cells exert an influence on the presynaptic endings, it may be that preganglionic neurons are connected to either NE- or E-secreting chromaffin cells. What is fairly clear is that the adrenal gland is nearly the sole contributor to circulating E and most of the NE in response to acute stressors (Butler and Wilson, 1985; Lacombe and Jones, 1990).

Overview of cardiovascular embryogenesis and postnatal conduction

The heart is the first functional organ to develop from the splanchnopleuric mesenchyme in the neural plate, which forms the heart through endocardial tubes in the cardiogenic region of the human embryo. The heart forms the pericardium, the septum, the chambers, and a foramen ovale for blood to bypass the lungs and enter the atria, valves, and form the circulation, and begins beating and pumping blood at around 21 days’ gestation. During the first 56 days as the structures develop, heart rate and blood pressure regulate according to the health of the mother and stage of gestation, setting the framework for lifetime functioning.

Generally, the heart is influenced by the sympathetic nervous system, which is involved with contraction and increase of heart rate. Stimulated nerves from the T1–T4 release the transmitted norepinephrine/noradrenaline, shortening repolarization, accelerating the rate of depolarization, and opening chemical or ligand-gated sodium and calcium ion channels. Norepinephrine binds to the beta-1 receptor and contraction causes an increase in heart rate. General heart rates are:

Resting heart rate of a fetus: 159–189 bpm.

Resting heart rate of a newborn infant: 129 bpm, reducing over time during the first 2 years postgestation.

Adult resting heart rate: 60–100 bpm and athletes: <60 bpm.

Heart rate during exercise: 150−220 bpm.

Developing sections involved in contraction are:

Sinoatrial (SA) node

Atrioventricular (AV) node

Left/right atria

Left/right ventricles

The SA is located in the upper section of the right atrium near the superior vena cava, fires electrical impulses and paces normal sinus rhythm causing the heart to contract.

The electrical impulse immediately travels to the left atrium via Bachmann's bundle, so the left and right atria contract together to open their respective valves to eject blood into their ventricles. From the SA node, the signal travels to the base of both atria to the AV node located near the AV septum to contract the valves and empty the blood into the ventricles. The electrical signal travels along the bundle of His to left and right bundle branches to the ventricles of the heart. The signal is carried by Purkinje fibers to contract the heart muscle.