3. Whereas activation of the SNS produces a diffuse physiologic response (mass reflex), activation of the PNS produces more discrete responses. For example, vagal stimulation may produce bradycardia with no effect on intestinal motility.
C. Autonomic Innervation
1. Heart. SNS and PNS innervation of the heart (via the stellate ganglion) influences heart rate (chronotropism), the strength of contraction (inotropism), and coronary blood flow.
a. The PNS cardiac vagal fibers are distributed mainly to the sinoatrial (SA) and atrioventricular (AV) nodes, such that the main effect of cardiac vagal stimulation is chronotropic. Strong vagal stimulation can arrest SA node firing and block impulse conduction to the ventricles.
TABLE 15-1 HOMEOSTATIC BALANCE BETWEEN DIVISIONS OF THE AUTONOMIC NERVOUS SYSTEM
b. The SNS has the same supraventricular distribution as the PNS but with stronger distribution to the ventricles. Normal SNS tone maintains contractility about 20% above that in the absence of SNS stimulation.
2. Peripheral circulation. The SNS is the most important regulator of the peripheral circulation. Basal ANS tone maintains arteriolar diameter at about 50% of maximum, thus permitting the potential for further vasoconstriction or vasodilation. By functioning as a reservoir for about 80% of the blood volume, small changes in venous capacitance produced by SNS-mediated venoconstriction produce large changes in venous return.
II. AUTONOMIC NERVOUS SYSTEM TRANSMISSION
A. Transmission of impulses across the nerve terminal junctional sites (synaptic cleft) of the peripheral ANS occurs through the mediation of liberated chemicals (neurotransmitters). These neurotransmitters interact with a receptor on the end organ to evoke a biologic response.
B. Parasympathetic Nervous System Neurotransmission
1. Acetylcholine (ACh) is the neurotransmitter at preganglionic nerve endings of the SNS and PNS and at postganglionic nerve endings of the PNS.
2. The ability of a receptor to modulate the function of an effector organ depends on rapid recovery to its baseline state after stimulation. ACh removal occurs by rapid hydrolysis by acetylcholinesterase (true cholinesterase). Pseudocholinesterase (plasma cholinesterase) is not physiologically significant in the termination (hydrolysis) of ACh action.
C. Sympathetic Nervous System Neurotransmission
1. Norepinephrine is the neurotransmitter at postganglionic nerve endings of the SNS (except in the sweat glands, where ACh is the neurotransmitter).
a. Adenosine triphosphate (ATP) is released with norepinephrine and thus functions as a co-neurotransmitter.
b. Epinephrine is the principal hormone released by chromaffin cells (which function as postganglionic SNS neurons) into the circulation to function as a neurotransmitter hormone.
2. Catecholamines: The First Messenger
a. Endogenous catecholamines are dopamine (neurotransmitter in the CNS), norepinephrine, and epinephrine. A catecholamine (including synthetic catecholamines) is any compound with a catechol nucleus (benzene ring with two adjacent hydroxyl groups) and an amine-containing side chain (Fig. 15-3).
b. The effects of endogenous or synthetic catecholamines on adrenergic receptors can be indirect (little intrinsic activity but stimulate release of stored neurotransmitter) and direct.
3. Inactivation of catecholamines is by reuptake back into presynaptic nerve terminals by extraneuronal uptake, diffusion, and metabolism.
III. RECEPTORS. Receptors appear to be protein macromolecules on cell membranes, which when activated by an agonist (ACh or norepinephrine) lead to a response by an effector cell. An antagonist is a substance that attaches to the receptor (prevents access of an agonist) but does not elicit a response by the effector cell.
A. Cholinergic receptors are subdivided into muscarinic (postganglionic nerve endings) and nicotinic (autonomic ganglia, neuromuscular junction) receptors. ACh is the neurotransmitter at cholinergic receptors. Atropine is a specific antagonist at muscarinic receptors.
B. Adrenergic receptors are subdivided into α, β, and dopaminergic, with subtypes for each category (Table 15-2).
1. α-Adrenergic Receptors in the Cardiovascular System
a. Coronary arteries. Postsynaptic α2 receptors predominate in the large epicardial conductance vessels. They contribute about 5% to total coronary artery resistance, which is why phenylephrine has little influence on resistance to blood flow in coronary arteries. Postsynaptic α2 receptors predominate in small coronary artery resistance vessels. The density of α2 receptors in the coronary arteries increases in response to myocardial ischemia.
TABLE 15-2 ADRENERGIC RECEPTORS AND ORDER OF POTENCY OF AGONISTS AND ANTAGONISTS
CNS = central nervous system; GI = gastrointestinal.
b. Peripheral Vessels. Presynaptic α2-vascular receptors mediate vasodilation, and postsynaptic α1– and α2-vascular receptors mediate vasoconstriction. Postsynaptic α2-vascular receptors predominate on the venous side of the circulation. Actions attributed to postsynaptic α2 receptors include arterial and venous vasoconstriction, platelet aggregation, inhibition of insulin release, inhibition of bowel motility, and inhibition of antidiuretic hormone release.
2. α Receptors in the Kidneys. The α1 receptors dominate in the renal vasculature (vasoconstriction modulates renal blood flow), and the α2 receptors predominate in the renal tubules, especially the loops of Henle (which stimulate water and sodium excretion).
3. β Receptors in the Cardiovascular System
a. Myocardium. Postsynaptic β1 receptors and presynaptic β2 receptors probably play similar roles in the regulation of heart rate and myocardial contractility. Increased circulating catecholamine levels associated with congestive heart failure result in downregulation of β1 receptors with relative sparing of β2 and α1 receptors. (β2 and α1 receptors increasingly mediate the inotropic response to catecholamines during cardiac failure.)
b. Peripheral Vessels. Postsynaptic vascular β receptors are predominantly β2.
4. b Receptors in the Kidneys. β1 receptors are more prominent than β receptors in the kidneys, and their activation results in renin release.
C. Adrenergic Receptor Numbers and Sensitivity
1. Receptors are dynamically regulated by a variety of conditions (ambient concentrations of catecholamines and drugs and genetic factors), resulting in altered responses to catecholamines and ANS stimulation.
2. Alteration in the number or density of receptors is referred to as upregulation or downregulation. Chronic treatment with clonidine or propranolol results in upregulation and a withdrawal syndrome if the drug is acutely discontinued.
IV. AUTONOMIC NERVOUS SYSTEM REFLEXES AND INTERACTIONS. The ANA has been compared to a computer circuit (sensor, afferent pathway, CNS integration, efferent pathway).
A. Baroreceptors located in the carotid sinus and aortic arch react to alterations in stretch caused by changes in blood pressure (Fig. 15-4). Volatile anesthetics interfere with baroreceptor function; thus, anesthetic-induced decreases in blood pressure may not evoke changes in heart rate. Compliance of stretch receptors and their sensitivity may be altered by carotid sinus atherosclerosis. (Carotid artery disease may be a source of hypertension rather than a result.)
B. Venous baroreceptors located in the right atrium and great veins produce an increased heart rate when the right atrium is stretched by increased filling pressure (Bainbridge reflex). Slowing of the heart rate during spinal anesthesia may reflect activation of venous baroreceptors as a result of decreased venous return.
V. CLINICAL AUTONOMIC NERVOUS SYSTEM PHARMACOLOGY. Drugs that modify ANS activity can be classified by their site of action and the mechanism of action or pathology (antihypertensives) for which they are administered.
A. Cholinergic Drugs. Muscarinic agonists act at sites in the body where ACh is the neurotransmitter.
1. Indirect Cholinomimetics. Anticholinesterases (neostigmine, pyridostigmine, edrophonium) inhibit activity of acetylcholinesterase, which normally destroys ACh by hydrolysis. As a result of this inhibition, ACh accumulates at muscarinic and nicotinic receptors. Simultaneous administration of an anticholinergic drug protects patients against undesired muscarinic effects (bradycardia, salivation, bronchospasm, intestinal hypermotility) without preventing the nicotinic effects of ACh (reversal of nondepolarizing muscle relaxants).
B. Cholinergic Drugs. Muscarinic antagonist refers to a specific drug action for which the term anticholinergic is often used (any drug that interferes with the action of ACh as a transmitter). Anticholinergic drugs (atropine, scopolamine, glycopyrrolate) interfere with the muscarinic actions of ACh by competitive inhibition of cholinergic postganglionic nerves.
1. There are marked variations in sensitivity to anticholinergic drugs at different muscarinic sites.
2. Central anticholinergic syndrome is characterized by symptoms that range from sedation to delirium, presumably reflecting inhibition of muscarinic receptors in the CNS by anticholinergics (this is unlikely with glycopyrrolate, which cannot easily cross the blood–brain barrier). Treatment is with physostigmine. Its tertiary amine structure allows it to cross the blood–brain barrier rapidly; other anticholinesterases are quaternary ammonium compounds that lack the lipid solubility necessary to gain prompt entrance into the CNS.
C. Sympathomimetic Drugs. Catecholamines and sympathomimetic drugs continue to be the pharmacologic mainstay of cardiovascular support for the low-flow state (Table 15-3). It is necessary to become familiar with only a few drugs to manage most clinical situations (Table 15-4). Low-output syndrome is present when an individual has abnormalities of the heart, blood volume, or blood flow distribution. When low-output syndrome is present for more than 1 hour, it usually reflects all three abnormalities.
1. Septic shock is the most common distributive abnormality, and volume repletion is an important initial consideration. Treatment of cardiogenic shock requires multiple autonomic interventions.
TABLE 15-3 DOSES AND PRINCIPAL SITES OF ACTION OF ADRENERGIC AGONISTS
*Dose to treat hypotension.
†Dose to treat cardiac arrest.
IV = intravenous.