1. Effects of the Autonomic Nervous System on the Heart
Parasympathetic nervous system
Lowers heart rate
Sympathetic nervous system
Increases heart rate
Increases contractility (force generation by myocardial cells)
Shortens the contraction time for myocardial cells
Shortens the myocardial action potential

3. NROSCI/BIOSC 1070 MSNBIO 2070 September 7, 2018
Control 1

5. Brain Regions that Participate in Autonomic Control

6. Key Players in Autonomic Regulation
Nucleus Tractus Solitarius
Receives all visceral afferents

7. Lateral Reticulospinal Neurons
Key Players
Lateral Reticulospinal Neurons
Regulate Spinal Sympathetic Output
Hence, a cervical spinal lesion results in cessation of spinal autonomic outflow

8. Divisions of Autonomic Nervous System
Sympathetic Nervous System
Parasympathetic Nervous System
Enteric Nervous System

9. General Anatomy of Peripheral Sympathetic Nervous System
Exception: Adrenal Gland

10. Detailed Anatomy of Peripheral Sympathetic Nervous System
8% of fibers
In peripheral
nerves
Paravertebral
Ganglion
Prevertebral
Ganglion

11. Detailed Anatomy of Peripheral Sympathetic Nervous System

12. General Anatomy of Peripheral Parasympathetic Nervous System

13. Detailed Anatomy of Peripheral Parasympathetic Nervous System

14. Parasympathetic Nervous System
Output
Targets
III
Sphincter pupillae (mediates pupillary constriction) and the muscles of the ciliary body (control the shape of the lens)
VII
Salivary glands (except parotid) and the lacrimal and nasal glands IX
Parotid gland X
Most thoracic and abdominal viscera (heart, lungs, esophagus, stomach, small intestine, proximal colon, pancreas, and upper portion of the ureters)
Sacral Spinal Cord
Distal colon, rectum, bladder, lower portion of the ureters, external genitalia

15. Parasympathetic Nervous System
Vagal Preganglionic Neurons

16. Pharmacology of Autonomic Regulation
Exception: sympathetic postganglionic neurons innervating sweat glands, hair follicles, and some blood vessels in some species release ACH

17. Pharmacology of Autonomic Regulation

18. Pharmacology of Autonomic Regulation
Acetylcholine
Synthesized from Acetyl-COA and choline
reaction is catalyzed by choline acetyltransferase
inactivated by the enzyme acetylcholinesterase, as at the neuromuscular junction

19. Pharmacology of Autonomic Regulation

20. Pharmacology of Autonomic Regulation
Inactivation of Norepinephrine released from nerve terminals is through reuptake (rapid)
Inactivation of Epinephrine and Norepinephrine released from the adrenal gland occurs mainly in the liver through the actions of catechol-O-methyl transferase (slow)

21. Actions of Norepinephrine and Epinephrine on Targets
Example of G-Protein Mediated Second Messenger Production

22. Actions of Norepinephrine and Epinephrine on Targets
α1 and α2 receptors: NE > E
β1 receptors: NE = E
β2 receptors: E > NE

23. Actions of Norepinephrine and Epinephrine on Targets

24. Actions of Norepinephrine and Epinephrine on Targets

25. Actions of Acetylcholine on Targets

26. Affinity of Different Subtypes of Nicotinic Receptors for Drugs
Location
Agonists
Antagonists
Neuromusclar
Junction
acetylcholine,
carbachol,
suxamethonium
curare, pancuronium, α-conotoxin,
α-bungarotoxin
Autonomic
Ganglia
acetylcholine, carbachol, nicotine, epibatidine
mecamylamine,
α-bungarotoxin,
hexamethonium
Brain
acetylcholine, nicotine, epibatidine
α-conotoxin, mecamylamine

27. Effects of Ligand Binding to Peripheral Adrenergic or Cholinergic Receptors

28. How does the Sympathetic Nervous System Affect Cardiac Contraction?

32. Effects of Ligand Binding to Peripheral Adrenergic or Cholinergic Receptors

33. Role of the Adrenal Medulla
Typically, 80% of the secretion from the adrenal medulla is epinephrine, and the other 20% is norepinephrine. This fraction can be adjusted by the sympathetic nervous system.
Circulating catecholamines have effects that persist for 5-10X longer than those released from nerve terminals.
Epinephrine binds to β-receptors, as opposed to norepinephrine that has a higher affinity for α- receptors. Thus, epinephrine can elicit effects different from norepinephrine.
Circulating epinephrine affects every cell in the body, and not just those innervated by sympathetic nerve terminals.

34. Regulation of Autonomic Outflow
The activity of sympathetic preganglionic neurons is regulated by several brainstem areas:
The paraventricular nucleus of the hypothalamus
The rostral ventrolateral medulla
The raphe nuclei
The rostral ventromedial medulla
Similarly, a number of brain areas regulate parasympathetic preganglionic neuron firing
Without inputs to sympathetic and parasympathetic preganglionic neurons, there would be no activity in sympathetic and parasympathetic nerves.

35. The Role of Autonomic Regulation
Maintenance of baseline tone
Cannon’s classical view—fight or flight responses:
Increased arterial blood pressure
Increased blood flow to active muscles, concurrent with reduced blood flow to organs (e.g. GI tract) that are not required for muscular activity
Increased rates of cellular metabolism throughout the body
Increased blood glucose concentration
Increased glycolysis in the liver and muscle
Increased muscular strength
Increased rate of blood coagulation.
The modern view of homeostasis

36. “Non-Adrenergic Non-Cholinergic” Neurotransmission in the Autonomic Nervous System

37. Drugs that Affect Autonomic Neurotransmission
Drugs that potentiate transmitter action at synaptic terminals
Ephedrine, Amphetamine potentiate NE release
Neostigmine inhibits acetylcholinesterase action
Drugs that prevent neurotransmitter release
Reserpine prevents synthesis and storage of NE
Guanethidine prevents NE release from nerve terminals

38. Drugs that Affect Autonomic Neurotransmission
Drugs that are agonists or antagonists for particular receptors
Clonidine α2 agonist
Isoproterenol β agonist
Albuterol β2 agonist
Phenylephrine α1 agonist
Prazosin α1 antagonist
Propranolol β antagonist
Metoprolol β1 antagonist
α-Yohimbine (Rauwscoline) α2 antagonist
Nicotine nicotinic receptor agonist
Pilocarpine, Metacholine muscarinic receptor agonist
Hexamethonium nicotinic receptor antagonist
Atropine, Scopolamine muscarinic receptor antagonist

39. Clinical Note: The mechanism of action of Viagra (Levitra, Cialis)

40. Vasodilation in the Penis
For many years, nitrogen-containing molecules (e.g., nitroglycerin) have been know to produce vasodilation in particular vascular beds (heart, penis)
Over the past 2 decades, a gaseous agent (NO, nitric oxide) has been shown to be a signaling molecule in these vascular beds
This molecule is produced by endothelial cells forming the inner wall of blood vessels
The synthesis is controlled by the parasympathetic nervous system
The half-life is only a few seconds, and the agent is toxic

41. Just Say NO
Nitric oxide (NO) is a paracrine factor that induces smooth muscle relaxation. NO production is induced in cells adjacent to smooth muscle cells via a number of mechanisms, including ligand binding to a cell surface receptor.

42. Just Say NO
NO diffuses into adjacent smooth muscle cells and activates the enzyme guanylyl cyclase.
This enzyme catalyzes the dephosphorylation of GTP to cGMP, which serves as a second messenger for many important cellular functions, particularly for eliciting smooth muscle relaxation.

43. Just Say NO
Cyclic GMP induces smooth muscle relaxation by multiple mechanisms including:
Inhibiting Ca2+ entry into the sarcoplasm.
Activating K+ channels, which leads to hyperpolarization and reduced opening of voltage-gated Ca2+ channels.
Increased activation of myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to smooth muscle relaxation.

44. Mechanism of Action of Viagra, Levitra, Cialis
These drugs inhibit the enzyme phospho- diesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.

45. These drugs are fairly selective for PDE5, but there are limited actions on other enzymes. For example, Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina; this cross reactivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.
In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues can produce side effects.

46. Flibanserin: “Female Viagra”
Newly-approved drug to treat “hypoactive sexual desire disorder.”
Not related chemically to Viagra; Flibanserin acts on serotonin and dopamine receptors in the brain
Mixed data on whether Sildenafil and related drugs have efficacy in women.