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

Control 1 NROSCI/BIOSC 1070 MSNBIO 2070 September 5, 2014

Brain Regions that Participate in Autonomic Control Bottom line: The whole brain plays some role in autonomic regulation

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

The Primary Brain Areas Directly Involved in Regulating Sympathetic and Parasympathetic Outflow Spinal Cord Rostral Medulla Caudal Medulla

General Anatomy of Peripheral Sympathetic Nervous System Exception: Adrenal Gland

General Anatomy of Peripheral Parasympathetic Nervous System

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

Detailed Anatomy of Peripheral Parasympathetic Nervous System

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

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

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)

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

Actions of Norepinephrine and Epinephrine on Targets   and  2 receptors: NE > E   receptors: NE = E   receptors: E > NE

Actions of Norepinephrine and Epinephrine on Targets

Actions of Acetylcholine on Targets

Affinity of Different Subtypes of Nicotinic Receptors for Drugs LocationAgonistsAntagonists Neuromusclar Junction acetylcholine, carbachol, suxamethonium curare, pancuronium, α-conotoxin, α-bungarotoxin Autonomic Ganglia acetylcholine, carbachol, nicotine, epibatidine mecamylamine, α-bungarotoxin, hexamethonium Brainacetylcholine, nicotine, epibatidine α-conotoxin, mecamylamine

Effects of Ligand Binding to Peripheral Adrenergic or Cholinergic Receptors

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  -receptors, as opposed to norepinephrine that has a higher affinity for  - 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.

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.

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

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

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 Guanethidineprevents NE release from nerve terminals

Drugs that Affect Autonomic Neurotransmission Drugs that are agonists or antagonists for particular receptors Clonidine α 2 agonist Isoproterenol β agonist Albuterol β 2 agonist Phenylephrine α 1 agonist Prazosin α 1 antagonist Propranolol β antagonist Metoprolol β 1 antagonist α-Yohimbine (Rauwscoline) α 2 antagonist Nicotine nicotinic receptor agonist Pilocarpine, Metacholine muscarinic receptor agonist Hexamethonium nicotinic receptor antagonist Atropine, Scopolamine muscarinic receptor antagonist

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

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

Once inside the smooth muscle cell, NO activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP). This intracellular messenger activates an ATPase that pumps calcium out of the smooth muscle cell, thereby inhibiting interactions between actin and myosin. Relaxing the smooth muscle within the penis allows vasodilation to occur, producing an erection

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.

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.