Transcript PowerPoint - Honors Human Physiology

Effects of the Autonomic
Nervous System on the Heart
R Parasympathetic nervous system
‣ Lowers heart rate
R 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
NROSCI/BIOSC 1070
MSNBIO 2070
September 9, 2016
Control 1
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
Rostral Medulla
Spinal Cord
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
8% of fibers
In peripheral
nerves
Paravertebral
Ganglion
Prevertebral
Ganglion
Detailed Anatomy of
Peripheral Sympathetic
Nervous System
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
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
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
 1 and  2 receptors: NE > E
1 receptors: NE = E
2 receptors: E > NE
Actions of Norepinephrine and
Epinephrine on Targets
Actions of Acetylcholine on Targets
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
Brain
acetylcholine,
carbachol, nicotine,
epibatidine
acetylcholine, nicotine,
epibatidine
mecamylamine,
α-bungarotoxin,
hexamethonium
α-conotoxin,
mecamylamine
Effects of Ligand Binding to Peripheral
Adrenergic or Cholinergic Receptors
How does the Sympathetic Nervous System Affect Cardiac
Contraction?
Effects of Ligand Binding to Peripheral
Adrenergic or Cholinergic Receptors
Effects of Ligand Binding to Peripheral
Adrenergic or Cholinergic Receptors
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
Neostigmine
potentiate NE release
inhibits acetylcholinesterase action
Drugs that prevent neurotransmitter release
Reserpine
Guanethidine
prevents synthesis and storage of NE
prevents NE release from nerve terminals
Drugs that Affect Autonomic
Neurotransmission
Drugs that are agonists or antagonists for particular
receptors
Clonidine
Isoproterenol
Albuterol
Phenylephrine
Prazosin
Propranolol
Metoprolol
α-Yohimbine (Rauwscoline)
α2 agonist
β agonist
β2 agonist
α1 agonist
α1 antagonist
β antagonist
β1 antagonist
α2 antagonist
Nicotine
Pilocarpine, Metacholine
Hexamethonium
Atropine, Scopolamine
nicotinic receptor agonist
muscarinic receptor agonist
nicotinic receptor antagonist
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
CIALIS
VIAGRA
®
(tadalafil)
®
(sildenafil citrate)
• These drugs inhibit the enzyme phosphodiesterase 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.
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.