CV effects of Cholinergic Agonists and Antagonists

Question 1

What is the effect of Muscarinic Receptor Stimulation on:
• SA node
• Contractility
• Endothelium of Vessels in Heart, Brain, and Viscera

Specify Receptor Type*

Answer 1

SA node:
• Decelerates - M2 receptors

Contractility:
• Decreases - M2 receptors

Endothelium of vessels in Heart, Brain and Viscera:
• Synthesizes and Releases EDRF - M3 and M5 receptors

Question 2

What is EDRF?

Answer 2

Endothelin-Derived Relaxing Factor (EDRF)

• NO is in this category

Question 3

How do M2 receptors work when stimulated?

Answer 3

Couples by Gi/Go:
• Adenylyl cyclase Inhibition —> less cAMP
• Inward K+ channels activated
• Voltage Gated Ca2+ channels (L-type) inhibited

Result:
HYPERpolarization and Inhibition

Overall Inhibitory Effect

Question 4

What is the effect of M2 receptor stimulation on: 
• SA node
• AV node
• Atrium
• Ventricle 
• Smooth Muscle
• Peripheral nn.

Answer 4

PARASYMPATHETIC-TYPE EFFECTS:

Heart:
SA - Slowed spontaneous depolarization
AV - Slowed conduction Velocity
Atrium - Longer Refractory Period, Decreased Contraction
Ventricle - Slight Decrease in Contraction

Viscera:
• Increased Contraction

Peripheral nn:
• Decreased Ganglionic Transmission

Question 5

How do M3 receptors work when stimulated?

Answer 5

Gq/11 pathway:
• PLC stimulated to cleave PIP2 into DAG and IP3
• Ca2+ released from ER
• PKC activated by Ca2+ and activates lots of other paths

Question 6

What is the effect of M3 stimulation?

Answer 6

NO - synthesis and release is increased
sEPSP (slow excitatory post-synaptic potentials)
PLD2 (phospholipase D2) increased
PLA2 (phospholipase A2) increased 
AA (arachidonic acid synthesized)

**OVERALL EFFECT = vasodilation

Question 7

What drug acts on a muscarinic receptor?

Answer 7

Atropine** acts to inhibit

Question 8

What are the 3 general effects of Acetylcholine on the CV system?

Answer 8

• Decreased Heartrate
• Decreased AV node conduction Velocity
• Decreased force of Atrial Cardiac Contraction
• Vasodilation

Question 9

What effect does Ach have on the SA node specifically.

• explain this effect

Answer 9

Reduced Rate of Spontaneous Contraction

Effect:
• Increased Cell K+ by GPCR activation of K+ channel (beta-gamma) => Increased K+ current
• Inhibition of Ca2+ channels (L-type) => decreased Ca2+ intake => decreased Ca2+ current
• Inhibition of If => decreased pacemaker current

**More Negative cell = harder to depolarize

Question 10

Where does the majority of Acetylecholine (ACh) activity occur in the heart?

Answer 10

Mostly SA and AV nodes with little effect on other tissues

Question 11

What effect does down regulation of L-type Ca++ have on the heart?

Answer 11

ACh binding down regulates L-type Ca++ causing…
AV nodal effects:
• Decreased conduction
• Longer Refractory Period

*Heart beats softer and slower

Question 12

What effect does up reguation of Potassium channels have on heart rate?

Answer 12

Shorter Duration of Action Potential

*Heart doesn’t squeeze as hard

Question 13

How does ACh have an effect on Norepinephrine Release?

Answer 13

ACh binds (heteroreceptors) and decreases cAMP in neuron

**cAMP is needed for NE release

Question 14

T or F: muscular vessels receive parasympathetic signaling for them to constrict.

Answer 14

FALSE, the parasympathetic system does NOT act on vasculature

However if you put ACh on vessels they will respond but there are no synapses dumping ACh onto receptors in the body

Question 15

What happens if you inject IV ACh into someone?

• Why?

Answer 15

• Vasodilation occurs through NO release from M3 stimulation on ENDOTHELIAL cells
• REFLEX tachycardia then ensues to combat the hypotensive state

Question 16

What happens if the endothelial layer of of a vessel is damaged and underlying muscle is exposed to ACh?

Answer 16

ACh stimulates SMOOTH MUSCLE contraction so it will cause the SMOOTH MUSCLE of the vessel to contract

This is through DIRECT M3 stimulation to the muscle cell, not through indirect M3 stimulation in endothelium that causes NO production and absorption by muscle

Question 17

What is the effect of atropine binding to muscarinic receptors?
• Dose-Dependent Variance?

Answer 17

Low Dose:
• Binds M1 autoreceptors causing “pre-synaptic blockade”

High Dose:
• M2 receptors on SA node get blocked leading to TACHYCARIDIA in RESTING state- (“vagal tone antagonized”)

Question 18

If atropine causes tachycardia, how does this effect maximal heart rate?

Answer 18

*Atropine increases RESTING heart RATE ONLY - it causes loss of inhibition (vagal tone), not promotion of stimulation

Why?
• MAXIMAL heart rate is controlled by sympathetic stimulation so different receptors will be acted on by catecholamines for Max HR.

Question 19

What is the effect of Atropine on blood vessels?
• Dose dependency?
• Why?

Answer 19

Low Dose:
• NO effect

SUPER high dose:
• Flushing caused by increased rise in body temperature from inhibition of sweating

Question 20

What is atropine used for?

Answer 20

• Inhibit Temporary Over-activity of Vagal Tone on the Heart
• Blocks effects of parasympathomimetic drugs in the circulation (heroin overdose)

Question 21

SLIDE 15 of this lecture - lot of stuff left of…see if sweatman goes over it

Answer 21

SLIDE 15 of this lecture - lot of stuff left of…see if sweatman goes over it

Question 22

Abolishes reflex vagal cardiac slowing of asystole

Answer 22

Happens in: 
• Inhalation of Irritant Vapors
• Stimulation of Carotid Sinus
• Pressure on the eyeballs
• Peritoneal Stimulation
• Injection of contrast dye in catheterization

Question 23

Facilitates AV conduction

Answer 23

• Shortens functional Refractory Period of the AV node
• Improves patients with inferior or posterior wall Myocardial infarction by relieving severe sinus or nodal bradycardia or AV block