CV effects of Cholinergic Agonists and Antagonists Flashcards
What is the effect of Muscarinic Receptor Stimulation on:
• SA node
• Contractility
• Endothelium of Vessels in Heart, Brain, and Viscera
Specify Receptor Type*
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
What is EDRF?
Endothelin-Derived Relaxing Factor (EDRF)
• NO is in this category
How do M2 receptors work when stimulated?
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
What is the effect of M2 receptor stimulation on: • SA node • AV node • Atrium • Ventricle • Smooth Muscle • Peripheral nn.
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
How do M3 receptors work when stimulated?
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
What is the effect of M3 stimulation?
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
What drug acts on a muscarinic receptor?
Atropine** acts to inhibit
What are the 3 general effects of Acetylcholine on the CV system?
- Decreased Heartrate
- Decreased AV node conduction Velocity
- Decreased force of Atrial Cardiac Contraction
- Vasodilation
What effect does Ach have on the SA node specifically.
• explain this effect
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
Where does the majority of Acetylecholine (ACh) activity occur in the heart?
Mostly SA and AV nodes with little effect on other tissues
What effect does down regulation of L-type Ca++ have on the heart?
ACh binding down regulates L-type Ca++ causing…
AV nodal effects:
• Decreased conduction
• Longer Refractory Period
*Heart beats softer and slower
What effect does up reguation of Potassium channels have on heart rate?
Shorter Duration of Action Potential
*Heart doesn’t squeeze as hard
How does ACh have an effect on Norepinephrine Release?
ACh binds (heteroreceptors) and decreases cAMP in neuron
**cAMP is needed for NE release
T or F: muscular vessels receive parasympathetic signaling for them to constrict.
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
What happens if you inject IV ACh into someone?
• Why?
- Vasodilation occurs through NO release from M3 stimulation on ENDOTHELIAL cells
- REFLEX tachycardia then ensues to combat the hypotensive state
What happens if the endothelial layer of of a vessel is damaged and underlying muscle is exposed to ACh?
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
What is the effect of atropine binding to muscarinic receptors?
• Dose-Dependent Variance?
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”)
If atropine causes tachycardia, how does this effect maximal heart rate?
*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.
What is the effect of Atropine on blood vessels?
• Dose dependency?
• Why?
Low Dose:
• NO effect
SUPER high dose:
• Flushing caused by increased rise in body temperature from inhibition of sweating
What is atropine used for?
- Inhibit Temporary Over-activity of Vagal Tone on the Heart
- Blocks effects of parasympathomimetic drugs in the circulation (heroin overdose)
SLIDE 15 of this lecture - lot of stuff left of…see if sweatman goes over it
SLIDE 15 of this lecture - lot of stuff left of…see if sweatman goes over it
Abolishes reflex vagal cardiac slowing of asystole
Happens in: • Inhalation of Irritant Vapors • Stimulation of Carotid Sinus • Pressure on the eyeballs • Peritoneal Stimulation • Injection of contrast dye in catheterization
Facilitates AV conduction
- 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
