Cholinergic Agonists and Antagonists

Question 1

What does stimulation of the muscarinic M2 receptors in the heart cause?

Answer 1

Decreases neuronal activity in the

sinoatrial (SA) and atrioventricular nodes and decreases contractility in atrial tissue.

Question 2

What does stimulation of the muscarinic M3 and M5 receptors in the heart cause?

Answer 2

In the vasculature, stimulation of muscarinic M3 and M5 receptors brings about the synthesis and release of endothelin-derived relaxing factor (EDRF), the best
characterized of which is NO; a short-lived vasodilator.

Question 3

How do M2 muscarinic receptors work?

Answer 3

coupling to end effect occurs

through GI/G0 signaling, with inhibition of adenylate cyclase (AC) and a decrease in cAMP.

Question 4

What is the net effect of decreasing cAMP?

Answer 4

The net effect of this is activation of inward potassium channels and
inhibition of voltage-gated calcium channels leading to hyper-polarization and inhibition of neuronal activity

Question 5

What does hyper polarization cause in the heart?

Answer 5

• slowed depolarization and function of the SA node (decreased HR)
• decreased in conduction velocity of the AV node
• increased refractory period of the atrium leading to decreased contraction
• slightly less contraction in the ventricles
• smooth muscle contraction
• inhibition of ganglionic transmission in peripheral nerves

Question 6

What does M3 stimulation result in?

Answer 6

through Gq to increase levels of IP3 and diacylglycerol (DAG), with consequent increases in calcium
and protein kinase C

Question 7

What does increase in Ca2+ and PKC lead to?

Answer 7

depolarization and excitation leading to an increased sEPSP and action potential

Question 8

What does increased action potential lead to?

Answer 8

• the synthesis and release of NO in vasculature

Question 9

What is the one cholinergic agent?

Answer 9

Atropine

Question 10

What causes ACh release?

Answer 10

• ACh itself acting on M2 and M4 auto receptors
• NE acting on a-2A and a-2C receptors
• Adenosine A1, histamine H3, and opioid receptors
• local substances like NO

Question 11

What are the primary effects of ACh on the CV system?

Answer 11

• vasodilation
• decreased HR
• decreased AV node conduction velocity
• decreased force of atrial cardiac contraction

Question 12

What happens when ACh is released from ganglion in the heart?

Answer 12

ACh released from a varicosity of a postganglionic cholinergic axon
interacts with a sinoatrial node cell muscarinic receptor (M2R) linked via Gi/o to K+ channel opening, which causes hyperpolarization, and inhibition of cAMP synthesis

Question 13

What does reduced cAMP cause?

Answer 13

Reduced cAMP shifts the voltage-dependent opening of pacemaker
channels (If) to more negative potentials, and reduces the phosphorylation and
availability of L-type Ca2+ channels (ICa).

Question 14

What else does ACh do?

Answer 14

Released ACh also acts on an axonal
muscarinic receptor (autoreceptor) to cause inhibition of ACh release
(autoinhibition).

Question 15

How does ACh affect the SA node?

Answer 15

decreased HR primarily by decreasing the rate of spontaneous depolarization

Question 16

How does ACh affect the atria?

Answer 16

causes hyper polarization and a slower action potential duration by increasing Ik-ACh and also decreases cAMP formation leading to decreased NE release, decreasing atrial contraction

Question 17

How does ACh affect the AV node?

Answer 17

decreases conduction and increases the refractory period by inhibiting Ica-L

Question 18

T or F. In the His-Purkinje and ventricular myocardium, the effects of cholinergic stimulation are smaller than those in atria and nodal tissue

Answer 18

T

Question 19

Does vasculature

receive direct parasympathetic innervation?

Answer 19

No, but will respond to exogenous muscarinic

agonists/antagonists.

Question 20

What does IV dose of ACh produce?

Answer 20

vasodilation through the dilatory intermediate nitric oxide

Question 21

What happens if the vasodilation is too large?

Answer 21

reflex tachycardia may ensue

Question 22

What happens if IV ACh is released into damaged endothelium?

Answer 22

If a particular
vessel has damage to the endothelial surface, ACh will act directly on
muscarinic M3 receptors in the underlying smooth muscle causing smooth muscle
contraction (vasoconstriction).

Question 23

What is Atropine?

Answer 23

a muscarinic antagonist

Question 24

What are the effects of Atropine at low dose?

Answer 24

inhibition of the presynaptic M1 auto-receptors actually

leads to an increase in parasympathetic activity (and ACh release) and to a slight slowing of the heart rate (4-8 BPM)

Question 25

What are the effects of Atropine at higher dose?

Answer 25

At higher drug doses, blockade of the M2 receptors on the SA nodal pacemaker system leads to progressive tachycardic
effects, i.e., an increase in resting heart rate (maximal HR is unaffected)

Question 26

T or F. The direct effects of atropine on the vasculature are minimal

Answer 26

T, given that most vascular
beds lack significant cholinergic innervation and respond only to circulating
parasympathomimetics.

Question 27

What are the effects of Atropine on the vasculature?

Answer 27

counteracts peripheral vasodilation and causes a sharp fall in BP, but the effects are not constant

Question 28

What can higher doses of Atropine cause?

Answer 28

dilation of cutaneous blood vessels, especially in the blush area (Atropine flush)

Question 29

What is Atropine flush?

Answer 29

compensatory reaction permitting the radiation of heat to offset the atropine- induced rise in temp that can accompany inhibition of sweating

Question 30

What is Atropine used for?

Answer 30

• abolishes reflex vagal cardiac slowing or asystole
• prevents or abolishes bradycardia or systole from para-sympathomimetic drugs from electrical stimulation of the vagus
• facilitates AV conduction