Flashcards in Cholinergic Agonists and Antagonists Deck (30)
What does stimulation of the muscarinic M2 receptors in the heart cause?
Decreases neuronal activity in the
sinoatrial (SA) and atrioventricular nodes and decreases contractility in atrial tissue.
What does stimulation of the muscarinic M3 and M5 receptors in the heart cause?
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.
How do M2 muscarinic receptors work?
coupling to end effect occurs
through GI/G0 signaling, with inhibition of adenylate cyclase (AC) and a decrease in cAMP.
What is the net effect of decreasing cAMP?
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
What does hyper polarization cause in the heart?
-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
What does M3 stimulation result in?
through Gq to increase levels of IP3 and diacylglycerol (DAG), with consequent increases in calcium
and protein kinase C
What does increase in Ca2+ and PKC lead to?
depolarization and excitation leading to an increased sEPSP and action potential
What does increased action potential lead to?
- the synthesis and release of NO in vasculature
What is the one cholinergic agent?
What causes ACh release?
- 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
What are the primary effects of ACh on the CV system?
-decreased AV node conduction velocity
-decreased force of atrial cardiac contraction
What happens when ACh is released from ganglion in the heart?
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
What does reduced cAMP cause?
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).
What else does ACh do?
Released ACh also acts on an axonal
muscarinic receptor (autoreceptor) to cause inhibition of ACh release
How does ACh affect the SA node?
decreased HR primarily by decreasing the rate of spontaneous depolarization
How does ACh affect the atria?
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
How does ACh affect the AV node?
decreases conduction and increases the refractory period by inhibiting Ica-L
T or F. In the His-Purkinje and ventricular myocardium, the effects of cholinergic stimulation are smaller than those in atria and nodal tissue
receive direct parasympathetic innervation?
No, but will respond to exogenous muscarinic
What does IV dose of ACh produce?
vasodilation through the dilatory intermediate nitric oxide
What happens if the vasodilation is too large?
reflex tachycardia may ensue
What happens if IV ACh is released into damaged endothelium?
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
What is Atropine?
a muscarinic antagonist
What are the effects of Atropine at low dose?
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)
What are the effects of Atropine at higher dose?
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)
T or F. The direct effects of atropine on the vasculature are minimal
T, given that most vascular
beds lack significant cholinergic innervation and respond only to circulating
What are the effects of Atropine on the vasculature?
counteracts peripheral vasodilation and causes a sharp fall in BP, but the effects are not constant
What can higher doses of Atropine cause?
dilation of cutaneous blood vessels, especially in the blush area (Atropine flush)
What is Atropine flush?
compensatory reaction permitting the radiation of heat to offset the atropine- induced rise in temp that can accompany inhibition of sweating