L17. Pharmacology - Pharmacological Regulation of Cardiac Rate & Rhythm

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Questions and Answers

What is the primary intracellular effector of the β-adrenergic receptor signaling cascade?

Cyclic adenosine monophosphate

Adenylyl cyclase

Protein kinase A (correct)

Calmodulin

Which of the following receptors primarily mediates parasympathetic slowing of heart rate?

α1-adrenergic receptors

M2 muscarinic receptors (correct)

σ receptors

β2-adrenergic receptors

Which β-adrenergic receptor subtype is most abundant in the heart?

β1 receptors (correct)

All are equally abundant

β2 receptors

β3 receptors

What effect does sympathetic activation of β-adrenergic receptors have on intracellular cAMP levels?

It increases intracellular cAMP levels. Signup and view all the answers

What is a significant limitation of using nonselective β-adrenergic agonists like isoproterenol?

They have a high likelihood of eliciting adverse effects. Signup and view all the answers

Which statement correctly describes the primary role of sodium channels in cardiac physiology?

Sodium channels initiate the action potential through rapid depolarization. Signup and view all the answers

What is the effect of sympathetic activation on heart rate?

It increases the heart rate through adrenergic stimulation. Signup and view all the answers

Which class of arrhythmias is primarily associated with abnormalities in impulse initiation?

Ectopic rhythms. Signup and view all the answers

Which factor is crucial for the repolarization phase of the cardiac action potential?

Potassium channels opening. Signup and view all the answers

What is the primary function of potassium channel blockers in cardiac pharmacology?

They prolong action potentials by delaying repolarization. Signup and view all the answers

Adrenergic receptors are coupled through which signaling mechanism?

G-protein coupled mechanisms. Signup and view all the answers

Why is understanding ion channels essential in the context of arrhythmias?

They are the targets of pharmacological agents used to restore normal heart rhythm. Signup and view all the answers

Which physiological mechanism is primarily involved in the parasympathetic slowing of heart rate?

Increased potassium efflux leading to hyperpolarization. Signup and view all the answers

What causes inward rectification in potassium channels?

Intracellular magnesium or polyamines blocking the channel Signup and view all the answers

Which Kir channel is critical for maintaining the resting membrane potential in cardiac myocytes?

Kir2.1 Signup and view all the answers

What syndrome is associated with mutations in the KCNJ2 gene encoding Kir2.1?

Andersen-Tawil syndrome (type 1) Signup and view all the answers

What structure allows ions to permeate through the channel when it opens?

Selectivity filter loop Signup and view all the answers

How do Kir3 channels affect heart rate during parasympathetic stimulation?

They increase potassium conductance, slowing the heart rate. Signup and view all the answers

What role do muscarinic receptors of the M2 subtype play in cardiac function?

They reduce heart rate via G protein activation. Signup and view all the answers

Which characteristic is NOT associated with the alpha subunits in the voltage-dependent cation channel superfamily?

Ability to facilitate ion concentration gradients Signup and view all the answers

What effect do muscarinic receptor blockers like atropine have on cardiac function?

They antagonize the slowing of heart rate. Signup and view all the answers

What functional feature do the additional four helices provide in voltage-dependent cation channels?

Voltage sensing Signup and view all the answers

What pharmacological agents can facilitate the action of Kir3 channels?

Cholinesterase inhibitors Signup and view all the answers

Which type of potassium channels is assembled from tetramers of over a dozen subunits?

Kir channels Signup and view all the answers

Which channel's activity primarily determines the IKAch current in the heart?

Kir3 channels Signup and view all the answers

Which statement correctly describes the permeability of potassium ions across the membrane?

Potassium crosses the membrane more readily in the inward direction. Signup and view all the answers

What impact does acetylcholine have on cardiac action potential duration?

It shortens the duration. Signup and view all the answers

What is the overall role of voltage-dependent cation channels in cardiac physiology?

Help establish the cardiac myocytes membrane potential Signup and view all the answers

What physiological process is impaired in patients with Andersen-Tawil syndrome related to cardiac function?

Loss of potassium currents Signup and view all the answers

What pharmacological relevance do voltage-dependent cation channels have?

Important for treating cardiovascular diseases Signup and view all the answers

What is the primary role of HCN channels in the SA node?

Carrying the pacemaker current If Signup and view all the answers

Which mechanism is responsible for the acute termination of reentrant supraventricular arrhythmias?

Intravenous injection of adenosine Signup and view all the answers

How are sodium and calcium channels structured in terms of subunits?

Composed of four concatenated α subunits Signup and view all the answers

What type of G proteins do A1 adenosine receptors couple with?

Gi subtype Signup and view all the answers

What is the significance of the helices in the context of channel gating mechanisms?

Provide a mechanism for voltage sensitivity Signup and view all the answers

Which structural element forms the 'walls' of the voltage-dependent cation channels?

Two transmembrane helices Signup and view all the answers

What is the result of sympathetic activation on HCN channels?

They enhance the chronotropic effect Signup and view all the answers

Which ion influx dominates the action of HCN channels during pacemaker activity?

Sodium Signup and view all the answers

How does adenosine administration briefly affect the heart rhythm?

It induces a brief asystole Signup and view all the answers

What property of HCN channels allows them to play a role in the diastolic depolarization phase?

They activate upon hyperpolarization Signup and view all the answers

Which statement correctly describes the physiological effect of sympathetic signaling on the heart?

It increases both heart rate and contractility. Signup and view all the answers

What best describes the effect of adenosine on reentrant arrhythmias?

Terminates the reentrant circuit briefly Signup and view all the answers

How many different genes encode HCN channels in the human heart?

Four Signup and view all the answers

Study Notes

Ion Channels in Cardiac Physiology

Cardiac physiology is traditionally understood through the lens of action potentials and the underlying ionic currents.
Ion channels are integral membrane proteins that form pores through which ions can permeate the cellular membrane.
These channels can be classified into distinct families each of which is composed of one or more transmembrane helices.
The simplest alpha subunits in this ion channel superfamily are made of two transmembrane helices connected by the selectivity filter loop.
Many alpha subunits in this superfamily are made up of 2+4 helices, the two helices forming the walls of the channel plus 4 additional helices that form a voltage sensor.
These four additional helices form a voltage sensor protein module whose position responds to the electric field across the membrane.

Parasympathetic Slowing of Heart Rate

Kir channels (inwardly rectifying potassium channels) are tetrameric proteins assembled from subunits.
Kir channels are important for establishing the cardiac myocytes membrane potential.
Kir channels exhibit inward rectification, allowing potassium to cross the membrane in the inward direction more readily than in the outward direction.
Kir2.1 channels are important for maintaining a negative membrane potential in cardiac myocites.
Mutations in the Kir2.1 gene can lead to Andersen-Tawil syndrome (type 1), a rare disorder characterized by episodic paralysis, arrhythmias, and developmental abnormalities.
Kir3 channels are the final effector in the signaling mechanism that underlies the ability of acetylcholine to slow the heart during parasympathetic stimulation.
Acetylcholine, released from the vagus nerve, activates muscarinic receptors of the M2 subtype.
M2 receptors couple to G proteins of the Gi subtype, triggering the dissociation of the heterotrimeric G protein.
Released Gβγ subunits activate Kir3 channels, increasing potassium conductance and slowing the heart rate.
IKAch, the potassium current generated by Kir3 channels, contributes to the slowing of the heart rate and shortens the duration of the cardiac action potential in the atria.
Muscarinic receptor blockers, such as atropine or scopolamine, antagonize this mechanism.
Cholinesterase inhibitors, such as physostigmine, facilitate this mechanism.
A1 adenosine receptors, similar to muscarinic M2 receptors, couple to Gi proteins and activate Kir3 channels, offering a therapeutic approach for acute termination of reentrant supraventricular arrhythmias using adenosine.

Sympathetic Acceleration of Heart Rate

The sinoatrial (SA) node, the heart's pacemaker, initiates action potentials that propagate to the atria and the ventricle.
The autonomous firing of SA node cells is supported by the presence of a set of voltage-dependent ion channels, including HCN channels.
HCN channels are cation non-selective channels carrying a current known as If (pacemaker current).
HCN channels are activated upon hyperpolarization, contributing to the slow diastolic depolarization in the SA node.
Sympathetic activation increases heart rate (chronotropic effect) and force of contraction (inotropic effect).
Sympathetic stimulation releases norepinephrine and epinephrine, which activate adrenergic receptors, including α1, α2, and β subtypes.
All β adrenergic receptors couple to Gs, activating adenylate cyclase and leading to a rise in intracellular cAMP.
Increased cAMP activates protein kinase A, which phosphorylates a variety of targets.
The heart primarily expresses β1 and β2 adrenergic receptors, with β1 receptors being more abundant.
β adrenergic receptor activation increases adenylate cyclase activity, leading to a rise in intracellular cAMP, which binds to the cyclic nucleotide binding domain on HCN channel subunits.
This binding causes a rightward shift in the voltage dependence of HCN channels, resulting in a larger inward current and an increase in the slope of diastolic depolarization, leading to a faster heart rate.
Parasympathetic stimulation counteracts this by reducing intracellular cAMP through the activation of M2 receptors and Gi, shifting the voltage dependence of If to the left.
Nonselective β adrenergic agonists, such as isoproterenol (isoprenaline), increase heart rate and force of contraction, offering therapeutic options for increasing cardiac workload.

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Description

Explore the critical role of ion channels in cardiac physiology, focusing on action potentials and ionic currents. This quiz covers various types of ion channels, their structures, and functions including Kir channels and their impact on heart rate regulation.