L17. Pharmacology - Pharmacological Regulation of Cardiac Rate & Rhythm

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.