Cont. SICILIAN GAMBIT

6. Autonomic control mechanisms

One of the factors that influence arrhythmias is autonomic control.

Receptor systems are linked to their effectors via a complex series of steps. At the simplest level, these may involve "G proteins". These are guanidine triphosphate regulatory proteins that transduce a signal generated by receptor activation. G proteins have three subunits: beta and gamma, which are membrane bound, and alpha, which can, under certain circumstances, become unbound from the beta and gamma subunits. When the agonist binds to the receptor, the alpha subunits is unbound and free to interact with a variety of systems (second messengers, channels and pumps) giving rise to an effector response.

As a result of agonist (in the figure, norepinephrine) binding to the beta-adrenergic receptor, the alpha subunit of the G protein, G_s, transduces a linkage to the second messenger system adenylyl cyclase, which enzyme converts adenosine triphosphate to cyclic adenosine monophosphate. This turns on the enzyme protein kinase A, which, via breakdown of adenosine triphosphate to adenosine diphosphate (ATP to ADP), frees a phosphorus molecule which can phosphorylate the pacemaker channel, I_f, the potassium channel, I_k, as well as the calcium channels.

Phosphorylation of the I_f channel permits it to carry more sodium ions into the cell, thereby enhancing pacemaker rate.

Phosphorylation of the potassium channel carries more potassium out of the cell, accelerating repolarization and thereby decreasing action potential duration.

Phosphorylation of the calcium channel carries calcium into the cell, which would tend to increase pacemaker rate, increase plateau height and enhance contractility.

7. Mechanisms of arrhythmias: automaticity

Automaticity results from spontaneous depolarization during phase 4 of the action potential.

Automaticity occurring at low membrane potentials depends on a balance between inward current carried by calcium and outward currents carried by potassium. An important characteristic of abnormal automaticity is its relative insensitivity to overdrive pacing.

8. Mechanisms of arrhythmias: early afterdepolarization (EAD)

Another mechanism for abnormal impulse initiation is trigger activity based on afterdepolarizations.

Afterdepolarizations are oscillations in membrane potential. They may occur during phase 2 or 3 of the action potential. As opposed to automaticity, which can occur de novo, afterdepolarizations, whether early or delayed, depend on the preceding action potential for their initiation.

Early afterdepolarizations are bradycardia or pause dependent. I_k is an important determinant of depolarization, and, as the channel is blocked, action potentials can be prolonged and EAD can occur.

9. Mechanisms of arrhythmias: delayed afterdepolarization (DAD)

In contrast with EADs, delayed afterdepolarizations are tachycardia dependent. They may occur during phase 4 of the action potential. These oscillations occur following full repolarization and, if they reach threshold, can induce tachycardias.

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