Introduction

The atrioventricular (AV) node and perinodal area are comprised of at least three electrophysiologically distinct cells.^1,2 They are the atrionodal (AN), the nodal (N), and the nodal-His (NH) cells. These electrophysiological cell types appear to be located in the atrial transitional, midnodal (compact node, or upper node in rabbit) and posterior or low nodal extension zones, respectively, of the AV node as described morphologically.^1-3 These specialized tissues are the only normal electrical connection between the atria and the ventricles. The AV node may serve as a subsidiary pacemaker, but its primary function is to limit the number of impulses conducted from the atria to the ventricles. This function of the AV node is particularly important during fast atrial rates (e.g. atrial flutter or fibrillation) when only a fraction of impulses are conducted to the ventricles, whereas the remainder are blocked (concealed) in the AV node. The pharmacological modulation of this electrical impulse filtering function of the AV node is the focus of this mini review.

Small ovoid N cells in the compact AV node adjacent to the penetrating bundle of His appear to be responsible for the major part of AV conduction delay.^2-5 These cells are characterized by a "low" (less negative) resting membrane potential and action potential amplitude, slow rates of depolarization and repolarization (Figure 1), few intercellular connections such as gap junctions, and reduced excitability compared to surrounding cells.^2,5 Sodium channel density is lower in the midnodal zone of the AV node than in the transitional cell and lower nodal cell zones.⁶ An inward calcium channel current (I_Ca,L) is the basis of the upstroke of the N cell action potential.^2,5,7,8 AN, transitional atrial fibers, and NH cells have "higher" (high negative) resting potentials that are intermediate between those of N cells and either atrial or His bundle cells, respectively. The upstroke of the action potential in these cells depends mainly on a sodium inward current. Because the sodium current is larger and has more rapid kinetics than the calcium channel current of N cells, conduction is faster through atrial transitional and NH regions than through the compact AV node. "Fast pathway" conduction through the AV node apparently bypasses many of the N cells by use of transitional cells, whereas "slow pathway" conduction traverses the entire compact AV node.³ Importantly, the recovery of excitability after conduction of an impulse is faster for the slow pathway than for the fast pathway,⁹ for reasons that are not clear.

Neurotransmitters, autocoids, and drugs modulate the conduction of electrical impulses through the AV node (Figure 2) by altering the electrophysiological properties of AV nodal cells. Both the nodal cell ion channels and the receptors that regulate their activity are potential targets of neurotransmitters and drugs (see Table 1). The electrophysiological properties of N cells are a function of the presence and activity of various cell membrane ion channels.¹⁰ It should be noted that electrophysiological studies to define the presence and functions of ion channels in human AV nodal cells have not been done. Current understanding of AV nodal cell electrophysiology is based primarily on results of studies of rabbit isolated AV nodal cells. It is clear, however, that the electrophysiology of the rabbit AV node differs from that of the dog and guinea pig AV nodes, and undoubtedly from the human as well. However, the activity of AV nodal cell ion channels is regulated by the sympathetic and parasympathetic neurotransmitters acetylcholine and norepinephrine in all hearts studied. The AV node is densely innervated by sympathetic and parasympathetic nerve fibers.^1,11,12 Nerve fibers are much less numerous in the compact node than in the surrounding transitional tissue1, but stimulation of autonomic nerves dramatically alters the action potentials of both N cells and transitional cells.² AV nodal cells have ©¬-adrenergic and M₂-muscarinic cholinergic surface membrane receptors for catecholamines and acetylcholine, respectively.¹³ These receptors are coupled to specific G proteins and signal-transduction pathways. AV nodal cells also have surface receptors for adenosine¹⁴ and very probably for many other endogenous compounds. The small size of the node, however, has precluded receptor quantification by radioligand binding.

The activity of calcium channels in AV nodal N cells is of fundamental importance for impulse conduction. Electrical impulses arriving at the AV node from atrial pathways depolarize nodal cells and thereby activate L-type calcium channels. The magnitude of the increase of inward calcium current (I_Ca,L) determines the velocity of depolarization during the upstroke of an action potential in N cells, and thus the velocity of AV nodal conduction. Catecholamines increase the magnitude of I_Ca,L by a pathway that includes activation of ©¬-adrenergic receptors, increases of adenylyl cyclase activity and cAMP, activation of protein kinase A, and channel phosphorylation.^15,16 Activation of the sympathetic nervous system and administration of ©¬-adrenergic receptor agonists increase I_Ca,L in N cells and have a positive dromotropic effect (increase conduction velocity) in the AV node.^17,18 In contrast, ©¬-blockers, acetylcholine, adenosine, and blockers of I_Ca,L (e.g., verapamil, diltiazem) reduce the amplitude of the N cell action potential and have a negative dromotropic effect (decrease conduction velocity). The inward sodium current, which is responsible for the rapid upstroke of the action potential in atrial and ventricular myocytes, is small in N cells.⁵ Reduction of this current by class I antiarrhythmic drugs has little effect on N cells, but decreases conduction in perinodal and extranodal cardiac conduction pathways with sodium channel-dependent action potentials. A small pacemaking current (I_f) may be at least partly responsible for the slow pacemaking activity of N cells.⁵ Pacemaking activity of N cells is increased by catecholamines and high concentrations of digitalis, and decreased by ©¬-adrenergic receptor antagonists, acetylcholine, adenosine, and calcium channel blockers. External acidosis reduces I_Ca,L,¹⁹ and thus decreases both pacemaking and AV nodal conduction.

Potassium currents regulate repolarization, excitability, and refractoriness of AV nodal cells. Efflux of potassium through the delayed rectifier I_Kr channel appears to be an important mechanism of repolarization of the action potential in rabbit nodal cells.²⁰ In dog, however, blockers of I_Kr prolong AV nodal conduction only slightly at doses that cause a significant decrease of the sinus rate.²¹ The effect of catecholamines on I_Kr is contested, ²² and may be species- and/or tissue-specific. The contribution of the delayed-rectifier potassium current I_Ks to repolarization and refractoriness of AV nodal cells also depends on species. It appears that I_Ks is present in guinea pig AV nodal cells but not in rabbit cells. Catecholamines are known to shift the relationship between voltage and activation of I_Ks in ventricular myocytes. Further study is needed to clarify the roles and regulation of the delayed rectifier currents I_Kr and I_Ks in AV nodal cells. The excitability of AV nodal cells can be markedly decreased by acetylcholine and adenosine, which increase the potassium current, I_K,Ach,Ado.^23,24 Activation of this current leads to hyperpolarization of the nodal cell membrane, reduction of excitability, increased refractoriness, and AV conduction slowing and/or complete AV block. Atropine, a muscarinic cholinergic receptor antagonist, and methylxanthines (e.g., the adenosine receptor antagonists, theophylline and caffeine) antagonize the negative dromotropic effects of acetylcholine and adenosine, respectively. A transient outward potassium current (I_to) is present in rabbit but not guinea pig AV nodal cells; its role in human nodal cells has not been determined.

Drugs acting on AV nodal cell ion channels

Calcium-channel blockers bind to the ¥á₁ subunit of the L-type calcium channel and decrease I_Ca.L.25 They reduce the rate of rise of the action potential in "slow response" tissues, such as the SA and AV nodes, where the fast sodium current is reduced or absent. Verapamil and diltiazem delay recovery of the calcium channel from the inactivated to the resting (and excitable) state, and thereby increase postrepolarization refractoriness of calcium channels in N cells.²⁵ The result is a slowing of AV nodal conduction. High concentrations of either drug may cause AV block. Effective and functional refractory periods for AV nodal conduction are increased in both antegrade and retrograde directions. The effect of verapamil, and to a lesser extent that of diltiazem, on recovery of excitability of the calcium channel is enhanced as the frequency of stimulation of the AV node increases.²⁶ Therefore, at high heart rates, the slowing of AV nodal conduction caused by verapamil and diltiazem is more prominent. Neither drug slows conduction through fast-conducting, sodium channel dependent, accessory A-V pathways. Verapamil is often used for acute termination of supraventricular tachycardias, when its effects to cause hypotension and reduced ventricular contractility can be tolerated. Hypotension causes a reflex increase of sympathetic nerve activity that acts to increase heart rate and AV nodal conduction, thus opposing the direct negative chronotropic and dromotropic effects of the calcium channel antagonist. The concomitant use of verapamil, ©¬-blockers and/or digoxin, all of which cause AV conduction slowing, is associated with an increased risk of AV block.^27,28 The dihydropyridine calcium channel blockers (nifedipine, nicardipine, amlodipine, etc.), which do not delay the recovery of the calcium channel from the inactivated to the resting state, have a minimal effect on AV nodal conduction at doses that cause therapeutic arterial vasodilation.

The class I antiarrhythmic drugs act as use-dependent blockers of the cardiac sodium channel (for a review, see [29]). They slow conduction and increase the refractory period in atrial and ventricular myocardium, including the His-Purkinje conduction system and AV accessory pathways. They have little direct effect on AV nodal N cells, which have few sodium channels. However, by virtue of actions on other ion channels and receptors, these drugs may alter AV nodal conduction. The type 1A drugs quinidine, procainamide, and disopyramide block the delayed rectifier potassium channel, I_Kr, and prolong the Q-T interval. In addition, disopyramide and quinidine have vagolytic activity, which may lead to a reduction of the degree of AV block during atrial tachycardia. Digitalis can be administered prior to quinidine to control the ventricular response. Propafenone is a moderately effective antagonist of ©¬-adrenergic receptors³⁰ and is commonly observed to cause a slowing of AV nodal conduction. Quinidine is indicated for treatment of supraventricular tachycardias. It is also used to increase the refractoriness of, and block conduction in, sodium-channel dependent AV accessory pathways, as in Wolff-Parkinson-White syndrome.

Theclass III antiarrhythmic drugs (e.g., dofetilide, ibutilide, amiodarone, bretylium) increase the duration of the action potential, and the effective refractory period, of atrial and ventricular myocytes (for a review, see [31]). The mechanism of action is to decrease the delayed rectifier potassium currents (e.g., I_Kr or I_Ks) during repolarization of the action potential. Roles for I_Kr and I_Ks in AV nodal cells are still being elucidated.^{20, 32-34} Inhibition of either I_Kr or I_Ks appears to have greater effects to decrease heart rate and to prolong the ventricular action potential than to decrease atrioventricular nodal conduction.^35,36 However, the class III drugs bretylium and amiodarone affect AV nodal conduction independently of I_K. Bretylium increases release and prevents reuptake of norepinephrine by nerve terminals, and therefore acutely potentiates but chronically attenuates regulation of AV nodal conduction by the sympathetic nervous system. Amiodarone reduces the activity of L-type calcium channels and is an antagonist of ©¬-adrenergic receptors. These actions of amiodarone cause a slowing of AV nodal conduction, and prolong AV nodal refractoriness. A slowing of AV nodal conduction and ventricular rate may increase the effects of the reverse rate-dependent pure class III agents (e.g., d-sotalol, dofetilide) to cause prolongation of the action potential durations of ventricular myocytes, and to cause torsades de pointes.

Drugs acting on AV nodal cell G protein-coupled receptors

Ligands of ©¬-adrenergic receptors markedly alter AV nodal conduction. ©¬-adrenergic receptors are found in all regions of the heart. Approximately two-thirds of ©¬-adrenergic receptors in the heart are of the ©¬1 subtype, and the rest are of the ©¬2 subtype.¹² The endogenous sympathetic neurotransmitter norepinephrine is a relatively selective agonist of the ©¬1 adrenergic receptor. Activation of sympathetic nerves accompanies heart failure, exercise, the "fight or flight" response, and a decrease of blood pressure. Nicotine and caffeine cause acute sympathetic nervous stimulation. Cocaine inhibits re-uptake by nerve terminals of released norepinephrine and thereby enhances its action. Regardless of mechanism, increased stimulation of AV nodal cell ©¬-adrenergic receptors causes increases of L-type calcium current, I_f, I_Kr, and adenylyl cyclase activity.³⁷ These actions lead to increases of pacemaking, excitability, action potential amplitude, and conduction velocity, and a decrease of the effective refractory period of AV nodal cells. As a result, the AV node is capable of conducting more impulses per unit time in the presence than in the absence of ©¬-adrenergic stimulation (Figure 2).³⁸ Both antegrade slow conduction and retrograde fast conduction through the AV node are increased.

Both selective (e.g., atenolol, bisoprolol, esmolol, metoprolol) and nonselective (e.g., propranolol, carvedilol, labetalol) antagonists of the ©¬1-adrenergic receptor slow AV nodal conduction and increase AV nodal refractoriness.^38,39 Wenckebach block may be caused by ©¬1-receptor antagonists. On the other hand, heart rate slowing caused by a ©¬-blocker leads to a reduction of AV nodal refractoriness and conduction time that counters the direct effect of the drug to prolong conduction time. AV nodal conduction slowing caused by digitalis, adenosine, and calcium channel blockers is augmented by concomitant administration of a ©¬-blocker. Thus, the use of digitalis followed by propranolol to control the ventricular rate during atrial fibrillation or flutter has the advantage of achieving therapy with lower than normal doses of each drug.⁴⁰

Adenosine is used clinically to diagnose and terminate acute episodes of paroxysmal supraventricular tachycardia (PSVT).^41,42 It is an endogenous metabolite of ATP. The A₁ subtype of adenosine receptor mediates the actions of adenosine on AV nodal cells.¹⁴ A₁-adenosine receptors are present in higher density in atrial and nodal tissues than in ventricular myocardium. Adenosine has a greater effect to slow AV nodal conduction than to decrease heart rate (in contrast to acetylcholine). Adenosine concentrations are increased in hypoxic tissue, and hypoxia-induced AV nodal conduction delay and block are mediated by adenosine.^43,44 The activated A₁-adenosine receptor stimulates inhibitory G proteins; G protein alpha subunits cause inhibition of adenylyl cyclase activity, whereas G protein ©¬¥ã subunits act to increase the potassium current, I_K,Ach,Ado. ^24,45,46 Adenosine attenuates catecholamine-induced adenylyl cyclase-mediated responses (including stimulation of I_Ca,L and I_f) and reduces the rate of rise, amplitude, and duration of AV nodal N cell action potentials (Figure 3).⁴⁷ Adenosine is also reported to increase the delayed-rectifier potassium current I_Ks in the AV node.⁴⁸ The effect of adenosine to increase I_Ks is rate-dependent.⁴⁸ Functionally, adenosine reduces the excitability and increases the effective refractory period of AV nodal cells.⁴⁷ Because the effective refractory period of AV nodal cells also increases as a function of atrial rate, the negative dromotropic effect of adenosine is greater at high than at low heart rates (Figure 2).⁴⁹ The frequency dependence of adenosine's effect to prolong AV nodal conduction time is reported to be more pronounced than that of verapamil.⁵⁰ Hyperkalemia enhances the effect of adenosine to increase I_K,Ach,Ado in AV nodal myocytes and augments the depressant effect of adenosine on AV nodal conduction.⁵¹ In patients with AV nodal re-entrant tachycardia, the doses of adenosine reported to depress conduction through the antegrade fast, antegrade slow, and rerograde fast conduction pathways were 1.4, 4.2, and 8.5 mg, respectively.⁵² The dose of adenosine required to prolong AV nodal conduction time is decreased in patients being treated with verapamil. Because adenosine is quickly metabolized in blood, it must be given as a rapid i.v. bolus infusion.

Adenosine is inherently safer than either verapamil or the soon-to-be-available synthetic adenosine analogues because of the brevity of its effect. However, adenosine is not selective for the A₁ receptor. Activation by adenosine of A_2A-receptors causes coronary vasodilatation. Infusion of adenosine to the systemic circulation causes activation of arterial endothelial A_2A- and A_2B-adenosine receptors that lead to systemic vasodilatation and a drop of blood pressure.⁵³ The effects of adenosine to decrease cardiac output and vascular resistance are countered by a reflex activation of the sympathetic nervous system, and elevation of heart rate. Selective agonists of the A₁-adenosine receptor do not cause vasodilatation and are less likely to trigger sympathetic activation. The selective A₁-receptor agonist CVT-510 is effective in terminating PSVT at doses that do not reduce blood pressure or alter sinus rate.^54,55 Adenosine increases airway resistance and its use is contraindicated in asthmatic patients. Because this latter effect of adenosine appears to be mediated by the A_2B receptor, selective A₁ receptor agonists may not increase airway resistance. Adenosine and A₁-adenosine receptor agonists decrease the duration of the refractory period of atrial myocardial cells and therefore facilitate rapid atrial conduction. A role for A₃-adenosine receptors in the human heart has yet to be demonstrated.

Dipyridamole potentiates, whereastheophylline (aminophylline), caffeine, and other A₁-adenosine receptor blockers antagonize the actions of adenosine and may increase AV nodal conduction. The direct effects of theophylline and caffeine on cardiac adenosine receptors, however, may be confounded by central effects of the drugs to stimulate the activity of the sympathetic nervous system. Antagonists of the A₁-adenosine receptor cause diuresis but do not decrease renal perfusion, and may be available for clinical use as diuretics in the near future. Treatment of PSVT in patients taking adenosine receptor blockers may require higher than normal doses of adenosine. The negative dromotropic effect of intravenously-administered ATP is mediated in great part by adenosine,¹⁴ as ATP is rapidly metabolized to adenosine in blood. ATP has additional actions not mediated by adenosine, through its binding to P2-purinergic receptors present on nerve cells and many other cells.⁵⁶

Parasympathetic nerve terminals, acetylcholinesterase, and receptors for acetylcholine are abundant in AV nodal tissue.^{1,11,12,57,58} M₂-muscarinic cholinergic receptors mediate most of the cardiac effects of the neurotransmitter acetylcholine.^57,59 Activation of these receptors by acetylcholine reduces the excitability and increases the refractoriness of N cells, and slows AV nodal conduction (Figure 2). The signaling pathways utilized by the M₂-muscarinic cholinergic receptor and the A₁-adenosine receptor in N cells are similar: an increase of I_K,Ach,Ado, inhibition of I_f, and inhibition of adenylyl cyclase activity.⁵⁸ A role for nitric oxide as mediator of the negative chronotropic and dromotropic actions of acetylcholine is supported by several studies.⁶⁰ Physical maneuvers to activate the parasympathetic nervous system (e.g., carotid sinus massage, Valsalva) cause acute slowing of AV nodal conduction. Many classes of drugs act directly or indirectly on muscarinic receptors. Vagotonic drugs such as propofol, digitalis, and morphine increase activity of the parasympathetic nervous system and cause AV conduction delay. Inhibitors of acetylcholinesterase (e.g., edrophonium, physostigmine, and nerve gases) decrease the rate of degradation of acetylcholine and amplify the effects of parasympathetic nervous activity to reduce both sinus rate and AV conduction. Muscarinic receptor antagonists (e.g., atropine) blunt the effects of parasympathetic nervous activity and increase both AV nodal conduction velocity and the fraction of atrial impulses conducted from the atria to the ventricles. Vagolytic actions of disopyramide and quinidine oppose the direct effects of these drugs to slow AV nodal conduction and may lead to a paradoxical reduction of the degree of AV block during atrial fibrillation or flutter. In contrast, the effect of quinidine to slow AV nodal conduction is increased in the presence of a ©¬-adrenergic receptor antagonist. Muscarinic cholinergic agonists are not used in clinical practice to slow heart rate, although high heart rates are known to be associated with poor outcomes in many cardiovascular disease states, and exercise-induced increases of vagal tone are beneficial. Safe, cardioselective M₂-muscarinic receptor agonists have not yet been developed. A weak agonist of the M₂-muscarinic receptor that effectively reduces "resting" heart rate with minimal slowing of AV nodal conduction may be useful.

Digitalis glycosides (e.g., digoxin, digitoxin) have long been used to control the ventricular rate in patients with chronic atrial fibrillation.⁶¹ Adenosine and/or verapamil are preferred to achieve a rapid or brief reduction of ventricular rate. Digitalis both slows AV conduction and prolongs the effective refractory period of the AV node, and thereby decreases the fraction of atrial impulses that are conducted through the node. These actions of digitalis on the AV node are primarily the result of its effect to increase vagal tone and release of acetylcholine from parasympathetic nerve terminals in the AV node. Sympathetic tone, on the other hand, is decreased by digitalis. The effect of digitalis on AV conduction is much reduced in patients that have a denervated heart.⁶² The vagotonic effect of digitalis occurs with a more rapid onset, and at a lower dose, than the inotropic effect.⁴⁰ The depressant effect of digitalis on AV nodal conduction is increased by hypokalemia and by concomitant administration of either a calcium-channel antagonist or a ©¬-blocker. Conversely, the effect of digitalis is reduced when sympathetic activity is elevated (e.g., exercise, heart failure). Combinations of digitalis with either a calcium-channel antagonist (verapamil, diltiazem) or a ©¬-blocker are especially effective to slow AV nodal conduction.⁴⁰ These combinations are preferable to monotherapy and may be particularly useful when sympathetic activity is chronically or repeatedly elevated. Digoxin may shorten the effective refractory period of atrial accessory pathways. Like acetylcholine and adenosine, digoxin reduces action potential duration in atrial myocytes and should not be used in patients in whom AV conduction through an accessory pathway has been documented. AV block, junctional automaticity, and ventricular extrasystoles are symptoms of digitalis toxicity. Interactions of digitalis with other drugs are many and necessitate frequent patient monitoring and review of medications.

In summary, pharmacological modulation of AV nodal transmission for therapeutic purposes such as ventricular rate control in patients with atrial fibrillation is an important component of everyday medical practice, and is based on well-established non-clinical and clinical data.

Figures (click on images for legends and to enlarge)

Figure 1.

Figure 2.

Figure 3.

Table

Effects of antiarrhythmic agents and neurotransmitters on the AV nodal "N" cell action potential, AV nodal conduction velocity, and the P-R interval.

Acknowledgements

We thank Erica Denison, for preparing the graphics of the figures for the manuscript.