Atrioventricular Nodal Conduction Time Research Articles

Antagonism of the Positive Dromotropic Effect of Isoproterenol by Adenosine: Role of Nitric Oxide, cGMP-dependent cAMP-phosphodiesterase and Protein Kinase G

A. Zima, A. E. Martynyuk, C. N. Seubert, T. E. Morey, C. Sumners, R. F. Cucchiara and D. M. Dennis. Antagonism of the Positive Dromotropic Effect of Isoproterenol by Adenosine: Role of Nitric Oxide, cGMP-dependent cAMP-phosphodiesterase and Protein Kinase G. Journal of Molecular and Cellular Cardiology (2000) 32, 1609–1619. We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A–H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 μ m), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 μ m). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A–H interval shortening were studied. Adenosine (3 μ m) inhibited isoproterenol-stimulated (0.1 μ m) ICa,L(β -ICa,L) by 46±6% (P<0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 μ m) and L-NNA (500 μ m) attenuated the effect of adenosine onβ -ICa,Lby 69±8% (P<0.001, n=16) and 69±7% (P<0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 μ m) reduced the inhibitory effect of adenosine on β -ICa,Lby 97±6% (P=0.004,n =15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 μ m) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 μ m) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 μ m) diminished β -ICa,L, but to a significantly smaller degree (16±4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.

ROLE OF GAP JUNCTION RESISTANCE IN RATE-INDUCED DELAY IN CONDUCTION IN A CABLE MODEL OF THE ATRIOVENTRICULAR NODE

A constant fast heart rate results in a time and rate dependent increase in AV nodal conduction time. The origin of this delay in conduction remains unknown due to limited access to corresponding cellular events. We have investigated the possible contribution of gap junction resistance in rate-induced delay in conduction using a one-dimensional model of the AV node. We use a cable that includes 100 cells: 30 AN cells, 40 N cells and 30 NH cells. The three cell types are modeled by varying the parameters of a modified Beeler Reuter ionic model. N cells have a low density of sodium current and are mainly activated by an ICa,L type current. Their resting potential is less negative and their upstroke slower than those of AN and NH cells. Cells are connected by gap junctions whose resistance is controlled by the intracellular calcium concentration. Stimuli are applied to the first AN cells. At a pacing rate of 400 ms, the gap junction resistance was AN 1.8 MΩ, N 32.0 MΩ and NH 3.6 MΩ and the total conduction time was 48 ms. Following a sudden decrease of cycle length from 400 ms to 250 ms, the conduction time progressively increased and reached a new steady-state of 77.7 ms after 800 beats. This increase of conduction time was mainly caused by a gradual increase of the gap junction resistance between N cells, which reached 46 MΩ at steady state. Rate and time dependent increase of conduction time was abolished when the gap junction resistances were kept constant. This model study suggests that the dynamic changes in gap junction resistance may play a key role in rate-induced AV nodal conduction delay.

Modulation of AV nodal and Hisian conduction by changes in extracellular space.

Previous studies have demonstrated that the extracellular space (ECS) component of the atrioventricular (AV) node and His bundle region is larger than the ECS in adjacent contractile myocardium. The potential physiological significance of this observation was examined in a canine blood-perfused AV nodal preparation. Mannitol, an ECS osmotic expander, was infused directly into either the AV node or His bundle region. This resulted in a significant dose-dependent increase in the AV nodal or His-ventricular conduction time and in the AV nodal effective refractory period. Mannitol infusion eventually resulted in Wenckebach block (n = 6), which reversed with mannitol washout. The ratio of AV nodal to left ventricular ECS in tissue frozen immediately on the development of heart block (n = 8) was significantly higher in the region of block (4.53 +/- 0.61) compared with that in control preparations (2.23 +/- 0.35, n = 6, P < 0.01) and donor dog hearts (2.45 +/- 0.18, n = 11, P < 0.01) not exposed to mannitol. With lower mannitol rates (10% of total blood flow), AV nodal conduction times increased by 5-10% and the AV node became supersensitive to adenosine, acetylcholine, and carbachol, but not to norepinephrine. We conclude that mannitol-induced changes in AV node and His bundle ECS markedly alter conduction system electrophysiology and the sensitivity of conductive tissues to purinergic and cholinergic agonists.

Effects of volatile anesthetics on atrial and AV nodal electrophysiological properties in guinea pig isolated perfused heart.

Knowledge of the anesthetic effects on atrial and atrioventricular (AV) nodal electrophysiologic properties is fundamental to understand the modulatory role of anesthetics on the pathogenesis of supraventricular tachycardias, and to individualize the perioperative management of patients with supraventricular tachycardias or AV nodal conduction disturbances. Therefore the authors studied the effects of three commonly used volatile anesthetics on the electrophysiologic properties of the atrium and AV node. The concentration-dependent electrophysiologic effects of halothane, isoflurane, and desflurane (0-2 minimum alveolar concentration [MAC]) were studied in guinea pig Langendorff-perfused hearts fit with instruments to simultaneously measure atrial and AV nodal conduction times and atrial monophasic action potential duration. Atrial and AV nodal effective refractory periods were measured simultaneously using a computer-assisted premature stimulation protocol. The concentrations of anesthetics in the gas phase were monitored by an infrared gas analyzer. Volatile anesthetics caused markedly different concentration-dependent effects on atrial conduction, repolarization, and refractoriness, and on AV nodal function. At equianesthetic concentrations, halothane depressed atrial conduction the most, whereas desflurane caused the greatest shortening of atrial monophasic action potential duration. Halothane had no significant effect on atrial refractoriness, whereas at 2 MAC desflurane significantly shortened and isoflurane significantly prolonged atrial effective refractory periods by 18.1+/-13.5% and 13.2+/-14.7%, respectively. On an equi-MAC basis, the rank order of potency for the anesthetics to prolong AV nodal conduction time and AV nodal ERP was halothane > desflurane > isoflurane. The different electrophysiologic effects of volatile anesthetics in the atrium and AV node suggest that these agents may modulate atrial dysrhythmogenesis in distinctly different ways.

Magnesium and cardiovascular disease.

Magnesium and cardiovascular disease.

Spatial distribution of nerve processes and beta-adrenoreceptors in the rat atrioventricular node.

Atrioventricular (AV) nodal conduction time is known to be modulated by the autonomic nervous system. The presence of numerous parasympathetic and sympathetic nerve fibres in association with conduction tissue in the heart is well authenticated. In this study, confocal microscopy was used to image the distribution of antibodies directed against the general neuronal marker PGP 9.5, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and beta1 and beta2-adrenoreceptors. Serial 12 microm sections of fresh frozen tissue taken from the frontal plane of the rat atrioventricular node, His bundle and bundle branches were processed for histology, acetylcholinesterase (AChE) activity and immunohistochemistry. It was found that the AV and ventricular conduction systems were more densely innervated than the atrial and ventricular myocardium as revealed by PGP 9.5 immunoreactivity. Furthermore, the transitional cell region was more densely innervated than the midnodal cell region, while spatial distribution of total innervation was uniform throughout all AV nodal regions. AChE-reactive nerve processes were found throughout the AV and ventricular conduction systems, the spatial distribution of which was nonuniform exhibiting a paucity of AChE-reactive nerve processes in the central midnodal cell region and a preponderance in the circumferential transitional cell region. TH-immunoreactivity was uniformly distributed throughout the AV and ventricular conduction systems including the central midnodal and circumferential transitional cell regions. Beta1-adrenoreceptors were found throughout the AV and ventricular conduction systems with a preponderance in the circumferential transitional cell region. Beta2-adrenoreceptors were localised predominantly in AV and ventricular conduction systems with a paucity of expression in the circumferential transitional cell region. These results demonstrate that the overall uniform distribution of total nerve processes is comprised of nonuniformly distributed subpopulations of parasympathetic and sympathetic nerve processes. The observation that the midnodal cell region exhibits a differential spatial pattern of parasympathetic and sympathetic innervation suggests multiple sites for modulation of impulse conduction within this region. Moreover, the localisation of beta2-ARs in the AV conduction system, with an absence of expression in the circumferential transitional cell layer, suggests that subtype-specific pharmacological agents may have distinct effects upon AV nodal conduction.

Relation of the atrial input sites to the dual atrioventricular nodal pathways: crossing of conduction curves generated with posterior and anterior pacing.

The usually accepted definition of the dual pathway electrophysiology requires the presence of conduction curves with a discontinuity ("jump"). However, AV nodal reentrant tachycardia has been observed in patients with "smooth" conduction curves, whereas discontinuity of the conduction curve does not guarantee induction of stable reentry. We hypothesize that the duality of AV nodal conduction can be revealed by careful choice of stimulation sites during the generation of AV nodal conduction curves. In 21 rabbit heart atrial-AV nodal preparations, programmed electrical stimulation with S1-S2-S3 pacing protocol was applied either posteriorly at the crista terminalis input site (CrT) or anteriorly at the lower interatrial septum input site (IAS), or (in 8 preparations with surgically divided input sites) at both. We found that in intact preparations with "smooth" conduction curves, pacing at long coupling intervals produced shorter AV nodal conduction times from the IAS (56 +/- 9.8 msec vs 69 +/- 10.1 msec; P < 0.01). At short coupling intervals, in contrast, shorter conduction times were obtained from the CrT (173 +/- 21.8 msec vs 188 +/- 22.8 msec; P < 0.01). This resulted in a characteristic crossing of the superimposed IAS and CrT conduction curves. After division of the inputs, the IAS site had rapid conduction to the His bundle but a longer refractory period, whereas the CrT site had long conduction times and shorter refractory periods. Wavefronts entering the AV node from these two inputs can summate, resulting in improved conduction. Pacing protocols designed to accentuate the asymmetry between the AV nodal inputs can help to reveal the functional difference between the dual pathways and thus to better assess the properties of AV nodal conduction.

Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad.

The purpose of this study was to investigate the functional pathways of efferent vagal innervation to the atrial myocardium and sinus and atrioventricular (AV) nodes. Using vagally induced atrial effective refractory period shortening, slowing of spontaneous sinus rate, and prolongation of AV nodal conduction time as end points of vagal effects, we determined the actions of phenol and epicardial radiofrequency catheter ablation (RFCA) applied to different sites at or near the atrial myocardium to inhibit these responses. We found that efferent vagal fibers to the atria are located both subepicardially and intramurally or subendocardially. Most efferent vagal fibers to the atria appear to travel through a newly described fat pad located between the medial superior vena cava and aortic root (SVC-Ao fat pad), superior to the right pulmonary artery, and then project onto two previously noted fat pads at the inferior vena cava-left atrial junction (IVC-LA fat pad) and the right pulmonary vein-atrial junction (RPV fat pad) and to both atria. A few vagal fibers may bypass the SVC-Ao fat pad and go directly to the IVC-LA or RPV fat pad and then innervate the atrial myocardium. Vagal fibers to the sinus and AV nodes also converge at the SVC-Ao fat pad (a few fibers to the sinus node go directly to the RPV fat pad) before projecting to the RPV and IVC-LA fat pads. Long-term vagal denervation of the atria and sinus and AV nodes can be produced by RFCA of these fat pads and results in vagal denervation supersensitivity. Vagal denervation prevents induction of atrial fibrillation in this model. The newly described SVC-Ao fat pad receives most of the vagal fibers to the atria and sinus and AV nodes. Elimination of the fat pads with RFCA selectively vagally denervated the atria and sinus and AV nodes.

Effects of magnesium sulphate on atrioventricular conduction times and surface electrocardiogram in dogs anaesthetized with sevoflurane

We have studied the effects of magnesium on atrioventricular (AV) conduction times and surface electrocardiogram during both sinus rhythm and atrial pacing in seven dogs anaesthetized with 1 MAC of sevoflurane. A bolus dose of magnesium sulphate (MgSO4) 30, 60 and 90 mg kg-1 significantly increased plasma magnesium concentrations from 1.3 (SEM 0.1) to 15.3 (1.3) mg dl-1. MgSO4 significantly prolonged A-H (AV nodal conduction time during sinus rhythm), St-H (intra-atrial and AV nodal conduction time during atrial pacing) and H-S (total ventricular conduction time) intervals at doses > or = 30 mg kg-1 ; H-V interval (His-Purkinje conduction time) at doses > or = 60 mg kg-1; RR and PR intervals and QRS duration at doses > or = 30 mg kg-1 in a dose-related manner during both sinus rhythm and atrial pacing. QTc interval remained unchanged during sinus rhythm. The doses of MgSO4 used did not have deleterious effects on AV conduction times and surface electrocardiogram during 1 MAC of sevoflurane anaesthesia. This finding suggests that MgSO4 in high doses was safe and may be indicated for cardiac arrhythmia and hypertension during sevoflurane anaesthesia. However, further study is required to apply these findings to clinical anaesthesia.

NO modulates autonomic effects on sinus discharge rate and AV nodal conduction in open-chest dogs.

The purpose of this study was to investigate the role of nitric oxide (NO) in mediating vagal and sympathetic modulation of spontaneous sinus cycle length (SCL) and atrioventricular (AV) nodal conduction time (A-H interval) in 62 open-chest mongrel dogs anesthetized with alpha-chloralose. Infusion of an NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA, 4 mg/ ml), into the sinus and AV nodal arteries attenuated significantly (P < 0.01) the negative chronotropic and dromotropic responses to vagal nerve stimulation (VS) and VS during ansae subclaviae stimulation (SS) or isoproterenol (Iso) infusion. Intravenous administration of L-arginine (100 mg/kg) reversed these responses toward control values, whereas D-arginine did not have a significant effect. L-NMMA significantly (P < 0.01) enhanced the effects of SS and Iso on SCL and A-H interval; L-arginine reversed these changes toward baseline. L-NMMA increased the minimum concentration of ACh needed to induce 50 or 100% prolongation of SCL or second-degree or complete AV block during concomitant Iso infusion. L-Arginine reversed these effects. NOS inhibition did not affect the direct cholinergic actions of ACh on SCL and A-H interval but enhanced adrenergic positive chronotropic and dromotropic effects. We conclude that NO plays a stimulatory role in mediating vagal neurotransmission and vagal modulation of sympathetic effects and an inhibitory role in mediating sympathetic neurotransmission.

Electrophysiologic and antiarrhythmic effects of intravenous bisoprolol in atrioventricular nodal reentry tachycardia

Beta-blockade may be useful in the termination and prevention of atrioventricular nodal reentry tachycardia (AVNRT). An electrophysiologic study was performed in 9 patients (4 men and 5 women; mean ± SD age, 56 ± 16 years) with documented AVNRT before and after the intravenous administration of 5 mg of bisoprolol. In 5 of the 9 patients, AVRNT was terminated by bisoprolol, and AVNRT could no longer be induced in 6 of the 9 patients. Bisoprolol significantly prolonged the Wenckebach cycle length but did not affect fast pathway refractoriness or atrioventricular (AV) nodal conduction time during sinus rhythm or various paced cycle lengths up to 430 milliseconds. Conversely, it significantly prolonged the mean atrium-His bundle (AH) interval during AVNRT from 244 ± 65 milliseconds to 320 ± 64 milliseconds. These observations suggest that the effects of bisoprolol on the AV node, primarily at short cycle lengths, are rate dependent. Due to AH prolongation, mean tachycardia cycle length significantly increased from 313 ± 58 milliseconds to 378 ± 50 milliseconds, but there was no difference in the relative amount of prolongation between responders (60.8 ± 26 ms) and nonresponders (64.6 ± 37 ms). Bisoprolol appears to be useful in the termination and prevention of AVNRT during programmed electrical stimulation studies. Its effects on the AV node are use dependent.

Alternation of atrioventricular nodal conduction time during atrioventricular reentrant tachycardia: are dual pathways necessary?

Alternation of atrial cycle length and AV nodal conduction time (NCT) is often observed during AV reentrant tachycardia. Both AV nodal dual pathway and rate-dependent function have been postulated to be involved in this phenomenon. This study was designed to determine the respective role of these two mechanisms in the alternation observed in an in vitro model of orthodromic AV reentrant tachycardia. The tachycardia was produced by detecting each His-bundle activation and stimulating the atrium after a retrograde delay, thereby simulating retrograde pathway conduction, in six isolated rabbit heart preparations. After a 5-minute stabilization period at a fast rate, the retrograde delay was decremented by 2 msec every minute until nodal blocks occurred. We observed a sequential alternation of the cycle length and NCT in four preparations in the short retrograde delay range. The magnitude of the alternation gradually increased as the retrograde delay was decreased and reached 4.6 +/- 0.5 msec during 1:1 conduction. The alternation increased further just prior to termination of the tachycardia by an AV nodal block. None of the preparations showed discontinuous AV nodal recovery curves. Moreover, an electrode positioned over the endocardial surface of the node showed that the alternation developed distally to the nodal inputs, which are believed to constitute a major component of dual pathways. A mathematical model predicted the alternation from known characteristics of rate-dependent nodal functional properties. NCT and cycle length alternation can arise during orthodromic AV reentrant tachycardia when the retrograde delay is sufficiently short. The characteristics of the alternation, presence of continuous recovery curves, intranodal location of the alternation, and mathematical modeling suggest that the alternation is predictable from the known functional properties of the AV node without postulating dual pathway physiology.

Effects of verapamil, propranolol, and procainamide on adenosine-induced negative dromotropism in human beings

Adenosine, verapamil, propranolol, and pracainamide are widely used antiarrhythmic drugs. The interactions among them are still not known in human beings. Adenosine-induced negative dromotropic effects were assessed by rapid bolus injection of adenosine during constant high right atrial pacing in each patient. The initial dose of adenosine was 0.5 mg and was followed by a stepwise increment of 0.5 mg until atrioventricular (AV) nodal block occurred. The negative dromotropic actions of adenosine were examined in the control state and in the following three protocols in three groups of patients: (1) In 12 patients (group 1), intravenous verapamil, 0.15 mg/kg, was given; (2) in 12 patients (group 2), intravenous propranolol, 0.1 mg/kg, was given; and (3) in 10 patients (group 3), intravenous procainamide, 15 mg/kg, was given. The dose—response curves of adenosine on AV nodal conduction were almost identical in the control state and after verapamil, propranolol, or procainamide injection. However, verapamil, in contrast to propranolol, significantly reduced the dose of adenosine required to produce AV nodal block, from 4.4 ± 0.7 mg to 2.7 ± 0.3 mg ( p < 0.01). Of note, procalnamide exerted no significant effects on adenosine-induced negative dromotropism on AV nodal conduction or AV nodal block. In conclusion, the negative dromotropic effects of adenosine are preserved and independent even in the presence of verapamil, propranolol, or procainamide. Both verapamil and propranolol can exhibit additive effects with adenosine in prolonging AV nodal conduction time; however, only verapamil can reduce the dose of adenosine required to produce AV nodal block. This finding indicates that the dose of adenosine may be reduced for patients who have already been treated with verapamil.

Atrioventricular conduction during adenosine-induced hypotension in dogs anaesthetized with sevoflurane

We have studied the effects of adenosine-induced hypotension on A-H interval (atrioventricular (AV) nodal conduction time during sinus rhythm), St-H interval (intra-atrial plus AV nodal conduction time during atrial pacing), H-V interval (His-Purkinje conduction time) and H-S interval (total ventricular conduction time) by His-bundle electrocardiography in addition to surface electrocardiogram during both sinus rhythm and atrial pacing in nine dogs anaesthetized with 1 MAC of sevoflurane. Stepwise increases in infusion rates of adenosine to 0.1, 0.3, 0.5 and 1.0 mg kg-1 min-1 produced a dose-related decrease in mean arterial pressure from 91 (6) to 38 (2) mm Hg. Adenosine significantly increased the A-H interval at infusion rates of 0.5 mg kg-1 min-1 and above, and the St-H interval at 1.0 mg kg-1 min-1. The H-V and H-S intervals remained unchanged. Heart rate decreased significantly only at 1.0 mg kg-1 min-1 with a significant increase in the PR interval. Adenosine-induced hypotension did not have deleterious effects on AV conduction times and the surface electrocardiogram in dogs anaesthetized with 1 MAC of sevoflurane. This may indicate that the effects of adenosine on AV conduction were small and therefore are unlikely to be a contraindication to the use of adenosine for inducing hypotension in patients with initially normal conduction during sevoflurane anaesthesia.

Using chaos control and tracking to suppress a pathological nonchaotic rhythm in a cardiac model.

Atrioventricular (AV) nodal alternans is a pathological cardiac condition characterized by a beat-to-beat alternation (period-2 rhythm) in AV nodal conduction time. Here we implement an AV nodal conduction model which undergoes a period-doubling bifurcation into alternans. We show that additive noise can be used to locate the unstable period-1 fixed point which underlies the alternans rhythm. We then use chaos control to suppress alternans by stabilizing the model about its unstable period-1 fixed point. We also show that the period-doubling bifurcation into alternans can be prevented by tracking the period-1 rhythm into its unstable regime. We demonstrate that these techniques are robust to imprecise measurements and experimental noise. Importantly, these methods require no knowledge of the underlying system equations. These findings suggest that chaos control and tracking may be useful for suppressing alternans in a clinical environment. \textcopyright{} 1996 The American Physical Society.

Electrophysiologic and proarrhythmic effects of intravenous inotropic agents

Intravenous inotropic agents promote increased myocardial contractility via elevation of myocyte calcium concentrations, a mechanism that is also known to promote the development of cardiac arrhythmias. The purpose of this article is to review the electrophysiologic effects and relative potential for proarrhythmia associated with dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone. Dobutamine increases sinoatrial node automaticity and decreases atrial and atrioventricular (AV) node refractoriness and AV nodal conduction time. The drug also decreases ventricular refractoriness in both healthy and ischemic myocardium. Dobutamine has been shown to increase heart rate in a dose-related fashion in animals and in humans. In humans, dobutamine has been reported to induce ventricular ectopic activity (VEA) in 3% to 15% of patients, although VEAs are often asymptomatic, requiring no intervention. Ventricular tachycardia (VT) associated with dobutamine appears to occur rarely. Patients with underlying arrhythmias or heart failure or those receiving excessive doses of dobutamine are at greatest risk for proarrhythmia. Dopamine increases automaticity in Purkinje fibers and has a biphasic effect on action potential duration. Dopamine has been reported to induce atrial or ventricular arrhythmias in animals. In humans, dopamine may be associated with dose-related sinus tachycardia but has also been reported to cause VEA, which is usually asymptomatic. Dopamine-associated VT appears to occur rarely. Dopamine produces greater elevations in heart rate or frequency of ventricular premature beats at a given value of cardiac index than does dobutamine. The phosphodiesterase inhibitors amrinone and milrinone increase conduction through the AV node and decrease atrial refractoriness. Intravenous administration of these drugs may result in sinus tachycardia in some patients and has been reported to cause VEA, which is often asymptomatic, in up to 17% of patients. VT has also been reported in association with short-term use of intravenous phosphodiesterase inhibitors. In summary, intravenous inotropic agents may be associated with proarrhythmic effects in some patients. The primary arrhythmias reported are sinus tachycardia and VEA, although other supraventricular or ventricular arrhythmias have been reported less commonly. However, clinically significant proarrhythmic effects associated with these agents appear to occur rarely, and, at conventional doses, intravenous inotropic agents are relatively safe with respect to proarrhythmic effects.

Frequency-dependent Effects of Propofol on Atrioventricular Nodal Conduction in Guinea Pig Isolated Heart

The use of propofol has been associated with episodes of bradycardias. The mechanism(s) underlying these phenomena are not well defined. Therefore we investigated (1) the chronotropic and dromotropic effects of propofol, (2) the frequency-dependent effects of propofol on the atrioventricular (AV) node, and (3) the physiologic mechanism(s) underlying propofol's effects on AV nodal conduction. Guinea pig isolated, perfused hearts were instrumented for measurement of atrial rate and AV nodal conduction time in spontaneously beating hearts, or stimulus-to-His bundle (S-H) intervals in atrially paced hearts. In addition, the Wenckebach cycle length, effective refractory period and S-H interval prolongation to an abrupt increase in pacing rate were measured to further define propofol's dromotropic effects and frequency-dependent behavior. Propofol, in a concentration-dependent manner, (1) slowed atrial rate and AV nodal conduction time in spontaneously beating hearts, (2) prolonged the S-H interval in atrially paced hearts, and (3) prolonged Wenckebach cycle length and effective refractory period. The negative dromotropic effect of propofol was greater during atrial pacing than in spontaneously beating hearts. Furthermore, this effect was enhanced at faster pacing rates, indicating frequency-dependent behavior. Atropine significantly antagonized propofol-induced S-H interval prolongation. The results of competition binding studies also supported a M2-muscarinic receptor-mediated mechanism. We conclude that in the isolated guinea pig heart, propofol slows atrial rate and depresses AV nodal conduction in a concentration-dependent manner. The negative dromotropic effect of propofol shows frequency dependence and is predominantly mediated by M2-muscarinic receptors. Given the marked rate dependence of propofol's AV nodal actions, this anesthetic agent may impart antidysrhythmic protection to those patients susceptible to supraventricular tachycardias.

Comparison of the Effects of Halothane, Isoflurane, and Sevoflurane on Atrioventricular Conduction Times in Pentobarbital-Anesthetized Dogs

It is not known how sevoflurane affects the cardiac conduction system.We compared the effects of halothane, isoflurane, and sevoflurane on specialized atrioventricular (AV) conduction times in eight pentobarbital-anesthetized dogs. AV conduction times with three inhaled anesthetics at end-tidal concentrations of 1 and 2 minimum alveolar anesthetic concentration (MAC), were measured by His-bundle electrocardiography during both sinus rhythm and right atrial pacing at a slightly higher rate than sinus one. Heart rate and arterial pressure were simultaneously recorded. Halothane prolonged AV nodal conduction time during sinus rhythm (A-H interval) at 2 MAC compared with the control value, whereas isoflurane and sevoflurane did not alter the A-H interval, His-Purkinje conduction time (H-V interval), and ventricular conduction time (H-S interval) during sinus rhythm at 1 and 2 MAC. All three inhaled anesthetics did not change AV conduction times during right atrial pacing. No significant difference in AV conduction times was observed between isoflurane and sevoflurane. Heart rate during sinus rhythm remained unchanged despite a decrease in arterial pressure with three inhaled anesthetics. The property of sevoflurane and isoflurane which does not affect the cardiac conduction system may be important in the stability of the cardiac rhythm during anesthesia with these drugs. (Anesth Analg 1995;81:249-53)

Alternans and period-doubling bifurcations in atrioventricular nodal conduc

A theoretical model, formulated as a finite difference equation is proposed for rate-dependent conduction properties of the atrioventricular (AV) node. The AV nodal conduction time, which is defined as the time interval from the atrial activation to the activation of the bundle of His, depends on the history of activation of the node. The theoretical model, which incorporates physiological concepts of recovery, facilitation and fatigue, accurately predicts a variety of experimentally observed complex rhythms of nodal conduction. In particular, alternans rhythms, in which there is an alternation in conduction time from beat to beat, are associated with period-doubling bifurcations in the theoretical model.

901-63 Role of Nitric Oxide in the Autonomic Modulation of Atrioventricular Nodal Conduction in Dogs

Nitric oxide (NO), synthesized from L-arginine, is involved in the modulation of autonomic neurotransmission. Recent in vitro and in vivo studies have shown that the negative chronotropic effect of carbachol or vagal stimulation was partially blocked by an L-arginine analog, NG-monomethyl-L-arginine (L-NMMA), that competetively inhibits NO synthase (NOS). The purpose of the present study was to assess in an open chest canine model whether the L-arginine-NO pathway may also playa role in the autonomic modulation of AV nodal conduction, and if so, whether this is prejunctional or postjunctional. To test for prejunctional actions, we assessed the dromotropic response to cervical vagal stimulation (VS: 2 Hz, 4.0 V. 4 ms) and VS during ansae subclaviae stimulation (SS: 2 Hz, 3.0 V. 4 ms, n = 5). To test for postjunctional actions, we determined the dromotropic response to intravenous isoproterenol infusion (5 mcg/min) before and during vagal stimulation (VS ± ISO, n = 5). VS, SS and ISO were repeated during selective infusion of L-NMMA retrogradely into the AV node artery (AVNA) and following reversal of NOS inhibition with L-arginine (100 mg/kg). Shown is the change in AV nodal conduction time (AH, msec) produced by VS before and during SS or isoproterenol at control state (saline infusion into AVNA, 1 ml!min), during L-NMMA infusion (4 mg/min) into AVNA, and after IV injection of L-arginine (100 mg/kg).Empty CellVSVS/SSVS/ISOControl139 ± 29120 ± 2795 ± 23L-NMMA*118 ± 21101 ± 2981 ± 31L-arginine†136 ± 27117 ± 2491 ± 26*p &lt; 0.01 vs baseline†p &lt; 0.01 vs L-NMMA p &lt; 0.01 vs baseline p &lt; 0.01 vs L-NMMA The negative dromotropic effect of VS. VS during SS and ISO is attenuated by L-NMMA and restored toward baseline by L-arginine, suggesting that NO plays a partial role at both prejunctional and postjunctional sites in the vagal modulation of AV nodal conduction.