Vagal effects on atrioventricular (AV) nodal conduction are accentuated by increases in heart rate. To establish the mechanism of these rate-dependent negative dromotropic actions, we studied the properties governing AV nodal adaptation to changes in heart rate in chloraloseanesthetized dogs in the absence and presence of bilateral cervical vagal nerve stimulation (20 Hz, 0.2 msec Billette and coworkers.816,18,22,26,27 Using the time from the His bundle spike to the next atrial activation (HA interval) as an index of AV

The study assessed the hydroalcohol extract effects of Crocus sativus L. (saffron) on (i) the basic and rate-dependent electrophysiological properties of the AV node, (ii) remodeling of the AV node during experimental atrial fibrillation (AF) and (iii) the role of nitric oxide (NO) in the effects of saffron on the AV node. Stimulation protocols in isolated AV node were used to quantify AV nodal recovery, facilitation and fatigue in four groups of rabbits (n = 8-16 per group). In addition, the nodal response to AF was evaluated at multiple cycle lengths and during AF. Saffron had a depressant effect on AV nodal rate-dependent properties; further, it increased Wenckebach block cycle length, functional refractory period, facilitation and fatigue (p < 0.05). A NO-synthase inhibitor (L-NAME) prevented the depressant effects of saffron on the AV node (p < 0.05). Saffron increased the zone of concealment in experimental AF (p < 0.05). The present research showed, for the first time, established electrophysiological remodeling of the AV node during AF by saffron. Saffron increased the AV nodal refractoriness and zone of concealment. These depressant effects of saffron were mediated by endogenous NO.

Calcium channel blockers depress atrioventricular (AV) nodal properties in vivo in a frequencydependent manner, suggesting that selective drug action during supraventricular arrhythmias may result from use-dependent properties. The present study was designed to examine whether or not the rate-dependent actions of diltiazem account for its therapeutic effects during atrial fibrillation. The determinants of the ventricular response to atrial fibrillation (concealed AV nodal conduction and AV node functional refractory period, AVFRP) were evaluated at multiple cycle lengths (with extrastimulus techniques) and during electrically induced atrial fibrillation (with indirect indexes from RR interval histograms) in anesthetized dogs. In the presence of diltiazem, AVFRP increased progressively relative to control as rate accelerated. At cycle lengths comparable to sinus rhythm in humans, AVFRP increased 10%, 17%, and 32% after doses 1, 2, and 3 of diltiazem, respectively. Drug-induced increases in AVFRP were greater at basic cycle lengths just above the Wenckebach point (17%, 48%, and 81%) and were maximal during atrial fibrillation (39%, 86%, and 154% increases for doses 1, 2, and 3, respectively). Diltiazem also increased the AV conduction system effective refractory period in a frequency-dependent manner without affecting the atrial effective refractory period, thereby increasing the potential zone of concealment into the AV node. Frequency-dependent increases in the zone of concealment were produced by diltiazem and were associated with marked increases in the standard deviation of RR interval histograms during atrial fibrillation (257%, 526%, and 923% increases after doses 1, 2, and 3, respectively). The combination of rate-dependent increases in AVFRP and zone of concealment resulted in a marked amplification of diltiazem's effects during atrial fibrillation, with mean RR interval increases (88%, 200%, and 300% after doses 1, 2, and 3, respectively) that were 8-10 fold greater than increases in AVFRP at cycle lengths comparable to sinus rhythm in humans. We conclude that diltiazem's frequency-dependent effects lead to highly selective depression of AV nodal function during atrial fibrillation. (Circulation 1989;80:380-

A number of functional properties of the atrioventricular (AV) node have been described in response to changes in the atrial input rate. The purpose of this study was 1) to develop quantitative descriptors of these properties, and 2) to determine whether they can account for rate-dependent changes in AV nodal conduction. The delay in AV nodal conduction of single premature beats (recovery) was found to be an exponential function of coupling interval with a time constant of 66 +/- 2 (+/- SE) ms. A single abbreviated (facilitation) cycle did not alter the time constant of recovery or basal conduction for a subsequent beat but shifted its recovery curve to the left to an extent exponentially related to the facilitation cycle length. The induction of a tachycardia with HA interval fixed so as to control the recovery and facilitation variables resulted in a first-order onset of AV conduction slowing (fatigue). The fatigue process had a time constant in the range of 70 beats and a magnitude that was a decaying exponential function of HA interval. An equation incorporating quantitative descriptors of recovery, facilitation, and fatigue accurately predicted rate-dependent changes in AH interval. We conclude that 1) the AV nodal properties of recovery, facilitation, and fatigue are amenable to quantitative characterization, and 2) rate-dependent changes in AV nodal conduction time can be well described in terms of these underlying properties.

Recent work has shown that alterations in the dynamic atrioventricular (AV) nodal response to changes in heart rate can significantly modify AV nodal function. The present study was designed to evaluate the nature and potential importance of sympathetic regulation of the rate-dependent properties of the AV node. Selective stimulation protocols and mathematical formulations were used to independently quantify AV nodal recovery, facilitation, and fatigue in 12 morphine-chloralose-anesthetized dogs. Vagal effects were prevented by bilateral vagal transection and intravenous atropine, and the sinus node was crushed to allow a broader range of pacing cycle lengths. In seven dogs with sympathetic nerves intact, beta-adrenergic receptor blockade increased the recovery time constant (tau rec) for the conduction of premature test beats from 47 +/- 2 (mean +/- SEM) msec (control) to 62 +/- 1 msec (p less than 0.001), whereas isoproterenol decreased tau rec to 38 +/- 1 msec (p less than 0.001). In addition, beta-blockade increased the maximum amount of rate-dependent AV nodal fatigue from 7 +/- 1 msec (at a cycle length of 198 +/- 9 msec [control]) to 17 +/- 2 msec (p less than 0.001). In five dogs with decentralized stellate ganglia, tau rec was decreased from 71 +/- 3 msec (control) to 57 +/- 4 msec and 48 +/- 2 msec (p less than 0.001 for each) by left stellate ganglion stimulation at 5 and 10 Hz, respectively. Maximum fatigue was similarly reduced from 16 +/- 1 msec (control) to 12 +/- 2 msec (p = NS) and 8 +/- 1 msec (p less than 0.01), respectively. Stellate ganglion stimulation, isoproterenol, and beta-blockade did not alter AV nodal facilitation. A mathematical model incorporating quantitative indexes of AV nodal function accurately accounted for tachycardia-dependent increases in the atrial-His activation interval, which were enhanced by beta-adrenergic receptor blockade and reduced by isoproterenol. Furthermore, this model showed that beta-adrenergic effects were increased by increasing heart rate, with the majority of the rate-dependent action being due to changes in the time course of AV nodal recovery. We conclude that beta-adrenergic receptor stimulation alters functional properties that govern the AV nodal response to changes in heart rate. These changes in functional properties alter the ability of the AV node to conduct impulses during tachycardia and, as such, could play a major role in the ability of sympathetic stimulation to promote and beta-adrenergic receptor blockade to prevent the occurrence of AV nodal reentrant arrhythmias.