Negative Dromotropic Effect Of Adenosine Research Articles

Time Course of Adenosine‐Induced Pulmonary Vein Reconnection after Isolation: Implications for Mechanism of Dormant Conduction

Adenosine (ADO) has been proposed to reconnect isolated pulmonary veins (PVs) postablation through hyperpolarization of damaged myocytes in an animal model. However, PV reconnection can occur via ADO-mediated sympathetic activation. We sought to determine the mechanism of ADO-induced PV reconnection in the clinical setting by characterizing its time course and location in patients undergoing PV isolation. Seventy-four patients (61 male; age 61 ± 10 years) undergoing PV isolation for atrial fibrillation (54 [73%] paroxysmal and 19 [27%] persistent) were studied. After each PV was isolated, a 12-mg intravenous bolus of ADO was administered and onset, offset, and location of ADO-induced PV reconnection and onset and offset of bradycardia were analyzed. In 22 (30%) patients, ADO-induced PV reconnection occurred in 34 of 270 (13%) PVs. In 24 (71%) PVs, the duration of ADO-induced reconnection exceeded that of bradycardia. The onset of ADO-induced reconnection occurred before the onset of bradycardia in 10 (30%) PVs and during bradycardia in 23 (70%) PVs. No PVs exhibited onset of reconnection after resolution of bradycardia. Common sites of PV reconnection included the carinal region (41% of right PVs and 29% of left PVs) and left PV-atrial appendageal ridge region (35% of left PVs). ADO-induced PV reconnection occurs during the bradycardic phase of the ADO bolus response and not during the late tachycardic phase. ADO-induced PV dormant conduction is closely associated with the negative dromotropic effects of ADO and suggests that hyperpolarization of the resting membrane is the unifying mechanism.

Free radicals potentiate the negative dromotropic effect of adenosine in guinea pig isolated heart

Objective — Adenosine is released during myocardial ischaemia and delays atrioventricular nodal (AV) conduction.We hypothesized that free radicals present during reperfusion potentiate the negative dromotropic effect of adenosine on the AV node.Methods and results — Guinea pig hearts were prepared using the Langendorff technique, paced (200 beats/min), and instrumented to measure the atrium-to-His bundle (A-H) interval, an index of AV nodal conduction time. Adenosine (2 μM) prolonged the A-H interval by 5.7±0.5 ms from a control value of 35.7±1.3 ms. (n = 10, P<0.05). In the absence of adenosine, the superoxide (O2-) generator pyrogallol (20 μM) did not affect the A-H interval (0.7±0.2 ms prolongation, n = 10). However, concurrent infusion of adenosine (2 μM) and pyrogallol (20 μM) lengthened the A-H interval by 11.0±0.8 ms from control (n = 10, P<0.001). This A-H interval prolongation was reversed by cyclopentyl-1,3-dipropylxanthine (100 nM), a selective A1-adenosine receptor antagonist (P<0.001, n = 5). Similarly, A-H interval prolongation was decreased to 4.3±0.4 ms when NG-methyl-L-arginine (100 μM), a nitric oxide (NO) synthase inhibitor, was infused (n = 4).The superoxide scavenger superoxide dismutase (200 U/ml) also diminished the A-H interval prolongation to 7.1±0.6 ms (n = 4, P<0.001). Ba2+ (100 μM), a blocker of the adenosine-induced inward potassium current (IK, ADO), did not significantly affect this potentiation (13.0±0.8 and 10.8±0.7 ms greater than control A-H interval in the absence and presence of Ba2+, respectively, n = 4).Conclusions — Superoxides and adenosine delay AV nodal conduction in a synergistic manner via a NO-dependent mechanism involving an IK, ADO-independent component. This phenomenon may contribute to the genesis of reperfusion arrhythmias.

Contribution of I(K,ADO) to the negative dromotropic effect of adenosine.

Despite the pathophysiological and therapeutic significance of the negative dromotropic effect of adenosine, its underlying ionic mechanism, and specifically the role of the adenosine-activated K(+) current (I(K,ADO)) is not experimentally defined. Therefore, we studied the contribution of I(K,ADO) to the negative dromotropic effect of adenosine. Effects of adenosine on single atrioventricular nodal and left atrial myocytes from rabbits were studied using the whole cell configuration of the patch clamp technique. Complementary experiments were done in rabbit and guinea pig isolated hearts instrumented to measure the atrium-to-His bundle interval. In contrast to its effect in atrial myocytes, Ba(2+) selectively and completely blocked I(K,ADO) at membrane potentials from -70 to 0 mV in atrioventricular nodal myocytes and abolished the adenosine-induced leftward shift of the reversal membrane potential. Ba(2+) alone did not significantly prolong the A-H interval, but markedly attenuated the A-H interval prolongation caused by adenosine. In guinea pig heart, EC(50) values ( pD(2) +/- SEM) for adenosine-induced atrium-to-His bundle interval prolongation were 3.3 micromol/L (5.48 +/- 0.04) and 13.2 micromol/L (4.88 +/- 0.05, P < 0.001) in the absence and presence of Ba(2+), respectively. Despite species-dependent differences in sensitivities to adenosine (guinea pig > rabbit), the relative contribution of adenosine-activated K(+) current to the atrium-to-His bundle interval prolongation was nearly identical. In guinea pig hearts it ranged from 37.8 % (P = 0.013) to 72.5 % (P < 0.001) at 2 to 6 micromol/L adenosine, respectively. I(K,ADO) contributes significantly to the negative dromotropic effect of adenosine, but predominantly at relatively high concentrations of the nucleoside.

Potentiation of the negative dromotropic effect of adenosine by rapid heart rates: possible ionic mechanism.

Adenosine-induced slowing of atrioventricular nodal conduction is a rate-dependent process that is potentiated by the A(1)-adenosine receptor allosteric enhancer, PD 81,723. The ionic mechanisms underlying these phenomena were investigated in guinea pig isolated hearts and single atrial myocytes by measuring the atrium-to-His bundle (A-H) interval and using patch-clamp recordings, respectively.A decrease in atrial cycle length from 300 to 190 ms decreased the concentration of adenosine needed to cause atrioventricular nodal block from 7.8 +/- 1.0 to 2.6 +/- 0.7 micromol/L (P < 0.001). Ba(2+) (100 micromol/L), a selective blocker of the adenosine-activated inward rectifier K(+) current I(K,ADO) in the atrioventricular node, failed to abolish this rate-dependent effect of adenosine. PD 81,723 (5 micromol/L) potentiated the negative dromotropic effect of adenosine even after I(K,ADO) was blocked by Ba(2+) and after attenuation of I(Ca,L) by adenosine was prevented by 8-Br-cAMP (1.5 mmol/L). In atrial myocytes, adenosine augmented a time- and voltage-dependent K(+) current (Ado-I(K)). Ado-I(K) was more sensitive to adenosine than I(K,ADO) (EC(50) values, 0.8 versus 1.4 micromol/L, P < 0.01). PD 81,723 blocked I(K,ADO), but potentiated Ado-I(K). Ado-I(K) was insensitive to Ba(2+) (P = 0.98), whereas it was blocked by chromanol 293B (5 micromol/L, P < 0.001). Unlike I(K,ADO), Ado-I(K) increased during rapid stimulation of myocytes (P < 0.001). Adenosine augments a time- and voltage-dependent K(+) current, Ado-I(K). The pharmacological and kinetic properties of Ado-I(K) are consistent with it playing an important role in the negative dromotropic effect of adenosine at lower concentrations of the nucleoside, at fast heart rates and in the presence of PD 81,723.

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.

Cellular basis for the negative dromotropic effect of adenosine on rabbit single atrioventricular nodal cells.

The effects of adenosine on action potentials, rate-dependent activation failure (the cellular basis for second-degree atrioventricular [AV] block), and the recovery of excitability in rabbit isolated single AV nodal cells were studied using the whole-cell patch-clamp technique. Adenosine (1 micromol/L) shortened the duration, depressed the amplitude, and reduced the rate of rise of the AV nodal cell action potential. Adenosine (10 micromol/L) caused a significant hyperpolarization (7 +/- 1 mV) of AV nodal cells. Adenosine increased the occurrence and the rate dependence of activation failure (Wenckebach periodicity) of AV nodal cells: this effect was concentration dependent and mediated by A1 adenosine receptors. The rate-dependent activation failure caused by adenosine was associated with a prolongation of the effective refractory period by 18 +/- 2 ms (P < .05), an increase in the duration of activation delay, and an elevation (from 0.22 +/- 0.04 to 0.30 +/- 0.03 nA, P < .05) of the threshold current amplitude required to activate AV nodal cells. The results suggest that the slowed recovery of excitability of AV nodal cells caused by adenosine forms the cellular basis for adenosine-induced second-degree AV block. Adenosine decreased ICa,L and activated IK,ADO of AV nodal cells. These actions of adenosine on ion currents may contribute to the effect of this nucleoside to depress excitability of AV nodal cells. The enhancement by adenosine of rate-dependent activation failure of AV nodal cells implies that the negative dromotropic effect of adenosine should be more pronounced during an episode of supraventricular tachycardia than during normal rhythm.

Rate-dependent properties of adenosine-induced negative dromotropism in humans.

The antiarrhythmic effects of sodium channel and calcium channel blockers are known to be rate dependent. Little is known about the rate-dependent effect of adenosine on human atrioventricular (AV) nodal conduction. The purpose of this study was to determine whether the negative dromotropic effect of adenosine is dependent on heart rate. Atrial pacing at 20-millisecond increments decreasing stepwise was performed, and the curves that relate the AH interval to the atrial pacing cycle length were analyzed. The change in AV nodal function was evaluated in three protocols: (1) In 8 group 1A and 6 group 1B patients, an intravenous infusion of adenosine at a dose of 140 and 320 micrograms.kg-1.min-1 was given, respectively; (2) a bolus injection of a fixed dose of adenosine was given to 12 group 2A patients without and 6 group 2B patients with propranolol (0.1 mg/kg) treatment; and (3) in 12 group 3 patients, the AV nodal function was evaluated after intravenous propranolol (0.05 mg/kg) and after subsequent intravenous aminophylline (loading dose, 5 mg/kg; maintenance dose, 0.9 mg.kg-1.h-1). No significant depression of AV nodal function could be demonstrated during intravenous infusion of adenosine. The bolus injection of adenosine could prolong the AH interval, which was dependent on heart rate and more significant at a shorter pacing cycle length. Intravenous propranolol significantly depressed the AV nodal conduction and shifted the curves of the AH interval versus the pacing cycle length to the right. Subsequent intravenous aminophylline shortened the AV nodal conduction time, however, in a rate-independent manner. The negative dromotropic effects induced by intravenous bolus injection of adenosine became more pronounced at fast atrial pacing rates. These results indicate that adenosine causes rate-dependent prolongation of AV nodal conduction in humans.

Endogenous adenosine does not activate ATP-sensitive potassium channels in the hypoxic guinea pig ventricle in vivo.

The activation of ATP-sensitive K+ (K+ ATP) channels by K+ ATP openers, eg, pinacidil, hypoxia, and ischemia, is known to shorten the ventricular action potential. Since adenosine is released in increased amounts during cardiac hypoxia and ischemia, the hypothesis that endogenous adenosine activates K+ ATP channels was tested in vivo in a guinea pig model. Anesthetized animals (n = 37) were subjected to transient acute global hypoxia by ventilation with 100% N2. Monophasic action potentials (MAP) were recorded in ventricular and atrial myocardium by use of custom-made Ag/AgCl electrode catheters. In addition, right atrial and left ventricular electrograms as well as systemic arterial blood pressure were monitored throughout the experiments. Under normoxic conditions, pinacidil (1.8 microgram/kg i.v., n = 8), a K+ ATP channel opener, shortened ventricular MAP duration (APD); this effect was reversed by glibenclamide, a potent K+ ATP channel blocker, but not by 8-cyclopentyl-1,3-dimethylxanthine (CPT), a potent A1-selective adenosine antagonist. Global hypoxia shortened atrial and ventricular APD. Glibenclamide but not CPT reversed this effect of hypoxia on ventricular but not atrial MAP. CPT but not glibenclamide reversed the effect of hypoxia on atrial MAP. In addition, CPT delayed the appearance of the atrioventricular (AV) nodal conduction block associated with global hypoxia. Finally, the ability of CPT to selectively attenuate A1-adenosine receptor-mediated effects of adenosine agonists in ventricular and supraventricular tissues was confirmed in 17 animals. CPT reversed the negative dromotropic effect of adenosine on AV nodal conduction and the antiadrenergic effect of N6-cyclopentyladenosine (CPA) mediated by A1-adenosine receptor but not the adenosine-induced decrease in systemic blood pressure caused by the vasodilatory action of the nucleoside mediated by A2-adenosine receptor. (1) Endogenous adenosine released during global cardiac hypoxia mediates, in part, AV nodal conduction delay and shortening of atrial but not ventricular APD. (2) The action of adenosine on atrial APD is mediated by A1 adenosine receptors, probably via IK,Ado,Ach. (3) Endogenous adenosine apparently does not play an important role in the early stages of acute global hypoxia-induced activation of K+ ATP channels. The present results are consistent with the hypothesis that the shortening of ventricular APD in the hypoxic heart is due, in part, to activation of K+ ATP channels.

Adenosine myocardial perfusion imaging in the noninvasive diagnosis and prognosis of coronary artery disease

AbstractAdenosine is a purine base compound which is of fundamental importance in many physiologic processes in the body, including vasodilation in most arterial vascular beds. Adenosine produces maximal or near‐maximal coronary vasodilation by interacting with the adenosine A2 receptors in the cell wall, on a dose dependent fashion. The mechanism of thallium‐201 myocardial perfusion defects induced by adenosine scintigraphy is a heterogeneity of myocardial blood flow due to a greater coronary flow increase in the normal arteries and a lesser increase in the stenotic arteries. The ultra‐short half‐life of adenosine (&lt; 10 sec) necessitates continuous intravenous administration at a dose of 140 μg/kg/min for six min. The excellent safety record of this regimen has been demonstrated in several thousand patients in the United States. Side effects occur in most patients during adenosine infusion. Chest pain occurs often and in some cases may be due to a true coronary steal phenomenon. In the author's experience, first degree AV block occurs in approximately 10% and second or third degree AV block in approximately 4% of the patients, and are due to the negative dromotropic effect of adenosine on the AV node. On the positive side, these untoward effects are very short‐lived and typically disappear within one or two minutes after discontinuing the adenosine infusion. No serious complications or fatalities have been observed to date with this test. The cumulative experience with adenosine thallium‐201 scintigraphy indicates high sensitivity and specificity in the diagnosis of coronary artery disease. Recent data also suggest it may be an excellent technique to assess a patient's prognosis early after a myocardial infarction. Adenosine‐induced coronary vasodilation, in combination with thallium‐201 or the new technetium‐99m perfusion agents, holds great promise in the assessment of patients with coronary artery disease. © 1993 Wiley‐Liss, Inc.

Negative dromotropism of adenosine under beta-adrenergic stimulation with isoproterenol

Adenosine depresses atrioventricular (AV) nodal function by binding to specific A 1 receptors which activate the acetylcholine, adenosine-regulated potassium current. In addition, adenosine can act to antagonize the effects of β-adrenergic stimulation on AV nodal function. To assess the negative dromotropic effects of adenosine under β-adrenergic stimulation, 15 patients were studied during clinical electrophysiologic study. During high right atrial pacing at a cycle length of 400 to 600 ms, adenosine was injected intravenously at an initial dose of 0.5 mg followed by a stepwise increment of 0.5 or 1.0 mg given at 5-minute intervals until a maximal dose of 12 mg was achieved or AV block developed. Intravenous isoproterenol (1 to 3 μg/min) was then infused to accelerate sinus rate by 20 to 30% during which intravenous injection of incremental doses of adenosine as described was repeated. The AV nodal conduction time (AH interval) was measured at each dose of adenosine. Dose-response curves of AV nodal conduction time (expressed as percent increase in AH interval) were studied during the control state and during isoproterenol infusion. The dose of adenosine required to produce AV nodal Wenckebach block, the increase in the AH interval by 50% (ED 50) and the maximal response (E max) were 3.4 ± 0.9 mg, 1.8 ± 0.9 mg and 60 ± 4%, respectively, in the control state, and 3.7 ± 0.8 mg, 2.0 ± 0.7 mg and 56 ± 4%, respectively, during isoproterenol infusion. No significant changes in ED 50, E max and the dose of adenosine yielding AV nodal Wenckebach block could be demonstrated between the control state and during isoproterenol infusion. Thus, the negative dromotropic effects of adenosine on AV nodal conduction remained unchanged with β-adrenergic stimulation. These findings suggest that adenosine may remain efficacious in terminating catecholamine-sensitive supraventricular tachycardia involving the AV node as part of the reentrant circuit.

Effect of adenosine on atrioventricular conduction. I: Site and characterization of adenosine action in the guinea pig atrioventricular node.

Adenosine has a negative dromotropic effect and modulates hypoxia-induced atrioventricular (AV) conduction delay. To further characterize the negative dromotropic effect of adenosine in the guinea pig heart, we determined the site of adenosine-induced AV conduction block; the effect of uptake and deamination of adenosine on its concentration-negative dromotropic effect, and the adenosine receptor that mediates this action. In isolated AV node preparations (n = 16), adenosine in a dose-dependent manner decreased significantly the duration and amplitude of the action potential of atrionodal and nodal cells and, in addition, markedly depressed the maximum rate of rise of the action potential of nodal cells. At high concentrations (greater than 20 microM), adenosine rendered nodal cells inexcitable. In isolated perfused hearts (n = 7), adenosine (5.7 microM) prolonged total AV conduction time by 21 +/- 2 msec. Of this prolongation, 83% was due to an increase in the nodal-to-His-bundle interval and the remaining 17% to an increase in the atrionodal to nodal interval. Infusion of adenosine to cause a 50% increase (EC50) in atria-to-His bundle (AH) interval prolongation resulted in a perfusate (arterial) adenosine concentration of 5.0 +/- 0.6 microM and effluent (venous) adenosine concentrations of 2.8 +/- 0.4 microM, i.e., an arteriovenous difference of 44% (n = 4). When adenosine uptake and deamination were inhibited with dipyridamole (0.5 microM) plus erythro-9-(2-hydroxy-3-nonyl)adenine (5 microM), respectively, the EC50s were 0.28 +/- 0.02 (perfusate) and 0.32 +/- 0.03 microM (effluent). These data indicate that when nucleoside metabolism is inhibited, arterial and venous concentrations of adenosine reach equilibrium. In an additional 10 hearts, the following rank order of potency of adenosine agonists in causing AH interval prolongation was found: N6-cyclopentyladenosine greater than N6-(L-2-phenyl-isopropyl)adenosine greater than 5'-N-ethylcarboxyamidoadenosine greater than or equal to 2-chloroadenosine greater than adenosine, which is compatible with activation of an A1-type receptor. In summary: the site of adenosine-induced AV conduction block is the nodal zone of the AV node, when adenosine uptake and deamination are inhibited, adenosine in concentrations similar to that released by hypoxia causes significant AH interval prolongation, and the adenosine receptor mediating the negative dromotropic effect of adenosine is of the A1-type.

Evidence for adenosine mediation of atrioventricular block in the ischemic canine myocardium.

Adenosine levels in oxygen-deprived myocardium can rise to 10- 100 microM concentrations known to cause atrioventricular (AV) conduction delay and block. We reported that the AV conduction delay and block caused by hypoxia is markedly attenuated by 10 microM aminophylline, and adenosine competitive antagonist. THe purpose of the present study was to investigate adenosine's role in ischemic AV conduction disturbances. Dogs were anesthetized and instrumented for His bundle and surface electrogram recordings. The total AV conduction time was subdivided in to atrial-His bundle (AH) and His bundle-ventricle intervals. The atrioventricular node artery (AVNA) was cannulated for selective injection of drugs in the AV node region. Adenosine (10 to 100 microgram), as a 2-ml bolus injection, rapidly produced a dose-dependent, transient increase in the AH interval; a 1,000-microgram dose caused second degree AV block. The duration of the increase in AH interval was also dose-dependent. Dipyridamole, and inhibitor of nucleoside transport, potentiated the negative dromotropic effects of adenosine, whereas aminophylline attenuated them. In some dogs, after cannulation of the AVNA, first and second degree AV block occurred spontaneously or were induced by rapid atrial pacing. Injection of the aminophylline (5 mg/kg, i.e.) or theophylline (100-1,000 microgram) into the AVNA rapidly reversed the AV blocks. Upon washout of the drugs the AV blocks recurred. We conclude that endogenously released adenosine may account for a major fraction of the AV conduction delay and block associated with impaired blood supply to the AV node, and the theophylline and aminophylline reverse the AV conduction defect by antagonizing the effects of adenosine.