The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity.

RATIONALE: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential. OBJECTIVE: We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680). METHODS AND RESULTS: Trabeculae were isolated from right atrial appendage biopsies of patients undergoing cardiac surgery. Premature atrial contractions (PACs) were induced by stimulation with isoproterenol (ISO, 100 nM) at increased [Ca]o (3.5 mM). Interestingly, compared to vehicle, PACs were significantly inhibited by exposure to GS-680 (at 100 and 300 nM). GS-680 also significantly decreased early and delayed afterdepolarizations in isolated human atrial myocytes. Moreover, GS-680 (at 100 or 300 nM) significantly inhibited diastolic SR Ca leak, measured as frequency of spontaneous SR Ca release events (Ca sparks) in isolated human atrial myocytes (Fluo-4 loaded) similar to the well-established peptide CaMKII inhibitor AIP. In accordance, GS-680 significantly reduced CaMKII autophosphorylation (Western blot) but enhanced developed tension after 10 or 30 s pause of electrical stimulation (post-rest behavior). Surprisingly, we found a strong negative inotropic effect of GS-680 in atrial trabeculae at 1 Hz stimulation rate, which was not observed at 4 Hz and abolished by beta-adrenergic stimulation. In contrast, GS-680 did not impair systolic force of isolated ventricular trabeculae from explanted hearts of heart transplant recipients at 1 Hz, blunted the negative force-frequency relationship (1-3 Hz) and significantly increased the Ca transient amplitude. CONCLUSION: The novel ATP-competitive and selective CaMKII inhibitor GS-680 inhibits pro-arrhythmic activity in human atrium and improves contractility in failing human ventricle, which may have therapeutic implications.

Effect of ranolazine on glycaemic control in patients with type 2 diabetes treated with either glimepiride or metformin.

AIM: To report the results of two phase III trials assessing the efficacy of ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy. METHODS: In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: When added to glimepiride, ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference -0.11% (95% CI -0.31, 0.1)]. CONCLUSIONS: Compared with placebo, addition of ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of ranolazine added to metformin for glycaemic control can be identified remains unclear.

Comparison of the antilipolytic effects of an A1 adenosine receptor partial agonist in normal and diabetic rats.

INTRODUCTION AND AIMS: Elevated plasma free fatty acid (FFA) concentrations play a role in the pathogenesis of type 2 diabetes (2DM). Antilipolytic agents that reduce FFA concentrations may be potentially useful in the treatment of 2DM. Our previous observation that CVT-3619 lowered plasma FFA and triglyceride concentrations in rats and enhanced insulin sensitivity in rodents with dietary-induced forms of insulin resistance suggested that it might be of use in the treatment of patients with 2DM. The present study was undertaken to compare the antilipolytic effects of CVT-3619 in normal (Sprague Dawley, SD) and Zucker diabetic fatty (ZDF) rats. RESULTS: ZDF rats had significantly higher fat pad weight, glucose, insulin and FFA concentrations than those of SD rats. EC(50) values for forskolin-stimulated FFA release from isolated adipocytes from SD and ZDF rats were 750 and 53 nM, respectively (p < 0.05). Maximal forskolin stimulation of FFA release was significantly (p < 0.01) less in ZDF rats (133 +/- 60 microM) compared with SD rats (332 +/- 38 microM). EC(50) values for isoproterenol to increase lipolysis in adipocytes from SD and ZDF rats were 2 and 7 nM respectively. Maximal isoproterenol-stimulated lipolysis was significantly (p < 0.01) lower in adipocytes from ZDF rats (179 +/- 23 microM) compared with SD rats (343 +/- 27 microM). Insulin inhibited lipolysis in adipocytes from SD rats with an IC(50) value of 30 pM, whereas adipocytes from ZDF rats were resistant to the antilipolytic actions of insulin. In contrast, IC(50) values for CVT-3619 to inhibit the release of FFA from SD and ZDF adipocytes were essentially the same (63 and 123 nM respectively). CVT-3619 inhibited lipolysis more than insulin in both SD (86 vs. 46%, p < 0.001) and ZDF (80 vs. 13%, p < 0.001) adipocytes. In in vivo experiments, CVT-3619 (5 mg/kg, PO) lowered FFA to a similar extent in both groups. Plasma concentrations of CVT-3619 were not different in SD and ZDF rats. There was no significant difference in the messenger RNA expression of the A(1) receptors relative to beta-actin expression in adipocytes from SD (0.98 +/- 0.2) and ZDF rats (0.99 +/- 0.3). CONCLUSION: The antilipolytic effects of CVT-3619 appear to be independent of insulin resistance and animal model.

Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium.

This commentary on the review by DA Saint in the current issue of the British Journal of Pharmacology focuses on the pathological role of late I(Na) in the heart, the evidence supporting inhibition of late I(Na) as a therapeutic target in ischaemic heart disease, and the therapeutic applications and challenges for development of new late I(Na) inhibitors. Recent reports from a large clinical outcome trial (MERLIN) of ranolazine, a drug known to inhibit late I(Na), indicated that it was safe and reduced recurrent ischaemia and arrhythmic activity. In combination with other results indicating that inhibition of late I(Na) reduces ischaemia, myocardial Ca(2+) overload, and electrical and mechanical dysfunction when late I(Na) is increased, the new clinical trial results suggest that reduction of cardiac late I(Na) is safe and therapeutically beneficial.

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.

Antiadrenergic effects of adenosine on His-Purkinje automaticity. Evidence for accentuated antagonism.

The effects of adenosine on the human His-Purkinje system (HPS) were studied in nine patients with complete atrioventricular (AV) block. Adenosine had minimal effect on the control HPS cycle length, but in the presence of isoproterenol increased it from 906 +/- 183 to 1,449 +/- 350 ms, P less than 0.001. Aminophylline, a competitive adenosine antagonist, completely abolished this antiadrenergic effect of adenosine. In isolated guinea pig hearts with surgically induced AV block, isoproterenol decreased the HPS rate by 36%, whereas in the presence of 1,3-dipropyl-8-phenyl-xanthine, a potent adenosine antagonist, the HPS rate decreased by 48% and was associated with an increased release of adenosine. Therefore, by blocking the effects of adenosine at the receptor level, the physiologic negative feedback mechanism by which adenosine antagonizes the effects of catecholamines was uncoupled. The results of this study indicate that adenosine's effects on the human HPS are primarily antiadrenergic and are thus consistent with the concept of accentuated antagonism. These effects of adenosine may serve as a counterregulatory metabolic response that improves the O2 supply-demand ratio perturbed by enhanced sympathetic tone. Some catecholamine-mediated ventricular arrhythmias that occur during ischemia or enhanced adrenergic stress may be due to an imbalance in this negative feedback system.

Reduction in preretinal neovascularization by ribozymes that cleave the A2B adenosine receptor mRNA.

Adenosine modulates a variety of cellular functions by interacting with specific cell surface G protein-coupled receptors (A1, A2A, A2B, and A3) and is a potential mediator of angiogenesis through the A2B receptor. The lack of a potent, selective A2B receptor inhibitor has hampered its characterization. Our goal was to design a hammerhead ribozyme that would specifically cleave the A2B receptor mRNA and examine its effect on retinal angiogenesis. Ribozymes specific for the mouse and human A2B receptor mRNAs were designed and cloned in expression plasmids. Human embryonic kidney (HEK) 293 cells were transfected with these plasmids and A2B receptor mRNA levels were determined by quantitative real-time RT-PCR. Human retinal endothelial cells (HRECs) were also transfected and cell migration was examined. The effects of these ribozymes on the levels of preretinal neovascularization were determined using a neonatal mouse model of oxygen-induced retinopathy (OIR). We produced a ribozyme with a Vmax of 515+/-125 pmol/min and a Kcat of 36.1+/-8.3 min(-1) (P< or =1x10(-5)). Transfection of HEK293 cells with the plasmid expressing the ribozyme reduced A2B receptor mRNA levels by 45+/-4.8% (P=5.1x10(-5)). Transfection of HRECs reduced NECA-stimulated migration of cells by 47.3+/-1.2% (P=7x10(-4)). Intraocular injection of the constructs into the mouse model reduced preretinal neovascularization by 53.5+/-8.2% (P=4.5x10(-5)). Our results suggest that the A2B receptor ribozyme will provide a tool for the selective inhibition of this receptor and provide further support for the role of A2B receptor in retinal angiogenesis.

Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells.

Adenosine, released in increased amounts by hypoxic tissues, is thought to be an angiogenic factor that links altered cellular metabolism caused by oxygen deprivation to compensatory angiogenesis. Adenosine interacts with 4 subtypes of G protein-coupled receptors, termed A(1), A(2A), A(2B), and A(3). We investigated whether adenosine causes proliferation of human retinal endothelial cells (HRECs) and synthesis of vascular endothelial growth factor (VEGF) and, if so, which adenosine receptor subtype mediates these effects. The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), in a concentration-dependent manner, increased both VEGF mRNA and protein expression by HRECs, as well as proliferation. This proliferative effect of NECA was inhibited by the addition of anti-human VEGF antibody. NECA also increased insulin-like growth factor-I and basic fibroblast growth factor mRNA expression in a time-dependent manner and cAMP accumulation in these cells. In contrast, neither the A(1) agonist N(6)-cyclopentyladenosine nor the A(2A) agonist 2-p-(2-carboxyethyl) phenethylamino-NECA caused any of the above effects of NECA. The effects of NECA were not significantly attenuated by either the A(2A) antagonist SCH58261 or the A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine. However, the nonselective adenosine receptor antagonist xanthine amine congener completely inhibited the effects of NECA. Addition of antisense oligonucleotide complementary to A(2B) adenosine receptor mRNA inhibited VEGF protein production by HRECs after NECA stimulation. Thus, the A(2B) adenosine receptor subtype appears to mediate the actions of adenosine to increase growth factor production, cAMP content, and cell proliferation of HRECs. Adenosine activates the A(2B) adenosine receptor in HRECs, which may lead to neovascularization by a mechanism involving increased angiogenic growth factor expression.

Hyperkalemia enhances the effect of adenosine on IK,ADO in rabbit isolated AV nodal myocytes and on AV nodal conduction in guinea pig isolated heart.

BACKGROUND: The atrioventricular (AV) node is insensitive to changes in extracellular potassium concentration, [K+]o, because of the absence of the inward rectifier potassium current (IK1). However, we propose that in the presence of adenosine, elevated [K+]o should increase the adenosine-activated inward rectifier potassium current (IK,ADO) in AV nodal myocytes and hence augment the negative dromotropic effect of the nucleoside. METHODS AND RESULTS: The effects of normal (4.8 mmol/L) and high (8.0 mmol/L) [K+]o on adenosine-induced changes in resting membrane potential (Vm), IK,ADO, and membrane resistance (Rm) in rabbit isolated AV nodal myocytes and in AV nodal conduction delay (atrium-to-His bundle, AH, interval) in guinea pig isolated hearts were determined with the use of whole-cell patch-clamp and His bundle electrogram techniques, respectively. High [K+]o alone did not significantly affect membrane current, Rm, or Vm in AV nodal myocytes. However, high [K+]o in the presence of adenosine (3 micromol/L) markedly increased Im (-0. 249+/-0.038 to -0.571+/-0.111 nA, P<0.05) at -100 mV and reduced Rm (151+/-21 to 77+/-8 MOmega, P<0.02). Adenosine still hyperpolarized Vm from -48+/-2 to -65+/-1 mV (P<0.001). High [K+]o alone did not significantly affect the AH interval in isolated hearts. However, high [K+]o markedly lengthened the AH interval prolongation caused by adenosine (4 micromol/L, 7.9+/-0.8 vs 22.1+/-3.0 ms, P<0.001). The potentiating effect of high [K+]o on adenosine-induced delay in AV nodal conduction was abolished by BaCl2 (100 micromol/L). CONCLUSIONS: By increasing IK,ADO and decreasing Rm of AV nodal myocytes, elevated [K+]o, augments the depressant effect of adenosine on AV nodal conduction.

Dose and time effects of caffeine intake on human platelet adenosine A(2A) receptors : functional and biochemical aspects.

BACKGROUND-We determined whether repeated caffeine administration at different dosages and for different periods of time (400 or 600 mg/d for 1 week or 400 mg/d for 2 weeks) upregulates human platelet adenosine A(2A) receptors and is accompanied by increases in cAMP accumulation and decreases in aggregation and calcium levels after stimulation of A(2A) receptors by the selective agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA). METHODS AND RESULTS-Platelets were obtained from peripheral venous blood of 45 healthy human volunteers at the end of 2 weeks of caffeine abstinence and at 12, 60, and 108 hours after the last dose of caffeine. The lowest dose of caffeine, when given for only 7 days, had no effect. Increasing the total dose, either by giving 400 mg/d for 14 days or giving 600 mg/d, resulted in binding assays performed with the adenosine A(2A) receptor radioligand [(3)H]SCH 58261 [5-amino-7(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1, 5-c]pyrimidine], in the upregulation of A(2A) receptors. Moreover, the potency of HE-NECA to produce antiaggregatory effects, a rise in cAMP accumulation, and a decrease in calcium levels was significantly increased. CONCLUSIONS-Chronic caffeine intake can lead to upregulation of adenosine A(2A) receptors, which is accompanied by sensitization, in a time- and dose-dependent manner, to the actions of the agonist HE-NECA.

Paroxysmal supraventricular tachycardia with Wenckebach block: evidence for reentry within the upper portion of the atrioventricular node.

Paroxysmal supraventricular tachycardia with Wenckebach block is an uncommon electrocardiographic finding. Electrophysiologic studies performed in a patient who exhibited this phenomenon indicated that the tachycardia was not caused by either sinus node or intraatrial reentry or abnormal automaticity. The tachycardia cycle length decreased after atropine administration and increased in response to propranolol. Administration of either adenosine (75 to 112.5 micrograms/kg) or verapamil (10 mg) terminated individual episodes of tachycardia. After verapamil and when atrial extrastimuli were introduced, dissociation of atrial activity from His-ventricular activity could be observed even though atrioventricular (AV) nodal block with a clear Wenckebach periodicity could also occur. These findings suggest that paroxysmal supraventricular tachycardia may be produced by reentry located solely within the upper portion of the AV node.

Effect of adenosine and adenosine-5'-triphosphate on atrioventricular conduction in patients.

This study was carried out to further elucidate the effects of adenosine and adenosine-5'-triphosphate (ATP) on atrioventricular (AV) conduction in patients. Adenosine (0.24 mg/kg) and ATP (0.28 mg/kg) were administered intravenously to 37 patients undergoing intracardiac electrophysiologic evaluation. Both adenosine and ATP depressed AV conduction by lengthening the atrial to His bundle (AH) interval. The effects of adenosine and ATP after rapid intravenous bolus administration were fast in onset (15 +/- 0.5 and 15 +/- 1.5 s, respectively), but transient in duration (10.5 +/- 0.5 s for ATP and 17 +/- 3 s for adenosine). Although muscarinic blockade with 0.04 mg/kg atropine shortened the AH interval from a control value of 123 +/- 12 to 74 +/- 4 ms, it did not modify the effects of adenosine or ATP, or both (that is, latency and duration of the effects were not significantly different from before atropine administration). In contrast, aminophylline, a competitive antagonist of adenosine, completely prevented the effects of adenosine and ATP. Aminophylline alone also shortened the AH interval from a control value of 98 +/- 9 to 74 +/- 9 ms. This decrease was blocked by propranolol (0.1 mg/kg), whereas propranolol did not influence the ability of aminophylline to antagonize the effects of adenosine or ATP, or both. Thus, the catecholamines released by aminophylline are unlikely to account for the ability of aminophylline to antagonize the effects of adenosine and ATP. In conclusion, these findings indicate that intravenously administered adenosine and ATP are equally effective in producing AV block that is antagonized by aminophylline but not by atropine.

Induction of atrioventricular node reentrant tachycardia with adenosine: differential effect of adenosine on fast and slow atrioventricular node pathways.

OBJECTIVES: This study sought to evaluate the sensitivity of fast and slow atrioventricular (AV) node pathways to incremental doses of adenosine in patients with typical AV node reentrant tachycardia. BACKGROUND: Although adenosine is known to depress conduction through the AV node, the relative sensitivity to adenosine of the anterograde fast and slow pathways in patients with dual AV node pathways and typical AV node reentrant tachycardia has not previously been studied. METHODS: Sixteen patients with dual AV node physiology and typical AV node reentrant tachycardia and 10 control patients were given incremental doses of adenosine during atrial pacing. RESULTS: In 14 of 16 patients with dual-AV node physiology, administration of small doses of adenosine during atrial pacing led consistently to transient block of impulse conduction in the fast pathway before block in the slow pathway, resulting in abrupt prolongation of the AH interval with continued 1:1 AV conduction. The mean (+/- SD) doses of adenosine required to cause conduction block in the fast and slow pathways were 2.7 +/- 3.0 and 7.2 +/- 4.7 mg, respectively (p = 0.004). In 9 of 16 patients, administration of low dose adenosine led to initiation of AV node reentrant tachycardia. The control patients showed no abrupt increases in AH interval with administration of adenosine during atrial pacing. CONCLUSIONS: In most patients with dual AV node pathways and typical AV node reentrant tachycardia, the fast pathway is more sensitive than the slow pathway to the effects of adenosine.

Effects of dipyridamole and aminophylline on hemodynamics, regional myocardial blood flow and thallium-201 washout in the setting of a critical coronary stenosis.

Experiments were performed to characterize the interaction of intravenous dipyridamole and aminophylline on thallium-201 transport kinetics, regional myocardial blood flow and systemic hemodynamics in the presence of a critical coronary artery stenosis. In 12 dogs with a critical left anterior descending coronary artery stenosis, arterial pressure decreased from a mean value (+/- SEM) of 107 +/- 6 to 94 +/- 3 mm Hg (p less than 0.05) and distal left anterior descending artery pressure decreased from 70 +/- 7 to 55 +/- 4 mm Hg (p less than 0.05) after intravenous administration of dipyridamole (0.25 mg/kg body weight). In the left anterior descending perfusion zone, the endocardial/epicardial flow ratio decreased from 0.70 to 0.36 and the intrinsic thallium washout rate was significantly prolonged. Intravenous aminophylline (5 mg/kg) reversed the dipyridamole-induced systemic hypotension and transmural coronary steal and restored the thallium washout rate to baseline values. In six other dogs, aminophylline alone resulted in no alterations in systemic and coronary hemodynamics or regional myocardial blood flow. As expected, dipyridamole-induced vasodilation and coronary steal were prevented by aminophylline pretreatment. These data show that in a canine model of partial coronary stenosis, systemic hypotension, adverse regional flow effects (coronary steal) and prolonged thallium-201 washout consequent to intravenously administered dipyridamole are promptly reversed by intravenous aminophylline administration. Aminophylline alone had no significant hemodynamic and coronary flow effects. This study provides further insight into the altered thallium kinetics occurring as a consequence of dipyridamole-induced vasodilation and suggests that the prompt reversal of symptoms and signs of ischemia with aminophylline in patients receiving intravenous dipyridamole for clinical imaging studies probably reflects the reversal of transmural coronary steal.

Adenosine-induced atrioventricular block: a rapid and reliable method to assess surgical and radiofrequency catheter ablation of accessory atrioventricular pathways.

Adenosine has been shown to inhibit anterograde and retrograde conduction through the atrioventricular (AV) node while having little or no effect on accessory pathway conduction. Its rapid onset of action and short half-life make it particularly suitable for repetitive measurements. In this study, the utility of adenosine was tested in assessing completeness of accessory pathway ablation. Sixteen patients with an accessory pathway were studied (eight surgical ablations, eight catheter ablations with radiofrequency energy). Before ablation, no accessory pathway was sensitive to adenosine. Twelve patients with pre-excitation showed high grade AV node block with maximal pre-excitation on the administration of adenosine during atrial pacing. Four patients with a concealed accessory pathway demonstrated high grade AV block without evidence of latent anterograde accessory pathway conduction. Preablation ventriculoatrial (VA) block was not observed in any of the 16 patients in response to adenosine during ventricular pacing. Immediately after accessory pathway ablation, all patients developed AV and VA block with the administration of adenosine during atrial and ventricular pacing, respectively. These findings were confirmed during follow-up study 1 week later. Atrioventricular block during atrial and ventricular pacing with adenosine affords a reliable and immediate assessment of successful pathway ablation.

Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias.

Adenosine has been shown to affect both sinus node automaticity and atrioventricular (AV) nodal conduction. The effects of increasing doses of intravenous adenosine were assessed in 46 patients with supraventricular tachyarrhythmias. Adenosine reliably terminated episodes of supraventricular tachycardia in all 16 patients with AV reciprocating tachycardia, in 13 of 13 patients with AV nodal reentrant tachycardia and in 1 of 2 patients with junctional tachycardia with long RP intervals. Adenosine produced transient high grade AV block without any effect on atrial activity in six patients with intraatrial reentrant tachycardia, four patients with atrial flutter, three patients with atrial fibrillation and in single patients with either sinus node reentry or an automatic atrial tachycardia. The dose of adenosine required to terminate episodes of supraventricular tachycardia was variable (range 2 to 23 mg). Side effects were minor and of short duration. These results demonstrate that adenosine is useful for the acute therapy of supraventricular tachycardia whenever reentry through the AV node is involved. When arrhythmia termination is not affected, atrial activity may be more readily analyzed during adenosine-induced transient AV block.

Mechanism of atropine-resistant atrioventricular block during inferior myocardial infarction: possible role of adenosine.

Mechanisms responsible for atrioventricular (AV) block during acute inferior myocardial infarction are only partially understood. Increased parasympathetic tone is the factor usually postulated; however, persistence of AV block after atropine administration is frequently observed. Adenosine, an endogenous ischemic metabolite, has well established depressant effects on AV node conduction. In this report, an episode of atropine-resistant AV block was reversed by aminophylline, a competitive adenosine antagonist, in a patient with an acute inferior myocardial infarction. This observation suggests a role for adenosine in the mediation of ischemia-induced AV node block.

Bradycardia after heart transplantation: reversal with theophylline.

OBJECTIVES: We attempted to demonstrate that theophylline, an adenosine receptor antagonist, can reverse bradyarrhythmias after orthotopic heart transplantation. BACKGROUND: Sinus node dysfunction, primarily sinus bradycardia, frequently occurs after orthotopic heart transplantation and may lead to permanent pacemaker implantation. Endogenous adenosine has been implicated as a cause of such posttransplantation bradyarrhythmia. METHODS: Twenty-nine transplant recipients (group 1) were given theophylline after bradyarrhythmias developed after transplantation. Data in these patients were compared with those in a control group of 18 patients without bradyarrhythmias (group 2) who were not given theophylline. RESULTS: The mean heart rate in group 1 increased from 62 +/- 7 to 89 +/- 10 beats/min after administration of theophylline (p < 0.0001); the mean heart rate in group 2 was 88 +/- 12 beats/min. Patients in group 1 required more days of temporary atrial pacing (3.5 +/- 1 vs. 1.5 +/- 3, p < 0.04) before the administration of theophylline than did patients in group 2. The length of hospital stay after transplantation did not differ significantly between groups 1 and 2 (17 +/- 7.5 vs. 20 +/- 16 days, p = NS). Age, gender, underlying disease, preoperative use of amiodarone, graft ischemia time or the incidence of moderate to severe rejection were not different between patient groups. CONCLUSIONS: The use of theophylline for posttransplantation bradyarrhythmias increased heart rate and facilitated the withdrawal of chronotropic support. We conclude that theophylline offers effective and specific therapy for heart transplant patients with early bradyarrhythmias, reducing the need for implantation of a permanent pacemaker.

Inflammatory agents regulate in vivo expression of fractalkine in endothelial cells of the rat heart.

Fractalkine is distinguished structurally from other chemokines in that it contains a mucin-like stalk that tethers a CX3C chemokine module to a transmembrane-spanning region; its expression in cultured endothelial cells has been shown to be up-regulated by tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1). The purpose of this study was to determine whether fractalkine is expressed, in a proinflammatory agent-regulated manner, by cardiac endothelial cells in vivo. Steady state levels of fractalkine mRNA were increased in rat cardiac tissues after in vivo treatment with lipopolysaccharide (LPS), IL-1, or TNF-alpha. In situ hybridization and immunohistochemical analysis revealed that endothelial cells of the coronary vasculature and endocardium were the principal source of proinflammatory agent-inducible fractalkine, although some fractalkine immunoreactivity was also found on the myocytes. These data are the first demonstration of in vivo cardiac endothelial cell fractalkine expression and regulation by proinflammatory agents such as LPS, IL-1, or TNF-alpha. Cardiac endothelial cell-expressed fractalkine may contribute to the influx of leukocytes into the heart during inflammation.

Role of adenosine as mediator of bradyarrhythmias during hypoxia in isolated guinea pig hearts.

Tissue concentrations of adenosine, an endogenous metabolite with negative chronotropic and dromotropic actions, are known to increase when myocardial oxygen supply is reduced. In this study the concentrations of endogenous adenosine released during a period of hypoxic perfusion were measured to determine whether they are sufficient to account for the effect of hypoxia on atrioventricular conduction in isolated perfused guinea pig hearts. In addition, the efficacy of competitive adenosine antagonism in reversing the effect of hypoxia on atrioventricular conduction and atrial automaticity were compared. Effluent samples for adenosine were collected at the onset of spontaneous and atrial pacing induced second degree atrioventricular block during hypoxic perfusion (PO2 3.07 kPa) and during the combined infusion of adenosine plus the nucleoside transport blocker, dipyridamole (PO2 71.1 kPa). The mean (SEM) atrial cycle lengths associated with the onset of atrioventricular block were 333(10) and 297(2) ms respectively. Effluent concentrations of adenosine associated with atrioventricular block during hypoxia (2342(160) pmol X min-1 X g-1 heart weight) were approximately equal to those obtained during the infusion of adenosine plus dipyridamole (2538(256) pmol X min-1 X g-1 heart weight) (no statistically significant difference). During hypoxic perfusion, among hearts showing spontaneous atrioventricular block and those in which atrial slowing prevented the onset of spontaneous block, the competitive adenosine antagonist aminophylline (60 mumol X litre-1) reversed either spontaneous or atrial pacing induced block without any effect on spontaneous atrial cycle length.(ABSTRACT TRUNCATED AT 250 WORDS)