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Biomedical subjects

A Pelleg

Publications and source records attributed to A Pelleg.

At least 37 records · Page 2Linked to original sources
PubMed1994

Responsiveness of in situ canine nodose ganglion afferent neurones to epicardial mechanical or chemical stimuli.

OBJECTIVE: The aim was to determine the capacity of nodose ganglion afferent neurones with epicardial sensory endings to respond to mechanical and chemical stimuli, in particular to purinergic compounds. METHODS: Alterations in spontaneous activity generated by epicardial afferent neurones in nodose ganglia in situ of 17 anaesthetised dogs were identified using extracellular recording techniques when mechanical and chemical stimuli were applied to their receptor fields, as well as during brief periods of coronary artery occlusion. RESULTS: 92 cardiac afferent neurones were identified. Localised epicardial distortion modified the activity generated by 34 neurones [0.19(SEM 0.02) to 1.2(0.4) impulses.s-1]. Application of bradykinin, substance P, N6-cyclopentyladenosine or beta, gamma-methylene adenosine 5'-triphosphate to localised epicardial fields altered the activity of 69 neurones. Thus the majority of identified epicardial neurones responded to chemical stimuli alone (63%) as opposed to mechanical stimuli alone (25%), 12% responding to both types of stimuli. Activity was enhanced overall by chemical stimuli from a mean range of 0.1-0.4 to 11.6-13.2 impulses.s-1. Following termination of short lasting chemical as opposed to mechanical stimuli, activity remained increased for up to 45 min. Activity generated by 16 chemosensitive neurones was modified by brief periods of coronary artery occlusion [0.26(0.12)-1.66(0.61) impulses.s-1]; activity increasing further [2.51(0.47) impulses.s-1] during reperfusion periods. CONCLUSIONS: (1) Chemical stimuli induce an order magnitude greater enhancement of activity generated by nodose ganglion cardiac afferent neurones than do mechanical stimuli, such enhancement persisting long after removal of chemical as opposed to mechanical stimuli. Thus qualitative and quantitative differences exists between central neuronal inputs derived from nodose ganglion epicardial afferent neurones sensitive to chemical as opposed to mechanical stimuli. (2) Adenosine and ATP can activate nodose ganglion cardiac afferent neurones.

Adenosine↗
PubMed1994

Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs. II. Vagal afferent traffic.

Extracellular ATP can act on chemosensitive vagal C-fiber nerve terminals in the lungs, thereby eliciting a pulmonary-cardiac depressor reflex. Previous studies have shown a right vagal dominance in afferent traffic elicited by intra-right atrial ATP. To elucidate the mechanism of this phenomenon, the following hypotheses were tested in a canine model. 1) Intra-right and intra-left pulmonary ATP elicit neural afferent traffic, which travels via the right and left vagus nerves, respectively. 2) Intra-right vs. intra-left pulmonary ATP causes similar suppression of sinus node automaticity. Data obtained in this study support both hypotheses and suggest that right vagal dominance in afferent neural traffic elicited by ATP is probably due to the action of ATP and/or its metabolites on nonpulmonary tissues.

Adenosine Triphosphate↗
PubMed1994

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

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: (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.

Action Potentials↗
PubMed1994

Novel approach for enhancing atrioventricular nodal conduction delay mediated by endogenous adenosine.

The 2-amino-3-benzoylthiophene derivative PD 81,723 potentiates the A1 receptor-mediated negative dromotropic effect of exogenous adenosine and adenosine receptor agonists in guinea pig isolated perfused and in situ hearts. The objective of this study was to determine whether PD 81,723 could amplify the cardiac actions of endogenous adenosine. Two approaches known to increase the myocardial interstitial concentration of adenosine--hypoxia, which increases the production of adenosine and the inhibition of adenosine kinase, which decreases its metabolism--were used to test this hypothesis. In guinea pig hearts in situ, PD 81,723 (2 mg/kg i.v.) potentiated the atrioventricular (AV) nodal conduction delay caused by hypoxemia (PaO2, 14 to 19 mm Hg). In guinea pig isolated hearts, PD 81,723 (5 mumol/L) increased by twofold the stimulus-to-His bundle (S-H) interval prolongations induced by both a 5-minute period of hypoxia (25% O2/70% N2/5% CO2) and the administration of the adenosine kinase inhibitor iodotubercidin (40 to 70 nmol/L) but had no effect on coronary conductance. Hypoxia and hypoxia plus PD 81,723 (5 mumol/L) caused equivalent increases in the concentration of adenosine in epicardial transudate, from 0.13 +/- 0.15 to 0.48 +/- 0.1 and 0.45 +/- 0.4 mumol/L, respectively. Similar to the allosteric enhancer, the nucleoside uptake blocker draflazine (0.1 mumol/L) also increased by twofold the S-H interval prolongation caused by hypoxia. In contrast to the allosteric enhancer, draflazine increased the concentration of adenosine in epicardial transudate during hypoxia from 0.48 +/- 0.15 to 1.5 +/- 0.4 mumol/L. Draflazine also increased coronary conductance by approximately twofold in guinea pig normoxic constant-fold perfused hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1993

Aggregation of human and canine platelets: modulation by purine nucleotides.

This study compared the responses of canine and human platelets to various aggregating agonists in the presence or absence of extracellular ATP and ATP analogues. Canine and human platelets were approximately equally reactive with ADP or collagen while the canine platelets were about 10 fold more sensitive to thrombin. Canine platelets were insensitive to the thromboxane mimetic U46619 but were synergistically aggregated by a mixture of ADP and U46619. Human platelets were very sensitive to U46619. Aggregations of human platelets with all of the above agonists were inhibited by extracellular ATP; beta, gamma methylene ATP (beta gamma ATP) and benzoyl ATP (BzATP) with a rank order suggestive of an interaction with P2x-like purinoceptors which support our previous findings. The comparable aggregations of canine platelets were likewise inhibited by ATP and its analogues but with a rank order suggestive of an interaction with P2y-like purinoceptors. ATP inhibited U46619- and ADP-induced aggregation of human platelets and ADP-induced aggregation of canine platelets, presumably, in part, due to competition for the ADP P2T receptor. However, when U46619 was added to either ATP or ATP analogue-inhibited ADP-treated canine platelets, the inhibition was nullified. Furthermore, we demonstrated, for the first time, that the canine thromboxane receptor becomes reactive to U46619 alone after incubation at room temperature for 3.5-5 hrs while human platelets become inactive under similar conditions. The implication of these studies is that there are significant differences in the canine and human platelet thromboxane and purine receptors. The future characterization of these differences and the mechanism by which they function should further our understanding of the impact of extracellular ATP on hemostasis and thrombosis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Adenosine in the heart: its emerging roles.

An important regulator of cardiac rhythm and coronary blood flow, adenosine is finding valuable applications in treatment and diagnosis. It should soon be available for cardiac imaging and eventually as a protective agent against acute myocardial infarction and reperfusion injury. Study of adenosine's uses is providing insights into its biologic effects in a variety of organ systems.

Adenosine↗
PubMed1993

Endogenous adenosine, A1 adenosine receptor, and pertussis toxin sensitive guanine nucleotide binding protein mediate hypoxia induced AV nodal conduction block in guinea pig heart in vivo.

OBJECTIVE: The aim was to study the mechanism of global hypoxia induced atrioventricular (AV) nodal conduction block in vivo using a guinea pig model. METHODS: Animals subjected to 10 min periods of global hypoxia, induced by decremental changes in O2 content in the inhaled gas mixture, were randomly divided into three groups: group I = control; group II = animals treated with a new selective A1 adenosine receptor antagonist, N0861 (N6-endo-norbornan-2-yl-9-methyladenine); and group III-animals treated with pertussis toxin, an irreversible inhibitor of specific guanine nucleotide binding proteins (G protein). RESULTS: Progressive incremental hypoxia was associated with progressive AV nodal conduction delay culminating in a complete block. In addition, there was an inverse relationship between the severity of hypoxia and time to AV nodal block. Both N0861 and pertussis toxin treatment significantly reduced the degree of hypoxia induced AV nodal conduction block and delayed its appearance. CONCLUSIONS: (1) Endogenous adenosine released during acute global hypoxia causes AV nodal conduction block observed under these conditions in the guinea pig heart in vivo; and (2) this action of adenosine in the AV node is mediated by an A1 adenosine receptor and a pertussis toxin sensitive G protein.

Adenine↗
PubMed1993

Mechanisms of action and therapeutic potential of adenosine and its analogues in the treatment of cardiac arrhythmias.

Adenosine is a purine nucleoside found in every cell of the human body. In addition to its well-established role in cellular metabolism, extracellular adenosine exerts pronounced effects on the cardiovascular system. These effects, mediated by specific cell surface receptors, include a negative chronotropic effect on cardiac pacemakers, a negative dromotropic effect on atrioventricular nodal conduction, an antiadrenergic effect, and a vasodilatory effect on blood vessels. In addition, adenosine can attenuate platelet aggregation and neutrophil activation and alter cardiac metabolism. Its electrophysiologic effects on atrioventricular nodal conduction constitute the rationale for the use of adenosine as an antiarrhythmic drug for the acute management of paroxysmal reentrant supraventricular tachycardias involving the atrioventricular node, as well as for its use as a diagnostic tool in broad complex tachycardias and in preexcitation. The antiadrenergic action of adenosine explains its potential use in the acute management of catecholamine-dependent ventricular tachycardias. Several of the other effects of adenosine suggest the use of this compound as well as its analogues as cardioprotective agents in the setting of myocardial ischemia (occlusion then reperfusion of coronary vessels, cardioplegia, coronary angioplasty, thrombolysis, and so forth).

Adenosine↗
PubMed1993

Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs.

To test the hypothesis that afferent traffic of the ATP-triggered vagal reflex travels mainly in the right vagus nerve, we quantitated the response of the sinus node pacemaker activity and atrioventricular (AV) nodal conduction to increasing doses of intra-atrial ATP under baseline conditions, in the presence of aminophylline, and subsequently after either right followed by left cervical vagotomy or vice versa. In addition, the effect of right vagal C-fiber afferent blockade on the action of ATP in the sinus node was also determined. Because vagal efferent traffic to the sinus and AV nodes travels mainly via the right and left vagus nerves, respectively, the working hypothesis predicted that left vagotomy would have a much smaller effect than right vagotomy on the negative chronotropic action of ATP in the sinus node and predicted similar effects of left vs. right vagotomy on the negative dromotropic action of ATP on AV nodal conduction. ATP suppressed sinus node automaticity and AV nodal conduction in a dose-dependent manner. The attenuation of the action of ATP on the sinus node by right vagotomy was much more pronounced than that caused by left vagotomy, while the negative dromotropic action of ATP in the AV node was similarly attenuated by right vs. left vagotomy. In addition, sinus node automaticity, which was only mildly attenuated by left vagotomy, was markedly suppressed by right vagal C-fiber afferent blockade. It was concluded that in the dog, afferent vagal traffic triggered by intra-right atrial ATP travels under these experimental conditions mainly via the right vagus nerve.

Adenosine Triphosphate↗
PubMed1993

Modulation of in situ canine intrinsic cardiac neuronal activity by locally applied adenosine, ATP, or analogues.

To determine whether adenosine or ATP can modify mammalian intrinsic cardiac neurons, these substances, as well as their analogues 5'-(N-ethylcarboxamido)-adenosine (NECA), N6-cyclopentyladenosine (CPA), and beta,gamma-methylene ATP (beta,gamma-mATP), were applied in microliter quantities adjacent to spontaneously active canine atrial ganglionated plexus neurons in 14 anesthetized open-chest dogs. Adenosine, NECA, and CPA induced neuronal responses, neuronal activity being either increased or decreased in 81, 86, and 86% of the sites tested, respectively. Cardiovascular responses were elicited by these agents in 21-31% of neurally active loci. ATP and beta,gamma-mATP elicited neuronal responses in 100 and 70% of tested loci, respectively. Associated cardiovascular responses were elicited by ATP and beta,gamma-mATP in 35 and 18% of the sites, respectively. After acute decentralization of the intrinsic cardiac nervous system, neuronal responses were elicited by purines in 73% of the previously active sites, while cardiovascular responses were either attenuated or eliminated. It is concluded that exogenous purine nucleosides and nucleotides can modulate the activity generated by in situ intrinsic cardiac neurons presumably by acting on P1 and P2 purinoreceptors. Furthermore, these data indicate that purine sensitive intrinsic cardiac neurons are involved in cardiac regulation.

Adenosine↗
PubMed1993

Selective potentiation by an A1 adenosine receptor enhancer of the negative dromotropic action of adenosine in the guinea pig heart.

The drug (2-amino-4,5-dimethyl-3-thienyl)-[3(trifluoromethyl)-phenyl]methanone (PD 81,723) has been shown to enhance allosterically A1 adenosine receptor binding in brain membranes. The objective of this study was to determine the specificity and selectivity (A1 versus A2) of PD 81,723 as an enhancer of the negative dromotropic effect of exogenous adenosine in guinea pig isolated and in situ hearts. In isolated hearts, PD 81,723 alone produced only a small stimulus to His bundle (S-H) interval prolongation of 1.5 to 4 msec, which was completely reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase. PD 81,723 (5 microM) significantly decreased the EC50 value of adenosine for prolongation of the S-H interval from 6.7 +/- 0.6 to 4.4 +/- 0.5 microM. The potentiation of the negative dromotropic effect of adenosine by PD 81,723 was dose dependent, i.e., 5 and 10 microM PD 81,723 enhanced the maximal S-H interval prolongation caused by 3 microM adenosine by 207% and 609%, respectively. In contrast, the same concentration of PD 81,723 had no effect on either the S-H interval prolongation caused by carbachol or MgCl2 or the coronary vasodilatory effect of adenosine. In in situ hearts, PD (2 mumol/kg i.v.) alone caused only a small but not significant negative dromotropic effect, increasing the atrium to His interval from 58 +/- 2 to 61 +/- 1 msec. However, the same dose of PD 81,723 caused a significant leftward and upward shift of the adenosine dose-response curve for inducing atrium to His bundle interval prolongation and increased the degree of atrioventricular block caused by adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1992

Effects of N6-endonorbornan-2-yl-9-methyladenine, N0861, on negative chronotropic and vasodilatory actions of adenosine in the canine heart in vivo.

The pharmacology of N6-endonorbornan-2-yl-9-methyladenine (N0861), a new selective antagonist of adenosine at the A1 adenosine receptor subtype (A1-AdoR), was studied in vivo using a canine model. First, the pharmacokinetics of N0861 were determined in anesthetized dogs. The time-dependent decay of plasma levels of N0861 fitted a two-compartment polyexponential model with alpha-phase t1/2 = 3.80 min and beta-phase t1/2 = 80.55 min. Secondly, the effect of N0861 on the negative chronotropic and vasodilatory actions of adenosine in the canine heart were determined. N0861 attenuated the negative chronotropic action of adenosine (1-6 mumol/kg; rapid bolus into the right atrium) on sinus node pacemaker activity in a dose-dependent manner (pA2 = 4.23). For example, the maximal prolongation of sinus cycle length induced by 6 mumol/kg adenosine was 82 +/- 13% under baseline conditions and 57 +/- 10, 34 +/- 5 and 34 +/- 6% during infusion of N0861 at incremental rates leading to plasma levels of 7.75 +/- 1.02, 14.15 +/- 0.87, and 19.71 +/- 1.83 micrograms/mL, respectively. In contrast, N0861 did not inhibit but had a tendency to potentiate the vasodilatory action of adenosine (thought to be mediated by the A2 adenosine receptor subtype (A2-AdoR)) on the left anterior descending and circumflex coronary arteries. These data indicate that two different receptors, similar to the typical A1-AdoR and A2-AdoR, mediate the electrophysiologic and vasodilatory actions of adenosine in the canine heart, respectively, and that N0861 is a selective antagonist of adenosine at A1-AdoR in the canine heart in vivo.

Adenine↗
PubMed1990

Differential sensitivity of cardiac pacemakers to exogenous adenosine in vivo.

Adenosine exerts pronounced depressant effects on cardiac pacemakers. Previous studies in vitro have indicated that different pacemakers exhibit variable sensitivity to adenosine: ventricular greater than junctional greater than sinus node pacemakers. This study tested the hypothesis that ventricular pacemakers are more sensitive to adenosine than sinus node pacemakers in vivo in an experimental canine model and determined the mechanism involved in this phenomenon using specific pharmacological interventions. For this purpose, dogs with chronic atrioventricular block, stable ventricular escape rhythm, and bilateral stellectomy and cervical vagotomy were studied. Dose-response curves for negative chronotropic action of adenosine in the sinus node and ventricular pacemakers were obtained in group 1 under base-line conditions, during isoproterenol infusion, and after subsequent administration of propranolol; in group 2 before and after administration of quinidine; in group 3 before and after administration of aminophylline; and in group 4 before and after administration of 1,3-dipropyl-8-phenylxanthine amine congener (XAC). Adenosine exerted a dose-dependent negative chronotropic effect on sinus node and ventricular pacemakers. At all doses tested, this action was more pronounced in the ventricle. Isoproterenol accentuated the action of adenosine in the sinus node (by 60-138%; P less than 0.05) but suppressed it in the ventricle (-37 to 53%; P less than 0.05). These effects of isoproterenol were attenuated by propranolol. Quinidine suppressed the action of adenosine in the sinus node (-38 to -52%; P less than 0.05) but not in the ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1990

The pharmacology of adenosine.

Adenosine is a purine nucleoside present in every cell of the human body. It is released into the extracellular space under physiologic and pathophysiologic conditions characterized by increased oxygen demand:supply ratio. Adenosine can exert a wide spectrum of effects in various organs and tissues. Exogenous adenosine has a wide spectrum of effects in experimental animal models as well as humans. The pharmacokinetics, pharmacodynamics, and the interaction of adenosine with other drugs are reviewed.

Adenosine↗
PubMed1989

Extracellular potassium ion dynamics and ventricular arrhythmias in the canine heart.

The relation between extracellular potassium ion activity [( K+]o) and ventricular tachyarrhythmias was studied in an open chest canine model with the use of two protocols. In Protocol I, potassium chloride was administered into the proximal left anterior descending coronary artery at a rate of 0.125 mEq/min for either 20 min or until [K+]o = 20 mEq/liter, whichever came first. In Protocol II, the proximal left anterior descending coronary artery was occluded in one step and was reperfused 20 min later. Fifteen dogs were subjected to Protocol I, nine of which were also subjected to Protocol II. In the latter group, a recovery period of greater than or equal to 1 h separated the two protocols. Local K+ and intramyocardial activities were recorded with use of bifunctional ion-sensitive plunge electrodes at multiple sites located in the region of the left ventricle perfused by the left anterior descending artery and at one site outside of this region. The following variables were recorded and analyzed: Lead II electrocardiogram, heart rate, systemic arterial blood pressure, local [K+]o and its time derivative (dK+/dt), local electrograms and ventricular arrhythmias. Maximal [K+]o and dK+/dt were 23 +/- 3 mEq/liter and 9 +/- 1 mEq/liter per min in Protocol I and 14 +/- 1 mEq/liter and 3 +/- 1 mEq/liter per min in Protocol II, respectively. In both protocols, the occurrence of ventricular arrhythmias correlated with [K+]o (p less than 0.02) as well as with dK+/dt (p less than 0.05). Ventricular arrhythmias were more frequent and more severe in Protocol II than in Protocol I (p less than 0.05). Therefore, whereas K+ dynamics were more pronounced in Protocol I, ventricular arrhythmias were more severe in Protocol II. This occurrence was apparently due, at least in part, to less heterogeneous changes in K+ gradients during constant K+ infusion. It was concluded that, in addition to the magnitude of [K+]o, the rate of change of this variable (that is, dK+/dt) apparently plays an important role in the genesis of ischemic ventricular arrhythmias.

Animals↗