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Biomedical subjects

L Belardinelli

Publications and source records attributed to L Belardinelli.

At least 55 records · Page 3Linked to original sources
PubMed1996

Selective attenuation by N-0861 (N6-endonorboran-2-yl-9-methyladenine) of cardiac A1 adenosine receptor-mediated effects in humans.

BACKGROUND: To determine the adenosine receptor subtype selectivity of the novel antagonist N-0861, the A1 and A2 receptor-mediated cardiac effects of adenosine were investigated in 13 patients during continuous intravenous infusion and boluses of adenosine before and after intravenous infusion of N-0861. METHODS AND RESULTS: Measurements of the the atria-to-His (A-H) interval, chest pain severity, and coronary blood flow velocity were made before and after low-dose (69 microg x kg(-1) x min(-1)) intravenous infusion and bolus (2.5 mg) adenosine. Two doses of N-0861 were infused intravenously, and the adenosine protocol was repeated. N-0861 0.25 mg/kg abolished the negative dromotropic effect (A-H interval prolongation) and chest discomfort experienced during infusion of adenosine and attenuated discomfort observed during the boluses of adenosine; however, the increase in coronary blood flow velocity was not significantly affected. CONCLUSIONS: These actions of N-0861 support the concept that the negative dromotropic effect and anginalike pain caused by adenosine are A1 adenosine receptor-mediated, whereas the increase in coronary blood flow velocity is due to activation of A2 adenosine receptors. N-0861 appears to be an effective and selective A1 adenosine receptor antagonist in humans.

Adenine↗
PubMed1996

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.

Arrhythmia, Sinus↗
PubMed1996

Effects of verapamil and diltiazem on the ventricular rate during simulated atrial flutter in isolated guinea pig hearts.

To compare the direct effects of verapamil and diltiazem on the ventricular rate during atrial flutter, we developed an atrial flutter model in guinea pig isolated hearts. Atrial flutter was simulated by rapid atrial pacing (cycle length = 50 ms). At this atrial pacing cycle length, the shape of the frequency of distribution of the ventricular cycle lengths was comparable to that during spontaneous atrial flutter. Verapamil (0.01, 0.03 microM) and diltiazem (0.03, 0.09 microM) caused a comparable prolongation of the atrioventricular conduction time and atrioventricular refractoriness. Also, the anterograde Wenckebach cycle length was increased to a comparable degree by both substances. The mean ventricular cycle length during atrial flutter was comparable prolonged by both substances. The prolongation of the maximal ventricular cycle length was significantly more pronounced in the presence of verapamil. The time dependence of drug-induced alterations in atrioventricular conduction time during abrupt changes of heart rate is significantly more pronounced in the presence of verapamil compared to diltiazem. In conclusion, the more pronounced effect of verapamil on the maximal ventricular cycle length compared to the action of diltiazem may be explained by the slow binding kinetic of this drug to the Ca2+ channel resulting in a longlasting blockade of the Ca2+ channel.

Animals↗
PubMed1996

Electrophysiological and functional effects of adenosine on ventricular myocytes of various mammalian species.

The goal of this study was to determine the electrophysiological and functional effects of adenosine on ventricular myocytes of guinea pig, rabbit, rat, and ferret hearts. Adenosine (100 microM) shortened the action potential durations of rat and ferret myocytes by 14 +/- 1 and 57 +/- 7%, reduced the amplitudes of cell twitch shortening by 13 +/- 1 and 54 +/- 5%, and increased outward currents by 15 +/- 4 and 55 +/- 5%, respectively, but had no effect on guinea pig and rabbit myocytes. The properties of adenosine-activated outward current in rat and ferret ventricular myocytes indicated that this current is the adenosine-sensitive K+ current [IK(Ado)]. Adenosine had no significant effect on basal Ca2+ current but specifically inhibited isoproterenol-stimulated L-type Ca2+ current in myocytes of all species studied. Binding studies revealed that the density of A1 adenosine receptors (A1AdoR) was highest in ferret and lowest in rabbit myocytes, but the differential effects of adenosine among species could not be solely explained by differences in A1AdoR density. In summary, adenosine shortened the action potential and reduced the twitch shortening of rat and ferret but not of guinea pig and rabbit ventricular myocytes. Shortening of the action potential was associated with the activation of IK(Ado). The anti-beta-adrenergic action of adenosine appeared to be independent of species.

Action Potentials↗
PubMed1996

Nonspecific inhibition of adenosine-activated K+ current by glibenclamide in guinea pig atrial myocytes.

The ATP-sensitive K+ (KATP) channel blocker glibenclamide was reported to inhibit the K+ current activated by adenosine. This study investigated whether the inhibition by glibenclamide of the adenosine-induced current is due to a specific blockade of KATP channels in guinea pig atrial myocytes. In the absence of adenosine, the basal background current was an inward rectifier K+ current (IK1). Glibenclamide at concentrations of 10, 30, and 100 microM reduced the basal background K+ current by 15 +/- 6, 43 +/- 10, and 63 +/- 11%, respectively. In the presence of adenosine (10 microM), glibenclamide (30 microM) decreased the adenosine-induced K+ current by 39 +/- 3%. A similar inhibitory effect of glibenclamide on the outward K+ currents activated by either the muscarinic agonist carbachol or the nonhydrolyzable GTP analogue guanosine 5'-[gamma-thio]triphosphate was observed. A low concentration (1 microM) of glibenclamide did not significantly attenuate the current elicited by adenosine, although it completely abolished the outward K+ current activated by pinacidil, a KATP channel opener. Thus we conclude that the inhibition of adenosine-induced K+ current by glibenclamide at high concentrations (> 1 microM) is not due to a specific blockade of KATP channels, but rather, resulted from a blockade of IK1.

Action Potentials↗
PubMed1996

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.

Adenosine↗
PubMed1996

Binding of the novel nonxanthine A2A adenosine receptor antagonist [3H]SCH58261 to coronary artery membranes.

This study demonstrates quantification of A2A adenosine receptors (A2AAdoRs) in membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells. Radioligand binding assays were performed using the new selective A2AAdoR antagonist radioligand [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo [4,3-epsilon]-1,2,4-triazolo[1,5-c)pyrimidine ([3H]SCH58261). Binding of the radioligand to membranes was rapid, reversible, and saturable. The densities of A2AAdoRs in membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells were 900 +/- 61, 892 +/- 35, and 959 +/- 76 fmol/mg protein, respectively. Equilibrium dissociation constants (Kd values) calculated from results of saturation binding assays were 2.19, 1.20, and 0.81 nmol/L, and Kd values calculated from results of association and dissociation assays were 2.42, 1.01, and 0.40 nmol/L for [3H]SCH58261 binding to membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells, respectively. The specific binding of [3H]SCH58261 as a percentage of total binding at a radioligand concentration equal to the Kd value was 65% to 90% in the three membrane preparations. The order of ligand potencies determined by assay of competition binding to sites in porcine coronary membranes using [3H]SCH58261, unlabeled antagonists (SCH58261, 8-(3-chlorostyryl)caffeine [CSC], and xanthine amine congener [XAC]), and unlabeled agonists ([3H]2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoaden osine [CGS 21680], 2-hexynyl-5'-N-ethylcarboxamidoadenosine [HE-NECA], [3H]5'-N-ethylcarboxamidoadenosine [NECA], and R(-)N6-(2-phenylisopropyl)adenosine [R-PIA]) was SCH58261 > HE-NECA = CSC = CGS 21680 = XAC > NECA = R-PIA. The Hill coefficients of displacement by A2AAdoR ligands of [3H]SCH58261 binding were not significantly different from unity, indicating that [3H]SCH58261 bound to a group of homogeneous noninteracting sites in all membrane preparations. The order of ligand potencies to compete for [3H]SCH58261 binding sites in porcine striatal and PC12 cell membranes was, in part, different from that for porcine coronary arterial membranes. The different rank orders of potencies for agonists and antagonists at A2A receptors of porcine coronary arteries, striatum, and PC12 cells and significant differences in absolute values of potency of ligands in the three preparations may indicate the existence of different subtypes of A2AAdoRs. The antagonist radio-ligand [3H]SCH58261 should be of value for pharmacological characterization of A2A adenosine receptors in other preparations.

Animals↗
PubMed1996

A novel irreversible antagonist of the A1-adenosine receptor.

We determined the effects of 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanth ine (FSCPX), a putative irreversible antagonist of the A1-adenosine receptor, on cardiac A1-adenosine receptor-mediated responses and on the specific binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX) to guinea pig cardiac and brain membranes. FSCPX (5 microM) completely reversed the increase in K+ current of guinea pig atrial myocytes caused by 100 microM adenosine (259 +/- 30 to 20 +/- 7 pA) but had no significant effect on K+ currents caused by either 0.5 microM carbachol or 100 microM GTP gamma S. The attenuation of K+ current by FSCPX was both time and concentration dependent and persisted after washout of the antagonist. Pretreatment of atrial myocytes with FSCPX (50 nM) markedly attenuated the activation of K+ current and the inhibition of isoproterenol-stimulated I(Ca,L) caused by adenosine by 90.1% and 84.2%, respectively, but did not alter the responses of atrial myocytes to carbachol. FSCPX (1 microM) irreversibly antagonized the A1-adenosine receptor-mediated increase in atrioventricular nodal conduction time of isolated perfused guinea pig hearts from 10.5 +/- 0.5 to 0.7 +/- 0.6 msec but did not significantly alter the A2-adenosine receptor-mediated decrease in coronary resistance. Preincubation of guinea pig cardiac membranes with 0.1, 1.0, or 3.0 microM FSCPX for 30 min reduced the Bmax of [3H]CPX binding by 41 +/- 10%, 67 +/- 6%, and 80 +/- 1% (mean +/- standard error, three experiments), respectively, with no significant change in the Kd. Similarly, 0.1 and 1.0 microM FSCPX irreversibly reduced the binding of [3H]CPX to guinea pig forebrain membranes by 65 +/- 5% and 83 +/- 2% (four experiments), respectively, but did not reduce the binding of [3H]CGS 21680, an A2a-adenosine receptor agonist, to striatal membranes. FSCPX did not affect the potency of 5'-guanylylimidodiphosphate to inhibit the binding of [3H]CCPA, an A1-adenosine receptor agonist, to brain membranes. The results indicate that FSCPX is a specific, irreversible, A1-adenosine subtype-selective receptor antagonist.

Adenosine↗
PubMed1996

Differential antagonism of cardiac actions of adenosine by theophylline.

OBJECTIVE: To determine the relative sensitivity of cardiac A1- and A2-adenosine receptor-mediated effects to antagonism by theophylline in man. METHODS: Baseline measurements of the A-H interval (A1-adenosine receptor-mediated effect) and coronary blood flow (A2-adenosine receptor-mediated effect) were made in 10 patients with angiographically normal coronary arteries. Adenosine was then administered as a continuous intravenous infusion followed by a rapid intravenous bolus, and measurements repeated. Theophylline (5 mg/kg i.v.) was then administered, and the adenosine infusion repeated. To corroborate the results found in man, the cardiac A1- and A2-adenosine receptor-mediated effects were measured in guinea pig isolated hearts exposed to increasing concentrations of adenosine, in the absence and presence of theophylline (60 microM). RESULTS: Compared to baseline, adenosine infusion and bolus caused significant prolongation of the A-H interval (109 +/- 41 vs. 116 +/- 44 vs. 168 +/- 57 ms, respectively), and increase in coronary blood flow (46 +/- 37 vs. 86 +/- 71 vs. 172 +/- 98 ml/min, respectively). Theophylline abolished the prolongation of the A-H interval during adenosine infusion and bolus (99 +/- 36 and 107 +/- 44 ms, respectively), yet had minimal effect on the increase in coronary blood flow (63 +/- 51 and 136 +/- 121 ml/min, respectively). In guinea pig isolated hearts, theophylline was shown to significantly antagonize the A2-adenosine receptor-mediated effects only when the concentrations of adenosine were < or = 1.0 microM. CONCLUSIONS: In man, theophylline completely antagonizes the A1-adenosine receptor-mediated prolongation of the A-H interval, but has minimal effect on the A2-receptor-mediated coronary vasodilation, particularly when adenosine concentrations exceed 1.0 microM.

Adenosine↗
PubMed1995

Theophylline for the treatment of atrioventricular block after myocardial infarction.

OBJECTIVE: To show that second- or third-degree atrioventricular block occurring as an early complication of acute inferior myocardial infarction is mediated by adenosine. SETTING: Cardiac care unit. DESIGN: Uncontrolled, observational, hypothesis-driven study. PATIENTS: Patients who developed clinically significant atrioventricular nodal blockade within 4 hours of admission for acute inferior myocardial infarction. INTERVENTION: Theophylline, 100 mg/min intravenously to a maximum of 250 mg. MEASUREMENTS: Continuous multilead electrocardiographic monitoring before and after administration of theophylline. RESULTS: During a 6-month period, eight men who had had acute inferior myocardial infarction developed clinically significant atrioventricular block. Three had third-degree block, and five had high-grade second-degree block. In all patients, 1:1 atrioventricular nodal conduction was restored and normal sinus rhythm reappeared within 3 minutes of the administration of theophylline. All patients remained free of arrhythmia for at least 24 hours. CONCLUSIONS: Adenosine produced by the ischemic myocardium may induce atrioventricular nodal block. In our patients, atrioventricular nodal block was resistant to conventional therapy such as atropine, but it responded to the adenosine antagonist theophylline.

Adenosine↗
PubMed1995

Endogenous adenosine is an antiarrhythmic agent.

BACKGROUND: Adenosine administered intravenously terminates supraventricular tachycardias (SVT) involving the AV node as part of the reentrant circuit. Dipyridamole increases interstitial myocardial levels of this nucleoside. This study was designed to determine whether intravenous dipyridamole increases coronary sinus plasma adenosine concentrations ([Ado]cs) in humans to levels sufficient to alter electrophysiological parameters and terminate SVT. METHODS AND RESULTS: A custom-designed catheter and syringe for sampling blood for measurement of [Ado]cs was placed in the coronary sinuses of 7 patients. [Ado]cs and refractory periods and conduction characteristics of the atrium and AV node were determined after autonomic blockade and dipyridamole infusion (5 micrograms.kg-1.min-1 after a loading dose of 0.56 mg/kg). The atrial effective and functional refractory periods remained unchanged after dipyridamole infusion. In contrast, the AV nodal functional refractory period increased from 350 +/- 32 to 381 +/- 41 milliseconds (P = .03); the Wenckebach cycle length also increased from 309 +/- 47 to 350 +/- 57 milliseconds (P < .0001). Coincident with these changes, [ADO]cs increased from 0.18 +/- 0.11 to 0.31 +/- 0.12 mumol/L (P = .02). In another 10 patients with AV or AV nodal reentrant tachycardia, SVT was induced, and coronary sinus blood samples were drawn. Dipyridamole was infused, and coronary sinus blood samples were obtained after 15 minutes or coincident with termination of SVT. Mean [ADO]cs increased from 0.17 +/- 0.06 mumol/L during SVT to 0.38 +/- 0.21 mumol/L after dipyridamole (P = .02). Mean tachycardia cycle length increased from 334 +/- 132 to 375 +/- 139 milliseconds (P = .02); this effect was confined to the AV node, as demonstrated by an increase in AH interval from 171 +/- 144 to 214 +/- 140 milliseconds (P = .003). SVT terminated with the infusion of dipyridamole in 4 of the 10 patients. CONCLUSIONS: Administration of dipyridamole is associated with elevation of [ADO]cs, with coincident prolongation of the mean Wenckebach cycle length and AV nodal functional refractory period. During SVT, dipyridamole leads to prolongation of the AH interval and tachycardia cycle length and to an increase in [ADO]cs, with termination of SVT in four patients. These results support the hypothesis that adenosine may function as an endogenous antiarrhythmic metabolite.

Adenosine↗
PubMed1995

Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes.

The purpose of this review is to examine the role of the extracellular A1-adenosine (Ado) receptor in modulating membrane potential and currents in cardiac cells. The cellular electrophysiological effects of adenosine are both cell type- and species-dependent. In supraventricular tissues (SA, AV node, and atrium) of all species studied, the "direct" cAMP-independent activation of the inwardly rectifying K+ current IKAdo seems to be the most important action of adenosine. This current is activated by both adenosine and acetylcholine and flows through K+ channels with unitary slope conductance of about 45 pS and an open time constant of 1.4 ms. The density of K(+)-ACh,Ado channels is much less in ventricular than in atrial myocytes, and thus adenosine has little or no effect on the ventricular action potential. In atrial myocytes adenosine has a small inhibitory effect on basal L-type calcium current (ICa,L), but no effect on T-type calcium current (ICa,T). In ventricular myocytes, adenosine does not inhibit ICa,L (except ferret), ICa,T, or the sodium inward current INa. Adenosine has recently been shown to activate IKATP in ventricular membrane patches, but the relevance of this finding remains to be defined. Irrespective of cell type and species, adenosine inhibits membrane currents that are stimulated by beta-adrenergic agonists and other agents known to stimulate the activity of the enzyme adenylyl cyclase. This indirect cAMP-dependent mechanism of action has been shown to be responsible for the inhibition by adenosine of isoproterenol-stimulated ICa,L, delayed rectifier K+ current (IK), chloride current (ICl), the transient inward current ITi, and the pacemaker current IF. The importance of the actions of adenosine on membrane currents in modulation of atrial, ventricular, sinoatrial, and atrioventricular nodal function are discussed. Likewise, the antiarrhythmic and proarrhythmic actions of adenosine are discussed and the clinical implications of these actions are noted.

Adenosine↗
PubMed1995

Homologous desensitization of the A1-adenosine receptor system in the guinea pig atrioventricular node.

The objective of this study was to determine whether chronic infusion (7 days) of an A1-adenosine receptor (A1-AdoR) agonist, R-N6-phenylisopropyladenosine (R-PIA), causes homologous and/or heterologous desensitization of the atrioventricular (AV) nodal A1-AdoR system in the guinea pig. The negative dromotropic effects of adenosine, the A1-AdoR agonist N6-cyclopentyladenosine and the muscarinic cholinergic agonist carbachol on hearts from control and treated animals were compared. The potencies of adenosine and N6-cyclopentyladenosine to prolong AV nodal conduction time of hearts from treated animals were significantly reduced compared with control. In contrast, no difference in the potency of carbachol to prolong AV nodal conduction time in the hearts from control and R-PIA-treated guinea pigs was found. The densities of A1-AdoRs in atria and ventricles of treated hearts were 54% (P < .05) and 36% (P < .05) lower than in control hearts, respectively. The number of A1-AdoRs with high affinity for agonists was 37% lower (P < .05) in ventricular membranes prepared from hearts of R-PIA-treated guinea pigs than in membranes from control hearts. In contrast, atrial or ventricular muscarinic acetylcholine receptor densities were not different in hearts of control compared with hearts of treated animals. An up-regulation of the density of nucleoside transporter sites was observed in hearts of treated animals. The quantities of Gi and G(o) in atrial membranes prepared from hearts of treated guinea pigs were lower by 46% and 80%, respectively, than the quantities of Gi and G(o) in atrial membranes prepared from hearts of control animals. It was concluded that chronic administration of R-PIA to guinea pigs desensitized the AV node to the negative dromotropic effect of adenosine in a homologous but not a heterologous manner and desensitization of the AV node response to adenosine was associated with down-regulation of A1-Ado receptors, a decrease in the fraction of A1-Ado receptors in the high-affinity state and a decrease in the contents of Gi and G(o) proteins.

Adenosine↗
PubMed1995

1,3-Dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine, a potent, specific and selective A1 adenosine receptor antagonist in the guinea pig heart and brain and in DDT1MF-2 cells.

The objective of this study was to characterize the adenosine receptor (AdoR) antagonistic properties of a newly synthesized alkylxanthine, 1,3-dipropyl-8[2-(5,6-epoxy)norbornyl]xanthine (ENX), and compare them to those of 1,3-dipropyl-8-(cyclo-pentyl)xanthine (CPX), 1,3-dipropyl-8-(3-noradamantyl)xanthine (NAX) and (+/-)-N6-endo-norbornan-2-yl-9-methyladenine (N-0861). The potencies and selectivities of ENX, CPX, NAX and N-0861 were determined by functional studies of guinea pig isolated perfused hearts, and by radioligand binding assays for A1 and A2a AdoRs in the guinea pig forebrain and striatum. ENX competitively antagonized A1 AdoR-mediated prolongations of atrioventricular nodal conduction time caused by Ado or by 2-chloro-N6-cyclopentyladenosine, but not those caused by carbachol (0.14 microM) or MgCl2 (3 mM). Schild analysis of 2-chloro-N6-cyclopentyladenosine-antagonist competition curves yielded pA2 values for ENX, CPX and NAX of 8.45 +/- 0.19, 8.55 +/- 0.28 and 8.79 +/- 0.15, respectively. ENX (30 microM) and N-0861 (30 microM) did not attenuate the A2 AdoR-mediated increase in coronary conductance caused by adenosine. CPX and NAX attenuated the coronary vasodilation caused by adenosine with IC50 values of 1.5 and 7.1 microM, respectively. Radioligand binding assays revealed that ENX, CPX and NAX and N-0861 had a 400-, 209-, 110- and 10-fold greater affinity, respectively, for A1 than for A2a AdoRs of guinea pig brain membranes. Thus, ENX was equipotent with CPX and NAX and more potent than N-0861 (pA2 = 6.2) as an antagonist at A1 AdoRs, but had lower affinity for A2 AdoRs in guinea pig hearts and brain striatum than did either CPX or NAX. In DDT1 MF-2 cells, all three alkylxanthines had similar affinities for A1 AdoRs, whereas the affinity of N-0861 for A1 AdoRs was significantly lower. ENX appears to be the most A1 AdoR subtype-selective of the alkylxanthine class of AdoR antagonists reported to date.

Adenosine↗
PubMed1994

Substituted 1,3-dipropylxanthines as irreversible antagonists of A1 adenosine receptors.

This report describes the synthesis of 29 xanthines containing a chemoreactive chloroaryl, beta-chloroethylamino, alpha,beta-unsaturated carbonyl, bromoacetyl, 3-(fluorosulfonyl)benzoyl, or 4-(fluorosulfonyl)benzoyl group as part of an exocyclic 1-, 3-, or 8-substituent. The xanthines inhibited the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX) to the A1 adenosine receptor (A1AR) of DDT1 MF2 cells at IC50s in the low-nanomolar to low-micromolar range. Seven of the 29 analogues irreversibly inhibited the binding of [3H]CPX without changing the KD of that ligand; five were 1,3-dipropylxanthines having the following reactive groups as 8-substituents: (bromoacetamido)methyl (24), (bromoacetamido)ethyl (25), (bromoacetamido)propyl (26), [4-(fluorosulfonyl)benzamido]methyl (33) or 3-[[4-(fluorosulfonyl)benzoyl]oxy]cyclopentyl (42). Both 8-cyclopentyl-3-[3-[[4- (fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (53) and 8-cyclopentyl-1,3-bis[3-[[4- (fluorosulfonyl)benzoyl]oxy]propyl]xanthine (55) inhibited [3H]CPX binding irreversibly. Five of the ligands, including 26, 33 (IC50 = 49 microM), and 53 (IC50 = 9 microM), antagonized the binding of [3H]NECA to the A2aAR of PC12 cells, but unlike binding to the A1AR, binding to the A2aAR was completely reversible. The potency of 33 (IC50 = 2 microM, 72% loss of CPX binding at 1 microM) and 53 (IC50 = 0.01 microM, 74% loss of CPX binding at 0.05 microM) and their selectivity for the A1AR suggest that those two ligands may be useful in studies of the structure and function of that receptor.

Adenosine↗
PubMed1994

Cardiovascular effects of a non-xanthine-selective antagonist of the A1 adenosine receptor in the anaesthetised pig: pharmacological and therapeutic implications.

OBJECTIVE: To study antagonism of A1 adenosine receptors in an anaesthetised open chest swine model, the selective A1 receptor antagonist, N6-endonorbornan-2-yl-9-methyladenine (N-0861), was examined to see if it attenuates bradycardia, augments reflex tachycardia associated with adenosine infusion, or both. Its effects were compared with those of the non-selective antagonist of adenosine A1 and A2 receptors, 8-(p-sulphophenyl)-theophylline (8-pST). METHODS: Twenty nine pigs were studied. The prolongation of P-R interval mediated by A1 receptors, the increase in left anterior descending coronary artery blood flow mediated by A2 receptors, and decreases in systemic and left ventricular pressures and first derivative of left ventricular pressure (dP/dt) were monitored in each animal assigned to one of three protocols. (1) Adenosine, 40 to 180 micrograms.kg-1.min-1, was infused for more than 6 min before and immediately after rapid infusion of 8-pST, 5 mg.kg-1 intravenously, or a solvent that did or did not contain N-0861, 0.2 mg.kg-1 intravenously (n = 14). (2) In the same animal, we compared N-0861 and 8-pST in reversing responses mediated by A1 and A2 receptors during two 10 min infusions of adenosine separated by a 1 h washout period (n = 7). (3) N-0861 with adenosine (mean dose, 0.4 mg.kg-1) was infused with or without complete autonomic blockade with atropine (2.5 mg.kg-1) and propranolol (2 mg.kg-1) (n = 8). RESULTS: Adenosine prolonged P-R interval (and cycle length in non-paced hearts), increased coronary flow, and decreased calculated coronary resistance. N-0861 alone did not affect any variable, but N-0861 with adenosine prevented or reversed A1 receptor mediated prolongation of P-R interval in paced hearts and cycle length in non-paced hearts and enhanced A2 receptor mediated coronary vasodilatation. Left ventricular dP/dt and rate-pressure product were maintained with N-0861 and adenosine, and N-0861 unmasked a postadenosine reflex tachycardia. Prolonged PR interval, decreased heart rate, and increased coronary flow were prevented or reversed by the non-selective antagonist 8-pST. CONCLUSIONS: Selectivity of N-0861 for the adenosine A1 receptor may, without reducing coronary blood flow, ameliorate bradyarrhythmia and maintain the positive inotropic response when exogenous adenosine is given or when interstitial myocardial adenosine is increased.

Adenine↗