Search PubMed⌕ Search

Biomedical subjects

L Belardinelli

Publications and source records attributed to L Belardinelli.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effects of adenosine on atrial refractoriness and arrhythmias.

OBJECTIVE: Transient atrial fibrillation is sometimes observed following adenosine administration and adenosine is known to shorten atrial action potential duration and refractory period. This study was designed to characterise the dose-response relationship of adenosine on these variables relative to arrhythmia induction with single atrial premature stimuli. The effects of adenosine during sustained atrial flutter were also determined. METHODS: Intravenous bolus doses of adenosine were given to pentobarbitone anaesthetised dogs following cervical vagotomy and autonomic blockade with atropine and nadolol. Monophasic action potential catheter recordings were obtained from the right atrium and a programmable stimulator was used for pacing. RESULTS: Placebo had no effect on monophasic action potential duration (MAPD) or atrial effective refractory period (ERP) and no arrhythmias were observed. Adenosine (0.1-1.0 mg.kg-1) produced dose related decreases in MAPD and ERP and transient atrial fibrillation (5-122 s) was repeatedly and reproducibly induced in 12 dogs. In six dogs, intravenous dipyridamole (0.25 mg.kg-1) enhanced the effects of adenosine on MAPD and ERP and increased the incidence of atrial fibrillation. In another six dogs, 8-sulphophenyltheophylline (5.0 mg.kg-1, intravenously) markedly blunted the effects of adenosine, and atrial fibrillation could no longer be induced by premature stimuli. In a separate series of experiments the effects of adenosine were evaluated in seven dogs in which sustained atrial flutter could reproducibly be induced by rapid atrial pacing. Administration of placebo never caused termination of the arrhythmia, whereas intravenous boluses of adenosine (0.1-1.0 mg.kg-1) decreased and produced variation in atrial flutter cycle length, and then terminated the arrhythmia in all cases. These effects of adenosine were also enhanced by dipyridamole and antagonised by 8-sulphophenyltheophylline. CONCLUSIONS: Adenosine produces a receptor mediated shortening of monophasic action potential duration and refractoriness which increases vulnerability to transient atrial arrhythmias. During sustained atrial flutter, these effects may also contribute to destabilisation and termination of the arrhythmia.

Action Potentials↗
PubMed1994

ATP promotes development of afterdepolarizations and triggered activity in cardiac myocytes.

The effect of extracellular ATP on transient inward current (Iti), delayed afterdepolarization (DAD), early afterdepolarization (EAD), and triggered activity were investigated in guinea pig isolated ventricular myocytes. ATP alone did not induce afterdepolarizations nor did it significantly alter the resting membrane potentials and action potentials. However, when it was applied with drugs known to increase intracellular Ca2+, ATP facilitated the induction of afterdepolarizations and triggered activity in approximately 60% of the cells. In the presence of isoproterenol, ATP increased the amplitude of Iti and DADs by 55 and 206%, respectively, and caused increases in the amplitude of L-type Ca2+ current (ICa) and EADs, which occasionally led to triggered activity. Similarly, addition of ATP increased the amplitude of Iti and DADs induced by elevated extracellular Ca2+ by 110 and 83%, respectively. Ryanodine inhibited the ATP-induced increase in Iti but not the increase in ICa. In the presence of BAY K 8644 or quinidine, ATP not only further prolonged the action potential durations by 18 +/- 4 and 17 +/- 4%, respectively, but also increased the amplitude of EADs. The present results show a novel arrhythmogenic effect of extracellular ATP, which facilitates the genesis of triggered arrhythmias when Ca2+ influx is increased, probably by further increasing Ca2+ influx from extracellular medium and Ca2+ release from intracellular stores.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Mechanism of the negative inotropic effect of adenosine in guinea pig atrial myocytes.

The ionic basis of the negative inotropic effect of adenosine on guinea pig atrial myocytes was studied. Membrane potentials and currents were measured using a whole cell patch-clamp technique. The contractility was assessed by video quantitation of cell twitch amplitude. Adenosine shortened action potential duration [measured at 90% repolarization (APD90)] and decreased twitch amplitude in a concentration-dependent manner. The maximal effects of adenosine (100 microM) were to reduce APD90 from 102 +/- 14 to 34 +/- 8 ms (n = 11) and twitch amplitude from 4.3 +/- 0.9 to 1.5 +/- 0.4 microns (n = 8). The concentration of adenosine that caused one-half of the maximal reductions of twitch amplitude and of APD90 was 0.6 microM. Reductions in APD90 and in twitch amplitude were parallel and highly correlated (r = 0.98). Decreases in twitch amplitude by adenosine could be mimicked by application of voltage-clamp pulses with durations similar to the durations of action potentials in the presence of adenosine. Clamp pulse could reverse adenosine-induced but not cadmium chloride-induced decreases in twitch amplitude. Adenosine activated the inwardly rectifying K+ current (IK,Ado), but did not significantly decrease the L-type Ca2+ current (ICa,L). Adenosine reduced the effects of BAY K 8644 on APD90 and twitch amplitude but did not attenuate the BAY K-induced increase in ICa,L. The effects of adenosine on APD90 and twitch amplitude could be reversed after activation of IK,Ado was inhibited by intracellular application of cesium and tetraethylammonium chloride.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Basis for the selective reduction of pulmonary vascular resistance in humans during infusion of adenosine.

The objective of this study was to demonstrate the basis for the selective reduction of pulmonary vascular resistance by intravenous infusion of adenosine. Secondary objectives of the study were to determine the rate of central infusion of adenosine at which the nucleoside appears in the systemic circulation and to relate this to hemodynamic events. Plasma concentrations of adenosine in the right and left atria were measured during peripheral (5 patients) and central (12 patients) infusions of adenosine in adults with normal pulmonary arterial pressures undergoing coronary artery bypass surgery. The hemodynamic effects of central (right ventricle) infusion of adenosine were also examined. The extraction of adenosine across the pulmonary vascular bed was found to be 73.6 +/- 4.8%. The mean maximal decrease in pulmonary vascular resistance index, 48.8 +/- 9.6%, occurred at an adenosine infusion rate of 30 micrograms.kg-1.min-1, whereas the systemic vascular resistance index remained unchanged. Thus, adenosine, administered centrally in anesthetized patients with normal pulmonary vascular resistances, selectively lower pulmonary vascular resistance. The basis for this selective effect is the substantial extraction of adenosine during passage through the pulmonary vascular bed.

Adenosine↗
PubMed1994

Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine.

The 2-amino-3-benzoylthiophene derivative PD 81,723 is an allosteric enhancer of agonist binding to brain A1 adenosine receptors. One aim of this study was to characterize and contrast the effects of PD 81,723 on the A1 receptor-mediated negative dromotropic and A2a receptor-mediated vasodilatory actions of adenosine and of a nonmetabolizable and unselective N6-(3-pentyl)adenosine derivative. A second aim was to determine the mechanism of action of PD 81,723. In guinea pig isolated hearts, PD 81,723 potentiated the adenosine and the N6-(3-pentyl)adenosine derivative-induced prolongations of the stimulus-to-His bundle (S-H) interval in a concentration-dependent manner. PD 81,723 (30 mumol/L) decreased the EC50 value for adenosine to prolong the S-H interval by ninefold from 7.4 +/- 1.2 to 0.8 +/- 0.1 mumol/L but did not increase the content of adenosine in cardiac effluent. PD 81,723 (30 mumol/L) increased the specific binding of the A1 agonist [3H]cyclohexyladenosine ([3H]CHA) to human atrial and guinea pig atrial and brain membranes by 38%, 78%, and 300%, respectively. PD 81,723 also increased the fraction of A1 receptors in the high-affinity binding state by an average of 56 +/- 13%. The dissociation rate of [3H]CHA from guinea pig brain membranes was decreased in the presence of PD 81,723 (10 mumol/L) from 0.55 +/- 0.01/min to 0.35 +/- 0.01/min. PD 81,723 did not alter the binding of the A1 antagonist [3H]cyclopentyldipropylxanthine to guinea pig brain membranes. The IC50 values for 5'-guanylylimidodiphosphate to reduce specific binding of [3H]CHA to guinea pig cardiac and brain membranes were increased from 1.5 +/- 0.2 and 2.0 +/- 0.2 mumol/L in the absence of PD 81,723 to 10 +/- 3.3 and 18 +/- 0.5 mumol/L, respectively, in the presence of PD 81,723 (30 mumol/L). PD 81,723 did not potentiate the coronary vasodilatory actions of the N6-(3-pentyl)adenosine derivative. Specific binding of the A2a agonist [3H]CGS 21680 to brain membranes and the nucleoside transporter ligand [3H]nitrobenzylthioinosine to cardiac membranes was unchanged in the presence of PD 81,723. The results suggest that PD 81,723 specifically potentiates the action of adenosine on A1 receptors by stabilizing receptor-G protein interactions in the presence of agonists.

Adenosine↗
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↗
PubMed1994

The cardiac effects of a novel A1-adenosine receptor agonist in guinea pig isolated heart.

Adenosine increases atrioventricular (AV) nodal conduction time and is used for termination of AV nodal re-entrant tachycardias, but it is rapidly metabolized. The purposes of the present study were to characterize the cardiac actions and effects of an orally active and stable adenosine analog, N6-cyclohexyl-2-O-methyladenosine (SDZ WAG-994) and to evaluate its potential as an antiarrhythmic agent. Guinea pig hearts were isolated and perfused with oxygenated Krebs-Henseleit solution. SDZ WAG-994 slowed the atrial rate and prolonged the AV nodal conduction time of spontaneously beating hearts in a concentration-dependent manner. The EC50 values for the negative chronotropic and dromotropic effects of SDZ WAG-994 were 0.69 +/- 0.04 and 1.49 +/- 0.54 microM, respectively. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.2 microM) significantly antagonized SDZ WAG-994-induced stimulus-to-His bundle (S-H) interval prolongation. The negative dromotropic effect of SDZ WAG-994 showed very strong frequency dependence. In hearts paced at an atrial cycle length of 300 msec (200 beats/min), the EC50 value of SDZ WAG-994 to prolong the S-H interval was 3.7-fold lower (0.40 +/- 0.02 microM) than in unpaced hearts, and at atrial pacing cycle lengths of 500 and 250 msec, 0.3 microM SDZ WAG-994 prolonged the S-H interval by 8 and 26 msec, respectively. SDZ WAG-994 also decreased coronary perfusion pressure (EC50 = 1.50 +/- 0.80 microM); this effect of SDZ WAG-994 was attenuated by adenosine deaminase and by 8-cyclopentyltheophylline (2 microM). Radioligand binding assays revealed that SDZ WAG-994 had a 280-fold greater affinity for A1- than for A2a receptors of the guinea pig brain. The marked frequency dependence of the negative dromotropic effect of SDZ WAG-994 suggests that this A1 agonist may be highly effective in the termination of AV nodal re-entrant tachycardias.

Adenosine↗
PubMed1993

[Substernal goiter: new diagnostic methods and treatment].

The authors report 47 cases of substernal goiters operated between 1971 and 1990. Forty-five patients had mediastinal-cervical-goiters (g.c.m.) and 2 had ectopic goiter (g.e.). Cervicotomy was performed in the 45 g.c.m., in 3 cases associated with sternal "split". The g.e. were treated with thoracotomy. Computed Tomography (TC) has been performed since 1984 in 26 patients; Magnetic Resonance (RM) since 1987 in 6 patients. The diagnostic accuracy for TC was 84.6% and 100% for MR on anatomical-topographic-definition, and 80.8% and 83.3% for presumptive diagnosis of nature, respectively. Considering the high diagnostic accuracy, the possibility to reconstruct the images in sagittal and coronal planes, the RM seems to be the elective diagnostic procedure for all substernal goiters.

Adult↗
PubMed1993

Failure of adenosine to terminate focal atrial tachycardia.

Adenosine has proven effectiveness in the diagnosis and treatment of a variety of tachycardias with both normal and widened QRS complexes in children and adults. Its effectiveness is due to its depressant effects on atrioventricular node conduction. Adenosine might also be effective against automatic tachycardia due to spontaneous activation in partially depolarized cells. This report describes a patient presenting with tachycardia with normal QRS complexes. While the adenosine did not restore sinus rhythm, it did disclose the mechanism of the arrhythmia. Since other investigators have reported successful interruption of automatic atrial tachycardia, this case suggests that automatic atrial tachyarrhythmia may be due to more than one mechanism.

Adenosine↗
PubMed1993

Selective A2-adenosine receptor agonists do not alter action potential duration, twitch shortening, or cAMP accumulation in guinea pig, rat, or rabbit isolated ventricular myocytes.

In this study, the hypothesis that mammalian ventricular myocytes possess A2-adenosine receptors was tested. Electrophysiological, contractile, and cAMP responses to the selective A2-adenosine receptor agonists 2-[2-(4-methylphenyl)ethoxy]adenosine (WRC-0090) and 2-(2-cyclohexylethoxy)adenosine (WRC-0013) and the nonselective adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) were measured using ventricular myocytes isolated from guinea pig, rabbit, and rat hearts. Pertussis toxin pretreatment and/or the selective A1-adenosine receptor antagonists 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and (+/-)N6-endonorbornan-2-yl-9-methyladenine (N-0861) were used to prevent activation of A1-adenosine receptors in these cells. Action potential duration at 50% repolarization was not altered by WRC-0090, NECA, or WRC-0013 with or without 0.1 microM DPCPX or pertussis toxin pretreatment, and WRC-0090 and NECA failed to prolong the action potential duration of myocytes exposed to 0.1 or 1 microM forskolin. WRC-0090 alone or with 0.1 microM DPCPX did not increase the amplitude of shortening of pertussis toxin-treated or untreated myocytes, and WRC-0090 or NECA did not significantly increase cAMP accumulation. In contrast to these results with myocytes, in the smooth muscle cell line DDT1MF-2 the effect of both selective A2-agonists on cAMP accumulation was biphasic: low concentrations (< or = 0.3 microM) increased but higher concentrations decreased accumulation of cAMP. The decreased cAMP accumulation seen at higher agonist concentrations was completely abolished by either 0.1 microM DPCPX or pretreatment of cells with pertussis toxin. In summary, the results of the present study do not provide evidence for A2-adenosine receptors on mammalian ventricular cardiomyocytes but confirm reports of the coexistence of both A1 and A2 subtypes of adenosine receptors on DDT1MF-2 cells.

Action Potentials↗
PubMed1993

[Alkalizing activity of a calcium-bicarbonate-containing water, evaluated for pH, in patients with gastroesophageal reflux].

Bicarbonate-calcic water Ferrarelle has been administered both in the fasting state and during meals to patients suffering from gastro-esophageal reflux disease submitted to computerized pHmetry. Marked and lasting increase of esophageal and gastric pH was observed with significant differences from the effect of tap water. In addition, patients reported improvement of heart burn and acidity after the administration of the bicarbonate-calcic water. The alkalizing effect of the mineral water employed is therefore fully confirmed.

Alkalies↗
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↗
PubMed1993

Correlation of (-)N6-phenylisopropyladenosine blood levels with cardiac responses in the anesthetized guinea pig.

This study was designed to develop a high-performance liquid chromatography-based analytical method to measure the blood concentration of (-)N6-phenylisopropyladenosine (R-PIA) in order to correlate such levels with cardiac responses, and to determine the pharmacokinetics of R-PIA. Experiments were carried out in anesthetized adult guinea pigs instrumented for measurement of the surface ECG. After i.v. (50 micrograms/kg; n = 9) or i.p. (3.5 mg/kg; n = 5) administration of R-PIA, the atrial rate and P-R interval were determined, and arterial blood samples (0.5 ml) were collected. The R-PIA content of plasma ultrafiltrates was determined by reversed-phase high-performance liquid chromatography. The ratio of R-PIA concentrations in whole blood and in ultrafiltrated plasma (free or unbound) at 35-37 degrees C was 2.51 +/- 0.10 (n = 7) and was relatively independent of R-PIA concentration. The concentration of unbound R-PIA in whole blood correlated well with cardiac responses. Two distinct patterns of cardiac response to varying R-PIA levels were observed. In 4 of 14 animals, R-PIA caused a prolongation of the P-R interval at a relatively constant atrial rate, whereas in 10 animals, R-PIA caused both a slowing of atrial rate and a prolongation of the P-R interval. An increase in the unbound concentration of R-PIA caused a decrease in atrial rate and an increase in P-R interval. Unbound R-PIA was rapidly cleared from blood (CL = 40 +/- 7 ml/kg/min) and had a large volume of distribution (VSS = 1.45 +/- 0.21 L/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1992

Effects of intracoronary dipyridamole infusion on regional myocardial blood flow and intrinsic thallium-201 washout in dogs with a critical coronary stenosis.

Intravenous dipyridamole (DP) infusion produces a significant endocardial-to-epicardial flow gradient distal to a critical coronary stenosis, resulting in diminished regional thallium-201 (Tl-201) uptake and washout. Intravenous DP can also produce a significant decrease in arterial blood pressure and therefore in coronary perfusion pressure. We determined to further clarify the mechanism of this transmural coronary "steal" employing intracoronary DP administration, thereby avoiding systemic hypotension. In five of eight dogs with a critical left anterior descending (LAD) stenosis, intracoronary DP caused no significant fall in systemic arterial pressure, a rise in epicardial flow from 1.15 +/- 0.2 to 1.75 +/- 0.2 ml/min/gm, and a slight fall in subendocardial flow from 1.15 +/- 0.2 to 1.03 +/- 0.5 ml/min/gm. Intracoronary DP caused no prolongation of the intrinsic Tl-201 washout rate. In three dogs that developed systemic hypotension after intracoronary DP, endocardial flow fell from 1.14 to 0.63 ml/min/gm, the epicardial/endocardial flow ratio fell to 0.35, and Tl-201 washout became more prolonged. Thus intracoronary DP in the setting of a critical LAD stenosis caused minimal endocardial-to-epicardial steal and had no effect on the intrinsic Tl-201 washout rate unless it was accompanied by a fall in systemic arterial pressure. The magnitude of the transmural steal was substantially less than reported in our previous experiments utilizing intravenous DP infusion. This study provides a further insight into the mechanism of DP-induced subendocardial ischemia and suggests that systemic hemodynamic alterations play an important role in the effects of the vasodilator on myocardial blood flow and Tl-201 kinetics.

Animals↗
PubMed1992

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.

Adenosine↗
PubMed1992

Evidence of spare A1-adenosine receptors in guinea pig atrioventricular node.

In normoxic, isolated perfused guinea pig hearts instrumented for measurement of atrioventricular nodal conduction time (AVCT), an analysis utilizing the irreversible A1-adenosine (Ado) antagonist, meta-1,3-phenylene diisothiocyanate xanthine amine cogener (m-DITC-XAC), a novel isothiocyanate derivative of 1,3-dialkylxanthine, was used to investigate whether spare A1-Ado receptors exist in the guinea pig atrioventricular (AV) node and the degree of amplification (reserve) between A1-Ado receptor occupancy and dromotropic response (e.g., AVCT slowing). The potency, dose dependency, and kinetic profile (time dependence of washout and washin) of m-DITC-XAC was determined and compared with those of known competitive (reversible) A1-Ado receptor antagonists. In the presence of m-DITC-XAC, Ado and N6-cyclopentyladenosine (CPA) produced submaximal dromotropic responses. In a series of 19 hearts, m-DITC-XAC caused 100% apparent antagonism of the effect of Ado on AVCT even after 60 min of washout. In contrast, greater than 90% of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and XAC-induced antagonism of the effect of Ado on AVCT dissipated within 35 min. Unlike XAC, which caused maximal attenuation of Ado's AVCT effect within 5 min and remained constant thereafter, m-DITC-XAC showed marked time- and concentration-dependent behavior. It was found that 5 min of 0.5 microM m-DITC-XAC pretreatment irreversibly inactivated 72% of the A1-Ado receptors mediating the dromotropic effect, and the estimated agonist equilibrium dissociation constant for CPA was 84 +/- 4 nM. The percent of spare A1-Ado receptors at the EC50 and extrapolated maximal S-H interval prolongation levels was 20 and 54%, respectively, and the reserve (coupling amplification) varied from 1 to 2.3 within the 0-50% maximal response range. In summary, m-DITC-XAC appears to specifically and irreversibly antagonize the negative dromotropic effect of Ado and CPA, and guinea pig AV nodal tissue possesses spare A1-Ado receptors.

Adenosine↗