Dopamine in the conscious dog with chronic heart-block

Summary The chronotropic effects of dopamine were studied in the conscious dog with chronic A-V block. Dopamine at 12.5–200 g/kg and 12.5–50 g/kg/min lowered atrial rate independently of dose. After blockade of muscarine receptors or alpha-adrenoceptors, it raised atrial rate. After blockade of dopamine receptors, dopamine still lowered atrial rate, and did so dose-relatedly after blockade of beta-adrenoceptors. It raised ventricular rate, and at high doses also induced ventricular rhythm disorders. Blockade of muscarine receptors enhanced the ventricular cardioaccelerator effect of dopamine (P<0.025) at 100 g/kg, while blockade of alpha-adrenoceptors reduced it (P<0.05). Blockade of dopamine receptors did not modify this effect, but blockade of beta-adrenoceptors reversed it. Dopamine at 25–200 g/kg raised mean blood pressure. This effect was enhanced by blockade of muscarine receptors, reversed by blockade of alpha-adrenoceptors, and was unaffected by blockade of beta-adrenoceptors or dopamine receptors. These results show that the atrial cardiomoderator effect of dopamine is a vagal reflex response to its hypertensive action, and that it is limited by its direct beta-adrenergic stimulating action. They also show that the ventricular cardioaccelerator effect of dopamine is attenuated by a reflex vagal depressor effect consequent to the induced hypertension. No evidence was found for the existence of positive chronotropic dopamine receptors in either atria or ventricles.A preliminary report of these findings was presented at the Symposium on Peripheral Dopaminergic Receptors, July 1978, in Strasbourg, France (Boucher et al. 1979b)     

The benzazepine SCH 23390 increases plasma levels of cortisol in the conscious dog

Summary The effect of neuroleptics on the hypothalamopituitary-adrenal system has been early recognized, but never adequately related to antipsychotic or side effects produced by dopamine antagonists. We are now presenting results showing that the newly characterized dopamine D-1 receptor antagonist, SCH 23390 (0.1 mg/kg i.v.) as well as the mainly dopamine D-2 receptor antagonists, haloperidol (0.1 mg/kg i.v.) and chlorpromazine (1 mg/kg i.v.), produced an increase of cortisol levels (108, 144 and 226% respectively, 20 min after the injection) determined by radioimmunoassay in blood samples collected from superficial veins of the legs of conscious dogs. The 5-HT₂ receptor antagonist, cyproheptadine (0.2 mg/kg i.v.), did not modify the cortisol levels. These results suggest that cortisol increase is an effect common to neuroleptic compounds, independently of their relative antagonistic action at dopamine D-1 or D-2 receptors.     

Mechanisms of chronotropic cardiac effects of alinidine and plasma concentration-response relationships in the conscious dog with chronic atrioventricular block

Summary The chronotropic cardiac effects of alinidine were studied in the conscious dog with chronic atrioventricular block. Alinidine at 0.5–4 mg/kg, i. e., at plasma concentrations between 42 ± 2 and 1625 ± 371 ng/ml, initially increased atrial rate dose-dependently. This effect fell off rapidly, but atrial bradycardia was never observed. After atropine and pindolol, which raised basal atrial rate, alinidine (2 mg/kg) decreased atrial rate, whereas after phenoxybenzamine, yohimbine or phentolamine, it produced atrial effects identical to those observed under basal conditions, i. e., initial tachycardia and no bradycardia. Alinidine dose-relatedly decreased ventricular rate. None of the pretreatments modified the maximal ventricular bradycardia, but interestingly after pindolol or yohimbine this effect developed more rapidly (maximal bradycardia between 3 and 5 against 30 min) and then declined progressively. Alinidine did not modify mean blood pressure at any dose. After atropine, phenoxybenzamine or phentolamine, alinidine remained without effect on mean blood pressure, but after pindolol or yohimbine, a hypotensive effect appeared concomitantly with the reduction of the ventricular bradycardia. These results show that the initial atrial cardioacceleration due to alinidine results from a direct vagolytic action of this drug and that the absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate. They also suggest that the ventricular brädycardia does not involve either the muscarinic cholinoceptors or the alpha- or beta-adrenoceptors, though the results obtained after pindolol or yohimbine suggest possible involvement of a fall in sympathetic tone by stimulation of presynaptic or central alpha₂-adrenoceptors, particularly in the persistence of the bradycardic effect. Overall, these results indicate that alinidine exerts, in the conscious dog, chronotropic effects that depend closely on basal heart rate, and so on the control that the autonomic nervous system exerts on the heart. This explains why under certain conditions — relatively low heart rate — alinidine may have a cardioaccelerator effect.Technical assistance Send offprint requests to M. Boucher at the above address     

The interaction of adenosine analogues with cAMP-generating and cAMP-independent positive inotropic agents in rabbit left atrium

Summary The effects of adenosine receptor stimulation on the contractile force of rabbit isolated left atrial preparations in the absence and presence of cAMP-generating and cAMP-independent agonists were investigated. Adenosine and the stable adenosine analogues 5-(Nethyl) carboxamido adenosine (NECA) and (–)-N⁶-phe-nylisopropyladenosine (R-PIA) produced a concentration-dependent direct negative inotropic effect. Responses to NECA and R-PIA were insensitive to atropine and were shifted to the right by the adenosine receptor antagonist 3-isobutyl-1-methyl xanthine (IBMX). NECA and R-PIA were found to reverse positive inotropic responses of left atria to the -adrenoceptor agonist, isoproterenol, but were less effective at reversing positive inotropic responses to the adenylate cyclase activator, forskolin, and were almost ineffective at reversing positive inotropic responses to a-adrenoceptor stimulation.Neither NECA nor R-PIA had a significant effect on basal CAMP levels or on CAMP levels elevated by isoproterenol in rabbit left atria. Similarly, R-PIA had no significant effect on basal cAMP levels or isoproterenol-induced increases in cAMP in the presence of adenosine deaminase to remove the influence of endogenous adenosine. Pretreatment of rabbits with 1.75 g/kg pertussis toxin attenuated both the direct negative inotropic response of left atria to NECA and responses to NECA in the presence of isoproterenol and forskolin to a similar extent. Pretreatment of left atrial preparations with the potassium channel antagonist 4-aminopyridine resulted in a dose dependent attenuation of responses to NECA alone and in the presence of isoproterenol and forskolin.These data suggest that adenosine receptors in rabbit left atria are not coupled to adenylate cyclase. Rather, both the direct negative inotropic response to adenosine analogues alone, and their reversal of positive inotropic responses to isoproterenol and forskolin may be mediated by increases in K⁺ conductance, which have been postulated to shorten the duration of the action potential and reduce the influx of Ca²⁺.Send offprint requests to K. M. MacLeod at the above address     

Effects of adenosine analogues on contractile response and CAMP content in guinea-pig isolated ventricular myocytes

Summary In the present study the effects of adenosine analogues were investigated on cAMP content and contractile response in guinea-pig ventricular myocytes. The adenosine analogues (–)-N⁶-phenylisopropyladenosine (R-PIA), 5-N-ethylcarboxamideadenosine (NECA) and (+)-N⁶-phenyl-isopropyladenosine (S-PIA) in the presence of 0.01 mol/l isoprenaline reduced contractile response concentration-dependently. R-PIA and NECA were about equipotent (IC₂₅: 0.01 mol/l and 0.039 mol/l respectively), while S-PIA was less potent (IC₂₅: 0.6 mol/l). Isoprenaline stimulated cAMP content was reduced by R-PIA (IC₂₅: 0.004 mol/l) and with lower potency by S-PIA (IC₂₅: 0.15 mol/l) but the extent of reduction of cAMP by R-PIA and S-PIA (to 55% and 64% respectively) was less than the reduction of contractile response (to 26% and 55% respectively). This suggests that the effects of R- and S-PIA on contractile response are only in part due to a reduction in cAMP content. In addition, NECA did not decrease cAMP content but decreased contractile response to the same extent as R-PIA. Similar results were obtained in the presence of the phosphodiesterase inhibitor Ro 20-1724. Time course studies revealed that the effects of R-PIA (1 mol/l) on cAMP content and contractile response coincided reaching steady state after 5 min and remained stable thereafter. The effects of NECA (1 µmol/l) on contractility also reached steady state within 5 min, whereas it did not change cAMP content. It is concluded that the reduction of contractility by adenosine analogues in the presence of isoprenaline can only in part be explained by a reduction of cAMP content. It is suggested that a cAMP-independent effect, possibly an activation of phosphatases, might be involved additionally.Abbreviations R-PIA (–)-N⁶-phenylisopropyladenosine - NECA 5-N-ethylcarboxamideadenosine - S-PIA (+)-N⁶-phenylisopropyl-adenosine - Ro 20-1724 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone Send offprint requests to J. Neumann at the above address     

Evidence against adenosine analogues being agonists at the growth hormone secretagogue receptor

Adenosine and adenosine analogues have been reported to act as agonists or partial agonists at the growth hormone secretagogue receptor 1a (GHSR1a). We have re-examined this question. A concentration-dependent increase in intracellular calcium concentration ([Ca(2+)](i)) was observed in GHSR1a transfected HEK 293-EBNA cells stimulated with adenosine (EC50: 0.2 microM) or 2-chloroadenosine (EC50: 1.1 microM) but also in untransfected HEK 293-EBNA cells stimulated with 2-chloroadenosine (EC50: 0.67 microM) or 5'-N-ethylcarboxamidoadenosine (NECA) (EC50: 0.045 microM). These findings support endogenous expression of adenosine receptors, presumably A(2B) receptors in HEK 293-EBNA cells. In GHSR1a transfected CHO cells, lacking adenosine receptors, the GHSR1a agonist hGhrelin (EC50: 2.4 nM) increased [Ca(2+)](i), but no effects of adenosine, 2-chloroadenosine or NECA were detected. An inverse agonist of GHSR1a, [d-Arg-1, d-Phe-5, d-Trp-7, 9, Leu-11] substance P, reduced hGhrelin effects but adenosine, 2-chloroadenosine or 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) did not. NECA increased the [Ca(2+)](i) in co-transfected (GHSR1a and A(2B) receptor) CHO cells (EC50: 0.053 microM), but no additive or synergistic effects on [Ca(2+)](i) or cAMP formation were observed after stimulation with NECA in the absence or in the presence of hGhrelin. In binding studies on GHSR1a transfected CHO cell membranes, [(125)I]-hGhrelin binding could be displaced by the GHSR1a agonist MK-0677 (IC50: 0.34 nM), hGhrelin (IC50: 1.5 nM), and the substance P analogue (IC50: 0.64 microM) but not by adenosine or 2-chloroadenosine. We conclude that adenosine and analogues do not act as agonists or partial agonists at the GHSR1a and that cross-talk between the GHSR1a and A(2B) receptors is limited.     

Effect of ajmaline on sustained ventricular tachycardia induced by programmed electrical stimulation in conscious dogs after myocardial infarction

Summary As yet the antiarrhythmic efficacy of ajmaline with regard to suppressing the induction of sustained ventricular tachycardia after myocardial infarction has not been determined. Therefore, programmed electrical stimulation was performed in 8 conscious, chronically instrumented mongrel dogs 8–20 days after a 4-hour occlusion of the left anterior descending coronary artery. At baseline all animals responded with sustained ventricular tachycardia. Thereafter, ajmaline was administered at two consecutive ix. doses: a bolus of 0.7 mg kg^–1 followed by infusion of 2 mg kg^–1 h^–1 and infusion of 4 mg kg^–1 h^–1. The induction of sustained ventricular tachycardia was prevented in 2/8 animals by 2 mg kg^–1 h^–1 ajmaline and in 1/8 animals by 4 mg kg^–1 h^–1 ajmaline. During sinus rhythm only 4 mg kg^–1 h^–1 ajmaline significantly increased QRS-duration and intraventricular activation times, but during rapid right ventricular pacing (cycle length = 330 ms) both doses of ajmaline increased QRS duration and intraventricular conduction times. 4 mg kg^–1 h^–1 ajmaline also increased the cycle length of induced sustained ventricular tachycardia. In 3 animals induction of sustained ventricular tachycardia during infusion of 4 mg kg^–1 h^–1 ajmaline was achieved by introduction of less extrastimuli than at baseline. Furthermore the coupling intervals of extrastimuli that induced sustained ventricular tachycardia were substantially prolonged by this dose. Inhomogeneity of conduction between left ventricular normal zone and left ventricular infarct zone was significantly increased by 4 mg kg^–1 h^–1 ajmaline during rapid right ventricular pacing, but not during sinus rhythm.We conclude that ajmaline has only limited efficacy with regard to the prevention of induction of sustained ventricular tachycardia after myocardial infarction. Drug-induced increases in tachycardia cycle lengths, as observed under the higher dose of ajmaline, were associated with a rate-dependent rise in cardiac electrical instability. Correspondence to H. Todt at the above address     

Effects of adenosine derivatives on human and rabbit platelet aggregation

Summary The inhibitory effects of several adenosine analogues, including the new A2-selective agonists 2-[p-(2-carboxyethyl)phenethylamino]-5-N-ethylcarboxamido-adenosine (CGS 21680) and 2-hexynyl-5-N-ethylcarbox-amidoadenosine (2-hexynyl-NECA), were investigated in vitro on human and rabbit platelet aggregation. The compounds examined inhibited ADP-induced platelet aggregation over a wide range of potency. The rank order of activity was similar between the two species thus showing that the rabbit is a useful animal model for studying the effects of adenosine derivatives on platelet aggregation. 2-Hexynyl-NECA was found to be the most potent adenosine compound of those currently available, having IC₅₀ values of 0.10 and 0.07 M in human and rabbit platelets, respectively. Conversely, the A1 agonists R(–)-N-⁶-(2-phenylisopropyl) adenosine (R-PIA), S(+)-N⁶-(2phenylisopropyl) adenosine (S-PIA) and 2-chloro-N⁶-cyclopentyl-adenosine (CCPA) were the least potent compounds with IC₅₀ values in the micromolar range. The potency of the compounds in inhibiting platelet aggregation was found to be highly correlated with their affinity for A2 receptors as measured using 3H-CGS 21680 binding in rat brain striatum.Correspondence to S. Dionisotti at the above address     

Adenosine and adenosine analogs inhibit phosphodiesterase activity in the heart

Summary Adenosine and its analogs (-)-N⁶-phenylisopropyladenosine and 5-N-ethylcarboxamideadenosine inhibit cAMP and cGMP phosphodiesterase activity in guinea-pig atrial and ventricular preparations at concentrations of 100 mol l^–1 and higher. These effects are probably unrelated to the inotropic effects of these substances. However, inhibition of cAMP breakdown may compensate for the adenosine-induced inhibition of adenylate cyclase and may thus at least partially explain why with this drug no changes in cAMP or cGMP content have previously been observed in intact cardiac tissue.     

Ventilatory effects of adenosine mediated by carotid body chemoreceptors in the rat

Summary The effects of intracarotid injections of adenosine and adenosine analogues [5-N-ethylcarboxamidoadenosine (NECA), 2-chloroadenosine (CADO), l-N⁶-phenylisopro-pyladenosine (l-PIA) and d-N⁶-phenylisopropyladenosine (d-PIA)] on ventilation were studied in rats anaesthetized with sodium pentobarbitone or urethane. Adenosine and its analogues increased in a dose-dependent manner respiratory ventilation determined as increases in tidal volume (V _T), respiratory frequency (f) and minute volume (V _E). These excitatory effects were abolished after section of the carotid sinus nerve. The order of potency of the adenosine analogues was NECA > CADO > d-PIA, l-PIA, and no marked stereoselectivity was found for the PIA isomers. The methylxanthine, theophylline, in a dose that did not modify respiratory ventilation, antagonized the excitatory action of CADO. An inhibitory, delayed and long-lasting effect of l-PIA on respiration was also observed after its intravenous administration, an effect which was not prevented by section of the carotid sinus nerves. It is concluded that adenosine can have both excitatory and inhibitory effects on ventilation, and that its excitatory effect mediated through carotid body chemoreceptors involves an A₂ adenosine receptor. Send offprint requests to J. A. Ribeiro at the above address     

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

Astrocytic adenosine kinase regulates basal synaptic adenosine levels and seizure activity but not activity-dependent adenosine release in the hippocampus

Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP. We have investigated the role that ADK plays in regulating the presence and effects of extracellular adenosine in area CA1 of rat hippocampal slices. Inhibition of ADK activity with 5′-iodotubercidin (IODO; 5 μM) raised extracellular adenosine, as measured with adenosine biosensors, and potently inhibited field excitatory post-synaptic potentials (fEPSPs) in an adenosine A₁R-dependent manner. In nominally Mg²⁺-free aCSF, which facilitated the induction of electrically-evoked epileptiform activity, adenosine biosensor recordings revealed that seizures were accompanied by the transient release of adenosine. Under these conditions, IODO also inhibited the fEPSP and greatly suppressed epileptiform activity evoked by brief, high-frequency stimulation. During spontaneous seizures evoked by the A₁R antagonist CPT, adenosine release was unaffected by IODO. This suggests that ADK activity does not limit activity-dependent adenosine release. On the basis of strong ADK immunoreactivity in GFAP-positive cells, astrocytes are likely to play a key role in regulating basal adenosine levels. It is this action of ADK on the basal adenosine tone that is permissive to seizure activity, and, by extension, other forms of activity-dependent neuronal activity such as synaptic plasticity.     

Dose-dependent effects of isosorbide-5-mononitrate on the venous arterial and coronary arterial system of conscious dogs

Summary Isosorbide-5-mononitrate (IS-5-MN), the main metabolite of isosorbide dinitrate shows antianginal efficacy and is being used increasingly as a drug for practical therapy. In conscious dogs we therefore measured the effects of increasing doses of IS-5-MN on hemodynamic parameters and the diameter of the circumflex artery. We found a dose dependent reduction of the mean right atrial pressure, the systolic blood pressure and a dilatation of the circumflex artery. For all three parameters threshold dosages were between 0.01 and 0.03 mg/kg. On the contrary peripheral and coronary resistance did not change at doses 0.3 mg/kg. The heart rate was significantly increased only at doses above 1 mg/kg and the diastolic blood pressure also showed a tendency to fall only at doses above 1 mg/kg. Cardiac output and coronary flow were not significantly altered over the entire dose range investigated, with the exception of a transient rise in coronary blood flow after the injection of 2.5 mg/kg IS-5-MN.From our results we can deduce that in the low dose range reduction of preload and dilatation of large arteries are the main effects of IS-5-MN. In contrast, no reduction of the coronary or peripheral resistance is to be expected.     

Coronary interactions between nifedipine and adenosine in the intact dog heart

Coronary vascular interactions between adenosine and the calcium entry blocker, nifedipine were studied in the open-chest, blood-perfused dog heart. Adenosine was administered either as a constant intra-coronary infusion or released endogenously during brief occlusions of the left anterior descending (LAD) coronary artery. Nifedipine was administered in therapeutic concentrations as a single i.v. bolus via the femoral vein. Prior to nifedipine treatment, adenosine (1.2 μmol/kg per min) produced a significant (P < 0.05) 2–3 fold increase in LAD flow. This response was reduced markedly (P < 0.05) in a dose-dependent manner by nifedipine (6–20 μg/kg). Following administration of an average dose of 11 μg/kg nifedipine, adenosine (1.2 μmol/kg per min) failed to elevate LAD flow significantly. Further, reactive hyperemia, produced by releasing a 30-s occlusion of the LAD, was significantly attenuated by these same nifedipine concentrations. The nifedipine-mediated attenuation could be partially overcome by prolonging the period of occlusion (60 s), or by increasing the rate of adenosine infusion. These results could not be accounted for by a nifedipine-mediated alteration of hemodynamics and suggest the possibility of pharmacological competition between adenosine and nifedipine at a vascular smooth muscle receptor.     

不同剂量右美托咪定用于清醒经鼻盲探气管插管的效果

目的 观察不同剂量右美托咪定用于清醒经鼻肓探气管插管的效果.方法 择期气管插管全麻下行手术病人51例,年龄32～46岁,ASA Ⅰ～Ⅱ级,所有病人均无心、脑血管疾病.随机分为单纯表面麻醉组(S组)、表面麻醉+右美托咪定0.5 μg/kg组(D1组)和表面麻醉+右美托咪定1.0 μg/kg组(D2组),每组17例.三组病...     

Evidence for an A2 adenosine receptor in guinea pig lung

Summary Adenosine receptors in guinea pig lung were characterized by measurement of cyclic AMP formation and radioligand binding. 5-N-Ethylcarboxamidoadenosine (NECA) increased cyclic AMP levels in lung slices about 4-fold over basal values with an EC₅₀ of 0.32 mol/l. N⁶-R-(–)-Phenylisopropyladenosine (R-PIA) was 5-fold less potent than NECA. 5-N-Methylcarboxamidoadenosine (MECA) and 2-chloroadenosine had EC₅₀-values of 0.29 and 2.6 mol/l, whereas adenosine and inosine had no effect. The adenosine receptors in guinea pig lung can therefore be classified as A₂ receptors. Several xanthine derivatives antagonized the NECA-induced increase in cyclic AMP levels. 1,3-Diethyl-8-phenylxanthine (DPX; K _i 0.14 mol/l) was the most potent analogue, followed by 8-phenyltheophylline (K _i 0.55 mol/l), 3-isobutyl-1-methylxanthine (IBMX; K _i 2.9 mol/l) and theophylline (K _i 8.1 mol/l). In contrast, enprofylline (1 mmol/l) enhanced basal and NECA-stimulated cyclic AMP formation. In addition, we attempted to characterize these receptors in binding studies with [³H]NECA. The K _D for [³H]NECA was 0.25 mol/l and the maximal number of binding sites was 12 pmol/mg protein. In competition experiments MECA (K _i 0.14 mol/l) was the most potent inhibitor of [³H]NECA binding, followed by NECA (K _i 0.19 mol/l) and 2-chloroadenosine (K _i 1.4 mol/l). These results correlate well with the EC₅₀-values for cyclic AMP formation in lung slices. However, the K _i-values of R-PIA and theophylline were 240 and 270 mol/l, and DPX and 8-phenyltheophylline did not compete for [³H]NECA binding sites. Therefore, a complete characterization of A₂ adenosine receptors by [³H]NECA binding was not achieved. In conclusion, our results show the presence of adenylate cyclase-coupled A₂ adenosine receptors in lung tissue which are antagonized by several xanthines.     

Evidence for separate receptors for ATP and adenosine in the guinea-pig taenia coli

Inhibitory actions of three pairs of congeneric ATP and adenosine analogues on the isolated guinea-pig taenia coli were compared with the actions of ATP and adenosine. 8-Bromoadenosine, and 9-beta-D-arabinofuranosyladenosine (ara-adenosine) were inactive; 2'-deoxyadenosine was a weak partial agonist. 8-Bromo-ATP, ara-ATP and 2'-deoxy-ATP behaved like ATP and elicited rapid relaxations of the taenia but were not potentiated by dipyridamole. The divergent effects of identical structural modifications to ATP and adenosine provide evidence for separate adenosine and ATP receptors in the taenia coli.     

Inhibition of the negative chronotropic action of adenosine by caffeine in the dog

The sinus node artery was perfused in situ in 15 dogs. Injection of adenosine into the sinus node artery induced a negative chronotropic effect at doses of 1, 3 and 10 μg. The negative chronotropic response to adenosine was blocked by 300 μg to of caffeine given into the same artery. On the contrarym, the negative chronotropic response to ACh was not inhibited but rather enhanced by caffeine, so that the atrial fibrillation threshold to ACh was lowered. Neither norepinephrine nor calcium when injected into the sinus node artery inhibited the deceleration response to adenosine.     

Evidence for adenosine A2 receptor involvement in the hypomobility effects of adenosine analogues in mice

The hypomobility induced by a series of adenosine analogues was investigated using a holeboard test and their behavioral potencies correlated to their reported adenosine A1 and A2 receptor affinities. All of the adenosine analogues dose dependently inhibited both exploratory behavior (head dipping) and locomotor activity. The rank order of potency 5'-ethylcarboxamido adenosine (NECA) greater than 5'-methylcarboxamido adenosine (MECA) greater than N6-[(R)-1-methyl-2-phenylethyl]adenosine (R-PIA) greater than N6-cyclohexyladenosine (CHA) = N6-cyclopentyladenosine (CPA) greater than N6-[(S)-1-methyl-2-phenylethylladenosine (S-PIA) greater than N6-(2-hydroxyethyl)adenosine (2-OH-ethyl) was observed for inhibiting both activities. The behavioral potency of these adenosine analogues correlates extremely well with their reported A2 receptor affinity (r2 = 0.93, P less than 0.01 and r2 = 0.86, P less than 0.05 for locomotor and head dipping activity respectively), but very poorly with their reported A1 receptor affinity (r2 less than 0.02, P greater than 0.50 for both activities). These results suggest that adenosine A2 receptors, but not A1 receptors, may be involved in the hypomobility induced by adenosine analogues.