Adenosine A<sub>1</sub> and A<sub>2</sub> receptors: Structure–function relationships

Galen, P. J. M. van; Stiles, Gary L.; Michaels, George S.; Jacobson, Kenneth A.

doi:10.1002/med.2610120502

Cited by 126 publications

(120 citation statements)

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“…Second, although the well-established antiplatelet effects of adenosine are attributed to A 2 receptor activation on the platelet surface, [22][23][24] our use of the nonspecific antagonist PD precludes the precise confirmation of the receptor subtype involved. Similarly, we cannot specify the site of action of adenosine: rather than activating platelet A 2 receptors per se, adenosine may have attenuated later platelet-mediated thrombosis in an indirect manner by, for example, reducing the release of superoxide anions (known to promote platelet aggregation and adhesion) 11,34 from neutrophils.…”

Section: Limitations and Unanswered Questionsmentioning

confidence: 99%

Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries

et al. 1998

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Background-Recent studies suggest that patients with angina before myocardial infarction exhibit improved recovery of coronary perfusion after thrombolysis by an as-yet-unknown mechanism. We therefore proposed that brief antecedent ischemia/reperfusion may, via release of adenosine, improve vessel patency in damaged and stenotic coronary arteries. Methods and Results-Anesthetized dogs underwent coronary injuryϩstenosis, resulting in repeated cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgment of platelet-rich thrombi. Vessel patency was assessed for 3 hours after stenosis by quantification of the nadir of the CFVs, duration of total thrombotic occlusion (flowϭ0), and area of the flow-time profile (expressed as percent of baseline flowϫ180 minutes). In protocol 1, dogs received 10 minutes of coronary occlusionϩ10 minutes of reflow or a comparable 20-minute control period before injuryϩstenosis. The median nadir of the CFVs was higher (4.0 versus 0.3 mL/min), median zero flow duration per 30-minute time interval was shorter (0.4 versus 15.1 minutes), and mean percent flow-time area was greater (54Ϯ8% versus 28Ϯ9%) in dogs that received antecedent ischemia versus controls (PϽ.05). These benefits of antecedent ischemia/reperfusion were largely mimicked by a 10-minute intracoronary adenosine infusion (400 g/min) in lieu of brief ischemia (protocol 2) and were abolished by administration of the adenosine A 1 /A 2 receptor antagonist PD 115,199 (3 mg/kg IV) before brief antecedent coronary occlusion (protocol 3). Conclusions-Brief antecedent ischemia attenuates subsequent platelet-mediated thrombosis in damaged and stenotic canine coronary arteries, due, in large part, to an adenosine-mediated mechanism. (Circulation. 1998;97:692-702.)

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Section: Limitations and Unanswered Questionsmentioning

confidence: 99%

Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries

et al. 1998

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“…The adenosine antagonists, 8-PT and DPCPX were specifically investigated to reinforce the receptor classification based on agonist potencies in this study, since they are able to differentiate between Al and A2 receptors. For instance, binding studies (see review by Van Galen et al, 1992) have established that 8-PT shows a small degree of selectivity for Al compared to A2 sites (Ki = 86 nM at A1 and 850 nM at A2) while DPCPX in contrast is highly selective for Al sites (Ki = 0.5 nM at Al and 340 nM at A2). The difference between the affinities and selectivity ratios of the two antagonists is also apparent in intact tissues where 8-PT is non-selective for Al and A2 receptors, whilst DPCPX has a 30-50 fold greater affinity for Al but is equi-effective with 8-PT at A2 receptors .…”

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confidence: 99%

Functional characterization of the adenosine receptor mediating inhibition of intestinal secretion

Hancock¹,

Coupar²

1995

British J Pharmacology

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Previous studies have shown that the mixed A1/A2 adenosine agonist 5′‐N‐ethylcarboxamido‐adenosine (NECA) inhibits intestinal fluid secretion which is thought to contribute to its antidiarrhoeal effect in the rat. The aim of this study was to characterize the adenosine receptor mediating this antisecretory effect via functional studies using a range of selective agonists and antagonists and by applying the pharmacological criteria of relative agonist and antagonist potencies. Adenosine agonists and antagonists were administered i.v. to anaesthetized rats. Intestinal secretion was then stimulated by i.a. infusion of vasoactive intestinal peptide (VIP, 0.8 μg min−1) and the net fluid transport across the wall of the jejunum was measured by a recirculation technique. The rank order of agonist potency to reduce the response to VIP was: NECA > N6‐cyclopentyladenosine (CPA) > R‐N6‐(2‐phenylisopropyladenosine) (R‐PIA) > S‐PIA > chloroadenosine (2‐CADO) > 2‐phenylaminoadenosine (CV‐1808). This order best complies with the rank order of agonist potency that represents activation of the recently described A2B receptor: NECA > 2‐CADO R‐PIA = CHA > S‐PIA > = CV‐1808 > = CGS‐21680. The most potent agonists (NECA, CPA and R‐PIA) had ED50 values in the low microgram range. The anitsecretory action of NECA (submaximal dose of 40μg kg−1) was antagonized equally (approximately 50%) by the selective adenosine antagonists 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 0.1 mg kg−1) and 8‐phenyltheophylline (8‐PT, 0.1 mg kg−1). This equipotent activity indicates the presence of an A2 and not an A1 receptor. It is suggested that adenosine A2B receptor agonists could be evaluated for potential use as antidiarrhoeal drugs.

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“…Although less is known about the A 3 -AdoR, it has been reported that this AdoR subtype mediates an inhibition of adenylyl cyclase and a stimulation of phospholipase C, resulting in an elevation of inositol phosphates (5, 6). The characterization, function, and regulation of the AdoRs have been greatly facilitated by the development of potent and selective agonists and antagonists (1,7,8). …”

mentioning

confidence: 99%

“…by cell surface receptors and at least four subtypes, designated A 1 , A 2A, A 2B , and A 3 , have been identified, with each subtype mediating cellular effects by coupling to G proteins (1)(2)(3)(4). The AdoR regulates the activity of several cellular components, including inhibition of adenylyl cyclase activity, stimulation of phospholipases A 2 and C, and guanylyl cyclase, and regulates the ion permeability of calcium and potassium channels (2)(3)(4).…”

mentioning

confidence: 99%

“…The AdoR regulates the activity of several cellular components, including inhibition of adenylyl cyclase activity, stimulation of phospholipases A 2 and C, and guanylyl cyclase, and regulates the ion permeability of calcium and potassium channels (2)(3)(4). The A 2 -AdoRs, on the other hand, mediate stimulation of adenylyl cyclase activity (1,2). Although less is known about the A 3 -AdoR, it has been reported that this AdoR subtype mediates an inhibition of adenylyl cyclase and a stimulation of phospholipase C, resulting in an elevation of inositol phosphates (5,6).…”

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Persistent Activation by and Receptor Reserve for an Irreversible A₁-Adenosine Receptor Agonist in DDT₁MF-2 Cells and in Guinea Pig Heart

et al. 1997

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SUMMARYThe p-and m-isothiocyanate adenosine derivatives N 6 - [4-[[[4-[[[[2-[[[(p-(m value for the radioligand to the remaining receptors. The relationship between irreversible A 1 -AdoR occupancy by p-DITC-ADAC and inhibition of cAMP accumulation revealed a relatively large receptor reserve (64%) for the maximal response. In guinea pig isolated hearts, m-DITC-ADAC (5 μM) prolonged the stimulus to His bundle (SH) interval by 2.1-fold; this response could be prevented by the antagonist 8-cyclopentyltheophylline (5 μM). However, after the SH interval prolongation was established, extensive washout or the addition of 8-cyclopentyltheophylline had little reversal effect on the m-DITC-ADAC response. Binding of [ 3 H]CPX to the guinea pig ventricular membranes after m-DITC-ADAC treatment and washing was reduced by 35%. The A 1 -AdoR occupancy response relationship for m-DITC-ADAC to prolong the SH interval indicated a small (10-20%) receptor reserve. Both p -and m-DITC-ADAC seem to be irreversible full agonists at the A 1 -AdoR and may prove to be useful probes to further investigate A 1 -AdoR structure-function relationships.Adenosine is a ubiquitous modulator of physiological processes that acts to both increase tissue oxygen supply and reduce metabolic demand. The actions of adenosine are mediated The AdoR regulates the activity of several cellular components, including inhibition of adenylyl cyclase activity, stimulation of phospholipases A 2 and C, and guanylyl cyclase, and regulates the ion permeability of calcium and potassium channels (2-4). The A 2 -AdoRs, on the other hand, mediate stimulation of adenylyl cyclase activity (1, 2). Although less is known about the A 3 -AdoR, it has been reported that this AdoR subtype mediates an inhibition of adenylyl cyclase and a stimulation of phospholipase C, resulting in an elevation of inositol phosphates (5, 6). The characterization, function, and regulation of the AdoRs have been greatly facilitated by the development of potent and selective agonists and antagonists (1,7,8). HHS Public AccessChemoreactive ligands are useful pharmacological probes in structure and function studies of receptors (9). These ligands are usually composed of two components: a pharmacophore and a reactive moiety. The pharmacophore is usually derived from known agonists or antagonists, which provide affinity and selectivity for the receptor. The reactive moiety allows covalent incorporation of the ligand into the receptor, which prevents ligand dissociation (9). These ligands have been used in a variety of studies, including determination of receptor reserve (10, 11), receptor subtype discrimination (12, 13), basal receptor turnover (14, 15), and ligand binding site mapping (16,17).Jacobson et al. (18) have synthesized a series of potential irreversible ligands for the adenosine receptor by modifying the high affinity agonist pharmacophore ADAC with substituents containing reactive electrophilic groups. Coupling of ADAC with 1,3-or 1,4-phenylene DITC produced p-and m-DITC-ADAC, which were sho...

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Adenosine A₁ and A₂ receptors: Structure–function relationships

Cited by 126 publications

References 164 publications

Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries

Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries

Functional characterization of the adenosine receptor mediating inhibition of intestinal secretion

Persistent Activation by and Receptor Reserve for an Irreversible A₁-Adenosine Receptor Agonist in DDT₁MF-2 Cells and in Guinea Pig Heart

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Adenosine A1 and A2 receptors: Structure–function relationships

Cited by 126 publications

References 164 publications

Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries

Brief Antecedent Ischemia Attenuates Platelet-Mediated Thrombosis in Damaged and Stenotic Canine Coronary Arteries

Functional characterization of the adenosine receptor mediating inhibition of intestinal secretion

Persistent Activation by and Receptor Reserve for an Irreversible A1-Adenosine Receptor Agonist in DDT1MF-2 Cells and in Guinea Pig Heart

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Adenosine A₁ and A₂ receptors: Structure–function relationships

Persistent Activation by and Receptor Reserve for an Irreversible A₁-Adenosine Receptor Agonist in DDT₁MF-2 Cells and in Guinea Pig Heart