Relative agonist potencies of C2-substituted analogues of adenosine: Evidence for adenosine A2B receptors in the guinea pig aorta

Martin, Pauline L.

doi:10.1016/0014-2999(92)90365-b

Cited by 60 publications

(36 citation statements)

References 8 publications

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“…its potential role in vascular tone (25,26), we determined BP in the A 2B AR-KO mice under basal conditions and in response to intravenous administration of adenosine at different concentrations. A 2B AR deficiency did not impact BP under basal conditions or after adenosine-induced vasodilation (Supplemental Figure 5 and Supplemental Table 3).…”

Section: Figurementioning

confidence: 99%

“…Despite this limitation, the A 2B AR has been implicated in several important biological events, including mediating vasodilation (25,26), inhibiting growth of rat aortic smooth muscle cells (27,28), and increasing the production of cytokines, such as IL-6, by vascular cells (29,30). In vitro studies described the A 2B AR as mediating augmentation of cytokine production by vascular cells (29,30), and adenosine has been described as a regulator of inflammatory response (31).…”

Section: Introductionmentioning

confidence: 99%

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The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

Yang

Zhang²,

Nguyen³

et al. 2006

Journal of Clinical Investigation

320

409

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Adenosine has been described as playing a role in the control of inflammation, but it has not been certain which of its receptors mediate this effect. Here, we generated an A 2B adenosine receptor-knockout/reporter gene-knock-in (A 2B AR-knockout/reporter gene-knock-in) mouse model and showed receptor gene expression in the vasculature and macrophages, the ablation of which causes low-grade inflammation compared with age-, sex-, and strain-matched control mice. Augmentation of proinflammatory cytokines, such as TNF-a, and a consequent downregulation of IkB-a are the underlying mechanisms for an observed upregulation of adhesion molecules in the vasculature of these A 2B AR-null mice. Intriguingly, leukocyte adhesion to the vasculature is significantly increased in the A 2B AR-knockout mice. Exposure to an endotoxin results in augmented proinflammatory cytokine levels in A 2B AR-null mice compared with control mice. Bone marrow transplantations indicated that bone marrow (and to a lesser extent vascular) A 2B ARs regulate these processes. Hence, we identify the A 2B AR as a new critical regulator of inflammation and vascular adhesion primarily via signals from hematopoietic cells to the vasculature, focusing attention on the receptor as a therapeutic target.

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Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

Yang

Zhang²,

Nguyen³

et al. 2006

Journal of Clinical Investigation

320

409

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“…Dionisotti et al (1994) (Williams et al, 1986), rat cloned A3 receptors expressed in chinese hamster ovary cell line (Olah et al, 1994) and in rat cortex (Bruns et al, 1987a) respectively. Evaluation of antagonism of adenosine receptor-mediated responses was further investigated in guinea-pig atria (Al receptor, Collis, 1983), guinea-pig Langendorff hearts (A2a receptor, Ueeda et al, 1991) and guinea-pig isolated aortae (A2b receptor, Hargreaves et al, 1991;Martin, 1992).…”

Section: Introductionmentioning

confidence: 99%

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A_2a selective adenosine receptor antagonist

Poucher

Keddie

Singh

et al. 1995

British J Pharmacology

330

222

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1 This paper describes the in vitro pharmacology of ZM 241385 (4-(2-[7-amino-2-(2-furyl) antagonized vasodilatation of the coronary bed produced by 2-chloroadenosine (2-CADO) and 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) with pA2 values of 8.57 (c.l., 8.45-8.68) and 9.02 (c.l., 8.79-9.24) respectively. 3 ZM 241385 had low potency at A2b receptors and antagonized the relaxant effects of adenosine in the guinea-pig aorta with a pA2 of 7.06, (c.l., 6.92-7.19). 4 ZM 241385 had a low affinity at A1 receptors. In rat cerebral cortex membranes it displaced tritiated R-phenylisopropyladenosine (R-PIA) with a pIC50 of 5.69 (c.l., 5.57-5.81). ZM 241385 antagonized the bradycardic action of 2-CADO in guinea-pig atria with a pA2 of 5.95 (c.l., 5.72-6.18). 5 ZM 241385 had low affinity for A3 receptors. At cloned rat A3 receptors expressed in chinese hamster ovary cells, it displaced iodinated aminobenzyl-5'-N-methylcarboxamido adenosine (AB-MECA) with a pIC50 of 3.82 (c.l., 3.67-4.06). 6 ZM 241385 had no significant additional pharmacological effects on the isolated tissues used in these studies at concentrations three orders of magnitude greater than those which block A2a receptors. At 10 gM it displayed only minor inhibition of the bradycardic effects in guinea-pig atria to some concentrations of carbachol. At 10 gM, ZM 241385 had a small inhibitory effect on relaxant effects of isoprenaline in guinea-pig aortae but no effect on sodium nitrite-induced relaxation. ZM 241385 (100 gM) was without effect on phenylephrine-induced tone in guinea-pig aortae. 7 ZM 241385 (10 gM) had no inhibitory effect on rat hepatocyte phosphodiesterase types I, II, III and IV but caused a small inhibition of the calcium calmodulin-activated type I enzyme. 8 ZM 241385 is the most selective adenosine A2a receptor antagonist yet described and is therefore a useful tool for characterization of responses mediated by A2 adenosine receptors.

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“…The Al/A2 antagonist, 8-PT (10 uM) abolished the inhibitory responses to NECA suggesting that NECA is not acting via an A3 receptor, as it is known that the rat A3 receptor is highly resistant to certain xanthine antagonists including 8-PT even at concentrations of 100 gM (van Galen et al, 1994). Moreover, the relaxations induced by NECA are not xanthine-insensitive responses as have been seen with high concentrations of agonists in tissues such as guinea-pig trachea (Brackett & Daly, 1991), aorta (Collis & Brown, 1983;Martin, 1992) and taenia caecum (Prentice et al, 1995). (Nicholls et al, 1996).…”

Section: Discussionmentioning

confidence: 88%

Differential development of adenosine A₁ and A_2b receptors in the rat duodenum

Peachey

Hourani

Kitchen

1996

British J Pharmacology

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1 The development of the adenosine Al and A2b receptors inducing relaxation of the rat duodenum was studied by use of a combination of functional and radioligand binding assays on rats aged between 5 and 30 days and compared with results previously found in adult rat duodenum. 2 1,3-[3H]-dipropyl-8-cyclopentylxanthine ( NECA was observed at all ages. In the presence of 10 nM DPCPX, the response to NECA was unaffected in the duodenum from animals aged 10 and 15 days. However, in duodenum from animals aged 20-30 days the concentration-response curve to NECA was shifted to the right suggesting that there is an Al component to the action of NECA at these ages. Schild analysis of the effects of increasing concentrations of DPCPX versus NECA on the duodenum from 25 day old animals generated a slope of 0.62 suggesting that NECA acts at Al and A2b receptors as in the adult. 6 The A2b-selective analogue, 2-[p-(carboxyethyl)-phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) (10 nM-10 IM) was without effect on the carbachol-contracted duodenum from 15 day old rats and the duodenum from 25 day old rats responded to the highest concentration of CGS 21680 only, suggesting that the A2 receptors here, as in the adult, are not of the A2a subtype. The adenosine antagonist, 8-phenyltheophylline (8-PT) (10 pM), abolished the inhibitory effects of NECA (100 nM-100 uM) on 10, 15 and 25 day old rat duodenum indicating that the responses to NECA were not mediated via an adenosine A3 receptor.7 These results show that adenosine Al receptors in rat duodenum are present and functionally viable from day 20 onwards and that the density of Al receptors varies with age, increasing up to day 25 and then declining at day 30 to a density commensurate with that found in the adult. The responses to CPA, mediated via the Al receptor, increase with age in a similar fashion. In contrast however, the response to NECA was evident from day 5, the earliest age studied, and from days 5-15 NECA acted via the A2b receptor subtype. However, from day 20 onwards NECA acted at a mixed population of A1 and A2b receptors. These results demonstrate the differential development of the Al and the A2b receptors in the rat duodenum.

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Relative agonist potencies of C2-substituted analogues of adenosine: Evidence for adenosine A2B receptors in the guinea pig aorta

Cited by 60 publications

References 8 publications

The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A_2a selective adenosine receptor antagonist

Differential development of adenosine A₁ and A_2b receptors in the rat duodenum

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Relative agonist potencies of C2-substituted analogues of adenosine: Evidence for adenosine A2B receptors in the guinea pig aorta

Cited by 60 publications

References 8 publications

The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A2a selective adenosine receptor antagonist

Differential development of adenosine A1 and A2b receptors in the rat duodenum

Contact Info

Product

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The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A_2a selective adenosine receptor antagonist

Differential development of adenosine A₁ and A_2b receptors in the rat duodenum