The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A<sub>2a</sub> selective adenosine receptor antagonist

Poucher, Simon M.; Keddie, J.; Singh, Parminder; Stoggall, S.M.; Caulkett, Peter W. R.; Jones, Gemma N.; Collis, Michael G.

doi:10.1111/j.1476-5381.1995.tb15923.x

Cited by 329 publications

(239 citation statements)

References 28 publications

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“…On the contrary, a role for nitric oxide has been clearly evident as regards the ®rst phase response to the nucleoside at the vascular level, which was signi®cantly reduced by L-NAME. This response reproduced by the A 2a agonist CGS21680 (Collis & Hourani, 1993) was antagonized by the A 2a antagonist ZM 241385 (Poucher et al, 1995) and blocked not only by L-NAME but also by methylene blue, a guanylate cyclase and NO-synthase inhibitor (Mayer et al, 1993). We can exclude that the e ect of methylene blue, L-NAME and ZM 241385 is due to the hypertensive action of these drugs since similar hypertensive activity induced by the a 1 -adrenergic agonist methoxamine did not modify the doseresponse curve to adenosine (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Nieri¹,

Martinotti²,

Calderone³

et al. 2001

British J Pharmacology

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1 Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic e ect at the highest doses. The ®rst phase hypotensive response was signi®cantly reduced by the nitric oxide (NO) synthase inhibitor L-NAME. 2 The A 2a /A 2b agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not signi®cantly modi®ed by the A 2b antagonist enprofylline. 3 The A 2a agonist CGS 21680 did not signi®cantly in¯uence basal HR while induced a hypotensive response antagonized by the A 2a selective antagonist ZM 241385, and reduced by both L-NAME and the guanylate cyclase inhibitor methylene blue. 4 The A 1 agonist R-PIA showed a dose-dependent decrease in BP with a drastic decrease in HR at the highest doses. The A 1 selective antagonist DPCPX signi®cantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones. 5 The A 1 /A 3 agonist APNEA, in the presence of the xanthinic non-selective antagonist 8-pSPT, maintained a signi®cant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine. 6 The selective A 3 agonist IB-MECA revealed a weak hypotensive and bradycardic e ect, but only at the highest doses. 7 In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A 2a -and NO-mediated hypotension, and a bradycardic e ect with a consequent hypotension, via atypical A 1 receptors. Finally, an 8-pSPT-resistant hypotensive response not attributable to A 3 receptor-stimulation or to release of histamine by mastocytes or other immune cells was observed. IntroductionFour classes of membrane surface adenosine receptors are described, de®ned A 1 , A 2a , A 2b and A 3 , through which the nucleoside in¯uences many functions in humans and other animals (Ralevic & Burnstock, 1998). As far as the cardiovascular system is concerned, adenosine slows heart rate (HR) and atrioventricular conduction and antagonizes the cardio-stimulatory e ects of catecholamines via cardiac A 1 receptors in di erent mammals (Belardinelli et al., 1989;Olsson & Pearson, 1990). An increase in blood pressure (BP) and HR has been described in rats and in cats via central A 1 receptors (St Lambert et al., 1994; SilvaCarvalho et al., 1993). In contrast, a dose-related decrease in BP and HR is observed after microinjection of adenosine into the caudal nucleus of tractus solitarii in the rat (Lo et al., 1998).As regards a direct e ect on blood vessels, A 1 purinoceptors mediate vasodilation in the porcine coronary artery (Merkel et al., 1992) but they are involved, on the contrary, in vasoconstrictor responses, i.e. in the rat kidney (Jackson, 1991), in guinea-pig pulmonary artery and aorta (Biaggioni et al., 1989;Stoggall & Shaw, 1990) and in hamster skin (Stojanov & Proctor, 1990;Proctor & Stojanov, 1991).Moreover, a signi®cant role of A 1 receptors in the regulation of BP also appears to be linked to a prejunction...

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Section: Discussionmentioning

confidence: 99%

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Nieri¹,

Martinotti²,

Calderone³

et al. 2001

British J Pharmacology

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“…The effect in innervated diaphragms from older adults or aged rats was also significantly different from that in infant rats (p Ͻ 0.05; ANOVA 1-way analysis of variance followed by Tukey's multiple comparisons test). Interestingly, when CADO (30 nM) was applied in the presence of the selective A 2A receptor antagonist, ZM 241385 (50 nM, Poucher et al, 1995), it caused inhibition of EPP amplitude ( Fig. 1A-D), which was more evident in innervated diaphragms from older adult (Ϫ12 Ϯ 2.4%, n ϭ 3; Fig.…”

Section: Relative Role Of Adenosine a 1 And A 2a Receptors Upon Agingmentioning

confidence: 96%

Neuromuscular transmission modulation by adenosine upon aging

Pousinha

Correia

Sebastião

et al. 2012

Neurobiology of Aging

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In infant rats adenosine A 2A receptor-mediated modulation of neuromuscular transmission predominates over A 1 receptor-mediated neuromodulation. We investigated whether aging affects this A 2A /A 1 receptor balance. Evoked (EPPs) and miniature end plate potentials (MEPPs) were recorded from single fibers of (weeks-old) infant (3-4), young adult (12-16), older (36 -38), and aged (80 -90) male rat-diaphragm. The non A 1 /A 2A selective agonist, 2-chloroadenosine (CADO; 30 nM) and the adenosine kinase inhibitor, iodotubericidin (ITU; 10 M) increased mean amplitude and quantal content of EPPs in infant, young adult, and older adult rats, but not in aged rats. The facilitatory effects were prevented by the A 2A receptor antagonist, ZM241385 (50 nM) and mimicked by the A 2A receptor agonist, CGS21680 (10 nM). The A 1 receptor agonist, 6-cyclopentyladenosine (CPA; 100 nM), decreased EPPs amplitude in all age groups. It is concluded that aging differently influences adenosine A 1 receptor and A 2A receptor-mediated presynaptic modulation of neuromuscular transmission, so that the facilitatory influence decreases upon aging, whereas the inhibitory influence remains unchanged in aged animals. The reduction of adenosine A 2A receptors upon aging may contribute to the age-related changes in neuromuscular function.

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“…It is likely, therefore, that the high potency phase of the E/[A] curve to NECA is mediated via A 2B receptors. This was con®rmed with the A 2A selective antagonist ZM 241385, which produced rightward shifts with pA 2 estimates of 7.65 (in the presence of endothelium) and 7.20 (in the absence of endothelium) which are not consistent with the a nity for ZM 241385 at A 2A receptors (9.02, Poucher et al, 1995) but are closer to the A 2B a nity value (7.1, Poucher et al, 1995). Likewise, in the presence of NBTI, to block uptake, E/[A] curves to adenosine were shifted to the right by ZM 241385 (0.1 mM) yielding a pA 2 of 7.5, suggesting activation of A 2B receptors.…”

Section: Controlmentioning

confidence: 99%

“…The new non-xanthine antagonist, 4-(2-[7-amino -2 -(2 -furyl) [1,2,4] -triazolo [2,3 -a][1,3,5]triazin -5-yl amino] ethyl) phenol (ZM 241385) has selectivity for A 2A over A 2B and A 1 (32 and 420 fold, respectively) with a pA 2 at A 2A receptors in the guinea-pig Langendor heart of 9.02 (Poucher et al, 1995). The advent of such compounds has allowed subclassi®cation of A 2 receptors in functional studies.…”

Section: Introductionmentioning

confidence: 99%

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

Prentice

Payne

Hourani

1997

British J Pharmacology

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1 In this study we have characterized the receptor(s) in the rat mesenteric artery mediating relaxant responses to adenosine and a number of adenosine analogues, N 6 -R-phenylisopropyladenosine (R-PIA), N 6 -cyclopentyladenosine (CPA) . We have also studied the e ects of endothelial removal and uptake inhibition by nitrobenzylthioinosine (NBTI) and the e ects of the A 3 receptor antagonist 1,3-dipropyl-8-(4-acrylate)phenylxanthine (BWA1433). 2 Adenosine, NECA, CPA and R-PIA all elicited relaxant responses in tissues precontracted with phenylephrine (1 mM) with the following potency order: NECA4R-PIA4adenosine=CPA. However, E/[A] curves to NECA were biphasic. CGS 21680 was inactive at concentrations up to 30 mM and IB-MECA elicited relaxant responses which were resistant to blockade by 8-SPT and BWA1433 (100 mM). 3 Removal of the endothelium produced a small but signi®cant decrease in the asymptote of the high potency phase of E/[A] curves to NECA with no change in p[A] 50 . E/[A] curves to adenosine were not altered by removal of the endothelium. However, there were small rightward shifts of E/[A] curves to CPA and R-PIA in the absence of endothelium. 4 Inhibition of uptake by NBTI (1 mM) had no e ect on E/[A] curves to NECA, CPA or R-PIA, but E/[A] curves to adenosine were signi®cantly left-shifted in the presence of NBTI. 5 8-SPT (10 ± 100 mM) caused signi®cant rightward shifts of the high potency phase of the E/[A] curves to NECA (pA 2 =5.63+0.26). The second phase of the concentration-response curve to NECA appeared to be resistant to blockade by 8-SPT, as were E/[A] curves for adenosine, CPA or R-PIA. However, in the presence of NBTI (1 mM), 8-SPT (100 mM) gave signi®cant rightward shifts of E/[A] curves to adenosine. 6 ZM 241385 (0.1 ± 1 mM) produced signi®cant rightward shifts of the high potency phase of NECA E/[A] curves (pA 2 =7.65+0.25 in the presence and 7.20+0.12 in the absence of endothelium), while curves to R-PIA were not signi®cantly shifted by 1 mM ZM 241385. In the presence of NBTI E/[A] curves to adenosine were signi®cantly rightward shifted by ZM 241385 (0.1 mM, pA 2 =7.50+0.16). 7 In conclusion, the results suggest activation of A 2B receptors located primarily on the smooth muscle by low concentrations of NECA and by adenosine under conditions of uptake blockade, and of another, as yet unde®ned site which may be intracellular, by higher concentrations of NECA, by CPA, R-PIA and adenosine under conditions where uptake is operational.,

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

Cited by 329 publications

References 28 publications

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Neuromuscular transmission modulation by adenosine upon aging

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

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

Cited by 329 publications

References 28 publications

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO

Neuromuscular transmission modulation by adenosine upon aging

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

Contact Info

Product

Resources

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