Direct preconditioning of cultured chick ventricular myocytes. Novel functions of cardiac adenosine A2a and A3 receptors.

Strickler, Jennifer; Jacobson, Kenneth A.; Liang, Bruce T.

doi:10.1172/jci118976

Cited by 124 publications

(166 citation statements)

References 37 publications

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“…A protective e ect following A 3 receptor stimulation at the cardiac level has been described in di erent animal models (Strickler et al, 1996;Stambaugh et al, 1997;Tracey et al, 1997) but the lack of any signi®cant e ect of the A 3 selective agonist IB-MECA (Gallo-Rodriguez et al, 1994) suggests that an A 3 -mediated in¯uence of adenosine on cardiac function can be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…At the cardiac level, A 3 receptor stimulants, administered prior to and during an ischaemic episode, have shown a protective action on heart cells in human and other animals (Strickler et al, 1996;Stambaugh et al, 1997;Tracey et al, 1997;Carr et al, 1997). Finally, a decrease in BP without any change in HR, mediated by A 3 receptor stimulation was observed in the rat by Stella et al (1998).…”

Section: Introductionmentioning

confidence: 93%

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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%

Section: Introductionmentioning

confidence: 93%

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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“…Acting through the A 2A adenosine receptor (AR), it suppresses prolonged inflammation [2] and causes vasodilation and inhibits platelet aggregation, thus increasing the amount of oxygen available to an organ under stress. Adenosine agonists selective for the A 3 AR are of interest as cerebroprotective [3], cardioprotective [4,5], and anticancer [6] agents.…”

Section: Introductionmentioning

confidence: 99%

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Gao

Mamedova

Chen

et al. 2004

Biochemical Pharmacology

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The affinity and efficacy at four subtypes (A 1 , A 2A , A 2B and A 3 ) of human adenosine receptors (ARs) of a wide range of 2-substituted adenosine derivatives were evaluated using radioligand binding assays and a cyclic AMP functional assay in intact CHO cells stably expressing these receptors. Similar to previous studies of the N 6 -position, several 2-substituents were found to be critical structural determinants for the A 3 AR activation. The following adenosine 2-ethers were moderately potent partial agonists (K i , nM): benzyl (117), 3-chlorobenzyl (72), 2-(3-chlorophenyl)ethyl (41), and 2-(2-naphthyl)ethyl (130). The following adenosine 2-ethers were A 3 AR antagonists: 2,2-diphenylethyl, 2-(2-norbornan)ethyl, R-and S-2-phenylbutyl, and 2-(2-chlorophenyl)ethyl. 2-(S-2-Phenylbutyloxy)a-denosine as an A 3 AR antagonist right-shifted the concentration-response curve for the inhibition by NECA of cyclic AMP accumulation with a K B value of 212 nM, which is similar to its binding affinity (K i = 175 nM). These 2-substituted adenosine derivatives were generally less potent at the A 1 AR in comparison to the A 3 AR, but fully efficacious, with binding K i values over 100 nM. The 2-phenylethyl moiety resulted in higher A 3 AR affinity (K i in nM) when linked to the 2-position of adenosine through an ether group (54), than when linked through an amine (310) or thioether (1960). 2-[2-(lNaphthyl)ethyloxy]adenosine (K i = 3.8 nM) was found to be the most potent and selective (>50-fold) A 2A agonist in this series. Mixed A 2A /A 3 AR agonists have been identified. Interestingly, although most of these compounds were extremely weak at the A 2B AR, 2-[2-(2-naphthyl)ethyloxy]adenosine (EC 50 = 1.4 µM) and 2-[2-(2-thienyl)-ethyloxy]adenosine (EC 50 = 1.8 (M) were found to be relatively potent A 2B agonists, although less potent than NECA (EC 50 = 140 nM).

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“…A 3 agonists are also protective in the heart, as well as the brain. In a chick ventricular myocyte culture (8) and in the isolated rabbit heart (9) activation of A 3 receptors by IB-MECA induced preconditioning, which greatly improved the outcome following an ischemic injury.…”

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confidence: 99%

Adenosine A3Receptor Agonists Protect HL-60 and U-937 Cells from Apoptosis Induced by A3Antagonists

Yao

Sei

Abbracchio

et al. 1997

Biochemical and Biophysical Research Communications

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Direct preconditioning of cultured chick ventricular myocytes. Novel functions of cardiac adenosine A2a and A3 receptors.

Cited by 124 publications

References 37 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

2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors

Adenosine A3Receptor Agonists Protect HL-60 and U-937 Cells from Apoptosis Induced by A3Antagonists

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