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Functional characterization of coronary vascular adenosine receptors in the mouse.

ABSTRACT: Coronary responses to adenosine agonists were assessed in perfused mouse and rat hearts. The roles of nitric oxide (NO) and ATP-dependent K(+) channels (K(ATP)) were studied in the mouse. Resting coronary resistance was lower in mouse vs rat, as was minimal resistance (2.2+/-0.1 vs 3.8+/-0.2 mmHg ml(-1) min(-1) g(-1)). Peak hyperaemic flow after 20 - 60 s occlusion was greater in mouse. Adenosine agonists induced coronary dilation in mouse, with pEC(50)s of 9.4+/-0.1 for 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethyl carboxamidoadenosine (CGS21680, A(2A)-selective agonist), 9.3+/-0.1 for 5'-N-ethylcarboxamidoadenosine (NECA, A(1)/A(2) agonist), 8.4+/-0.1 for 2-chloroadenosine (A(1)/A(2) agonist), 7.7+/-0.1 for N(6)-(R)-(phenylisopropyl)adenosine (R-PIA, A(1)/A(2B) selective), and 6.8+/-0.2 for adenosine. The potency order (CGS21680=NECA>2-chloroadenosine>R-PIA>adenosine) supports A(2A) adenosine receptor-mediated dilation in mouse coronary vessels. 0.2 - 2 microM of the A(2B)-selective antagonist alloxazine failed to alter CGS21680 or 2-chloroadenosine responses. pEC(50)s in rat were 6.7+/-0.2 for CGS21680, 7.3+/-0.1 for NECA, 7.6+/-0.1 for 2-chloroadenosine, 7.2+/-0.1 for R-PIA, and 6.2+/-0.1 for adenosine (2-chloroadenosine>NECA=R-PIA>CGS21680> adenosine), supporting an A(2B) adenosine receptor response. NO-synthase antagonism with 50 microM N(G)-nitro L-arginine (L-NOARG) increased resistance by approximately 25%, and inhibited responses to CGS21680 (pEC(50)=9.0+/-0.1), 2-chloroadenosine (pEC(50)=7.3+/-0.2) and endothelial-dependent ADP, but not sodium nitroprusside (SNP). K(ATP) channel blockade with 5 microM glibenclamide increased resistance by approximately 80% and inhibited responses to CGS21680 in control (pEC(50)=8.3+/-0.1) and L-NOARG-treated hearts (pEC(50)=7.3+/-0.1), and to 2-chloroadenosine in control (pEC(50)=6.7+/-0.1) and L-NOARG-treated hearts (pEC(50)=5.9+/-0.2). In summary, mouse coronary vessels are more sensitive to adenosine than rat vessels. A(2A) adenosine receptors mediate dilation in mouse coronary vessels vs A(2B) receptors in rat. Responses in the mouse involve a sensitive NO-dependent response and K(ATP)-dependent dilation.

SUBMITTER: Flood A

PROVIDER: S-EPMC1572876 | biostudies-other | 2001 Aug

REPOSITORIES: biostudies-other

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Project description:To investigate the effects of adenosine on endogenous Xenopus oocyte receptors, we analysed defolliculated oocytes injected with mRNAs for the G protein-activated inwardly rectifying K(+) (GIRK) channels. In oocytes injected with mRNAs for either GIRK1/GIRK2 or GIRK1/GIRK4 subunits, application of adenosine or ATP reversibly induced inward K(+) currents, although ATP was less potent than adenosine. The responses were attenuated by caffeine, a non-selective adenosine receptor antagonist. Furthermore, in uninjected oocytes from the same donor, adenosine produced no significant current. The endogenous receptor was activated by two selective A(1) adenosine receptor agonists, N(6)-cyclopentyladenosine (CPA) and N(6)-cyclohexyladenosine (CHA), and antagonized by a selective A(1) adenosine receptor antagonist, 1,3-dipropyl-8-cyclopenylxanthine (DPCPX) at moderate nanomolar concentrations, but insensitive to micromolar concentrations of selective A(2A) and A(3) adenosine receptor agonists, 2-[p-(2-carbonyl-ethyl)-phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) and N(6)-(3-iodobenzyl)-5'-(N-methylcarbamoyl)adenosine (IB-MECA), respectively. However, the pharmacological characteristics of the receptor were different from those of the cloned Xenopus A(1) adenosine receptor and previously proposed adenosine receptors. The adenosine-induced GIRK currents were abolished by injection of pertussis toxin and CPA inhibited forskolin-stimulated cyclic AMP accumulation. We conclude that an adenosine receptor on the Xenopus oocyte membrane can activate GIRK channels and inhibit adenylyl cyclase via G(i/o) proteins. Moreover, our results suggest the existence of an endogenous adenosine receptor with the unique pharmacological characteristics. As the receptor was activated by nanomolar concentrations of adenosine, which is a normal constituent of extracellular fluid, the receptor may be involved in some effects through the G(i/o) protein signalling pathways in ovarian physiology.

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Functional characterization of coronary vascular adenosine receptors in the mouse.

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