Cloning, Expression and Pharmacological Characterization of Rabbit Adenosine A 1 and A 3 Receptors (original) (raw)
Related papers
Effects of selective A1 and A2 adenosine receptor agonists on cardiovascular tissues
Naunyn-Schmiedeberg's Archives of Pharmacology, 1993
We investigated the negative chronotropic and vasodilating properties of new selective A1 and A 2 adenosine agonists such as 2-chloro-N6-cyclopentyladenosine (CCPA) and 2-hexynyl-5'-N-ethyl-carboxamidoadenosine (2-hexynyl-NECA) as compared with reference adenosine analogues. The potency of these compounds on heart rate was assessed in the rat atrial preparation and their activity on the vascular tone was determined in both rat aorta and bovine coronary artery. CCPA was found to be the most potent A t agonist of those currently available in producing negative chronotropic effects (ECs0 = 8.2 nM). The A 1 antagonist 8-cyclopentyl-l,3-dipropyl-xanthine (DPCPX) blocked CCPA activity in a dose-dependent manner. There was also a significant correlation between its biological effect and the affinity for A~ receptors as measured in the rat brain by [3H]-NU-cyclohexyladenosine (3[H]-CHA) binding. The A 2 selective agonist 2-hexynyl-NECA showed vasodilating properties comparable with those observed with the reference compounds, CGS 21680 and NECA. ECs0 values were 596 and 569 nM in rat aorta and bovine coronary artery, respectively. Moreover, the rank order of potency was similar in the two vascular districts examined, suggesting that the rat aorta is a useful model for studying the effects of adenosine derivatives on vascular tone. In addition, the potency of the compounds in inducing vasodilation was found to be correlated with their affinity for A 2 receptors as measured in the rat striatum by 3[H]-CGS 21680 binding.
International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors
Pharmacological reviews, 2001
Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are p...
Insights into the cardioprotective function of adenosine A(1) and A(3) receptors
Experimental and clinical cardiology, 2002
Cardioprotection (delaying of irreversible damage in hypoxia or prevention of doxorubicin [DOX] toxicity) is achieved by increasing the energy supply, or decreasing the energy demand in the cell and may be regulated through adenosine (ADO) receptor (AR) signalling. The aim of this study was to define of the protective role of ADO A(1)R and A(3)R against these two different kinds of stress conditions via direct action on isolated cardiomyocytes. Effects of A(1) and A(3) adenosine receptors were assessed by comparing morphological-functional tolerance, cellular energy state and contribution of the mitochondrial K(ATP) channels during development of hypoxia and DOX cytotoxicity. The primary cardiac myocyte cultures were treated in a hypoxic chamber of N(2) (100%) in glucose-free media. A second group of cells were treated on day 4 in culture with 0.5 to 5 muM DOX for 18 h and then incubated in drug-free growth medium for an additional 24 h or 72 h. The hypoxic and cytotoxic damage was ...
Evidence for an A2 adenosine receptor in human coronary arteries
European Journal of Pharmacology, 1988
The present study was an attempt to characterize the type of adenosine receptor in human coronary arteries obtained from organ donors with the use of adenosine analogs. Prostaglandin F,, (10m6 M) produced tonic contractions followed by phasic contractions and diltiazem (10m6 M) pretreatment changed the phasic contractions to tonic contractions. Adenosine and its analogs (5'-N-ethyl-carboxamide adenosine, NECA and N6-L-phenyl-isopropyl adenosine, L-PIA), produced concentration-dependent relaxations of the tonic contractions and the order of potency was found to be: NECA > L-PIA > adenosine. &Phenyltheophylline (5 X 1O-6 M) antagonized the relaxations produced by adenosine and its analogs. The data suggest the existence of A, adenosine receptor in human coronary arteries.
American journal of physiology. Heart and circulatory physiology, 2002
To determine whether adenosine A(3) receptors participate in adenosine-induced changes in coronary flow, isolated hearts from wild-type (WT) and A(3) receptor knockout (A(3)KO) mice were perfused under constant pressure and effects of nonselective and selective agonists were examined. Adenosine and the selective A(2A) agonist 2-[p-(2-carboxyethyl)]phenylethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) produced augmented maximal coronary vasodilation in A(3)KO hearts compared with WT hearts. Selective activation of A(3) receptors with 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) at nanomolar concentrations did not effect coronary flow, but at higher concentrations it produced coronary vasodilation both in WT and A(3)KO hearts. Cl-IB-MECA-induced increases in coronary flow were susceptible to both pharmacological blockade and genetic deletion of A(2A) receptors. Because deletion or blockade of adenosine A(3) receptors augmented coronary flow in...
Adenosine A2A and A2B receptors in cultured human and porcine coronary artery endothelial cells
American Journal of Physiology-Heart and Circulatory Physiology, 2000
We investigated the role of the cAMP link to the signal transduction mechanism coupled with adenosine A2A and A2Breceptors in cultured human coronary artery endothelial cells (HCAEC) and porcine coronary artery endothelial cells (PCAEC). 2-[4-[2-{2-[(4-aminophenyl)methylcarbonylamino]ethylaminocarbonyl}ethyl]phenyl]ethylamino-5′- ethylcarboxamidoadenosine (125I-PAPA-APEC) (PAPA-APEC) was used to demonstrate the specific binding in PCAEC membranes. The specific binding was saturable and reversible with a maximal number of binding sites (Bmax) of 240 fmol/mg protein, and scatchard analysis revealed a single class of binding site with an equilibrium dissociation constant ( K d) of 1.17 ± 0.035 nM. In competition experiments, adenosine receptor agonists showed the following order of potency (based on IC50): 5′-( N-ethylcarboxamido)adenosine (NECA) ≥ CGS-21680 > 2-chloroadenosine. This order appears to be consistent with the A2 adenosine receptor classification. We also studied the ef...
American Journal of …, 1999
Presently, the physiological significance of myocardial adenosine A 2a receptor stimulation is unclear. In this study, the influence of adenosine A 2a receptor activation on A 1 receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A 2a receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10 Ϫ8 M)-elicited contractile responses (ϩdP/dt max) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A 1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10 Ϫ7 M), but not the selective A 3 receptor antagonist 3-ethyl-5-benzyl-2methyl-4-phenylethynyl-6-phenyl-1,4-(Ϯ)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10 Ϫ7 M). The A 2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamidoadenosine (CGS-21680) at 10 Ϫ5 M attenuated the antiadrenergic effect of the selective A 1 receptor agonist 2-chloro-N 6cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 ϫ 10 Ϫ7 M)-elicited increases in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i) transients but did not influence Iso-induced changes in [Ca 2ϩ ] i transients in the absence of exogenous adenosine. These results indicate that adenosine A 2a receptor antagonists enhance A 1-receptor-induced antiadrenergic responses and that A 2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A 1 receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A 2a receptors in the normal mammalian myocardium is to reduce A 1 receptor-mediated antiadrenergic actions.
Handbook of Experimental Pharmacology, 2009
Adenosine is an autacoid that plays a critical role in regulating cardiac function, including heart rate, contractility, and coronary flow. In this chapter, current knowledge of the functions and mechanisms of action of coronary flow regulation and electrophysiology will be discussed. Currently, there are four known adenosine receptor (AR) subtypes, namely A 1 , A 2A , A 2B , and A 3. All four subtypes are known to regulate coronary flow. In general, A 2A AR is the predominant receptor subtype responsible for coronary blood flow regulation, which dilates coronary arteries in both an endothelial-dependent and-independent manner. The roles of other ARs and their mechanisms of action will also be discussed. The increasing popularity of gene-modified models with targeted deletion or overexpression of a single AR subtype has helped to elucidate the roles of each receptor subtype. Combining pharmacologic tools with targeted gene deletion of individual AR subtypes has proven invaluable for discriminating the vascular effects unique to the activation of each AR subtype. Adenosine exerts its cardiac electrophysiologic effects mainly through the activation of A 1 AR. This receptor mediates direct as well as indirect effects of adenosine (i.e., anti-β-adrenergic effects). In supraventricular tissues (atrial myocytes, sinua-trial node and atriovetricular node), adenosine exerts both direct and indirect effects, while it exerts only indirect effects in the ventricle. Adenosine exerts a negative chronotropic effect by suppressing the automaticity of cardiac pacemakers, and a negative dromotropic effect through inhibition of AV-nodal conduction. These effects of adenosine constitute the rationale for its use as a diagnostic and therapeutic agent. In recent years, efforts have been made to develop A 1 R-selective agonists as drug candidates that do not induce vasodilation, which is considered an undesirable effect in the clinical setting.