adenosine-5--(n-ethylcarboxamide) and metrifudil

1. Adenosine receptor agonists were evaluated for their activity at the putative adenosine A3 receptor which mediates a 'xanthine-resistant' hypotensive response in the anaesthetized rat. The compounds tested were: the A1/A3 receptor agonist, N-[2-(4-aminophenyl)ethyl]adenosine (APNEA), the non-selective adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236) and N6-cyclopentyl adenosine (CPA), the A2a receptor-selective agonists, 2-[[2-[4-(2-carboxyethyl) phenyl] ethyl] amino]-N- ethylcarboxamidoadenosine (CGS21680) and 2-phenylaminoadenosine (CV1808), and the moderately A2b selective agonist, N-[(2-methylphenyl)methyl]adenosine (metrifudil). 2. In confirmation of literature findings, APNEA (1-1000 nmol kg-1) induced hypotension and bradycardia; the hypotension was not blocked by pretreatment with the xanthine antagonist, 8-P-sulphophenyltheophylline (8-sPT; 40 mg kg-1, i.v.), whereas the bradycardia was attenuated. The non-xanthine antagonist, 9-fluoro-2-(2-furyl)-5,6-dihydro [1,2,4]triazolo[1,5-c]- quinazin-5-imine (CGS15943A; 3 mg kg-1 i.v.), also attenuated the bradycardia without affecting the hypotension. 3. The adenosine A1 receptor-selective agonists, GR79236 and CPA, both produced dose-dependent falls in blood pressure and heart rate which were antagonized by 8-sPT (40 mg kg-1) and CGS15943A (3 mg kg-1). 4. The adenosine A2a receptor-selective agonists, CGS21680 and CV1808, produced only a hypotensive response which was antagonized by 8-sPT (40 mg kg-1) and to a much greater extent by CGS15943A (3 mg kg-1), consistent with the response being mediated solely by A2a receptors. 5. The modestly A2b receptor-selective agonist, metrifudil, produced a dose-dependent fall in blood pressure and at higher doses a fall in heart rate. The hypotension induced by metrifudil was not antagonized by either 8-sPT (40 mg kg-1) or CGS15943A (3 mg kg-1) even though the bradycardia was abolished, suggesting that this agonist activates the putative A3 receptor.6. The non-selective adenosine receptor agonist, NECA, produced a hypotension and bradycardia that was attenuated by 8-sPT (40 mg kg-1), confirming previous work. The non-xanthine antagonist,CGS15943A (3 mg kg-'), also attenuated the hypotension and bradycardia. The bradycardia was blocked to a much greater extent, suggesting that NECA may therefore induce hypotension partly by activating the putative

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Blood Pressure; Female; Phenethylamines; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Quinazolines; Rats; Rats, Wistar; Triazoles

1. The purpose of the present study was to classify adenosine receptors into A1 and A2 subtypes in a wide range of isolated tissues and cell types (rat adipocytes and atria, guinea-pig ileum and atria (A1); guinea-pig aorta, dog coronary artery and human platelets and neutrophils (A2)) using the R- and S-diastereoisomers of N-phenylisopropyladenosine (PIA), N-cyclopentyladenosine (CPA), the novel compound, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236), N-[(2-methylphenyl)methyl]adenosine (metrifudil), 2-(phenylamino)adenosine (CV1808), and 2[[2-[4-(2-carboxyethyl)phenyl]ethyl]amino]-N- ethylcarboxamidoadenosine (CGS21680); N-ethylcarboxamidoadenosine (NECA) was used as a standard. 2. Results obtained in all tissue preparations previously reported to contain A1-receptors could be described by a single rank order of agonist potency: CPA > or = GR79236, R-PIA > or = NECA >> S-PAI > or = metrifudil > or = CV1808, CGS21680. 3. In contrast, two distinct rank orders of agonist potency were observed in preparations previously reported to contain A2-receptors. In dog coronary artery, human neutrophils and platelets the rank order of potency was: CV1808, CGS21680 > or = NECA > R-PIA > or = metrifudil > or = CPA > GR79236 S-PIA. However, in guinea-pig aorta the rank order was: NECA > metrifudil > R-PIA, CPA > CV1808, GR79236 > or = S-PIA, CGS21680. 4. The results of this study are consistent with the existence of three types of adenosine receptor: A1-and two subtypes of A2-receptor. The receptor present in dog coronary artery, human platelets and neutrophils, probably corresponds to the A2a subtype, whilst that present in the guinea-pig aorta may be of the A2b subtype.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Adipose Tissue; Animals; Aorta, Thoracic; Blood Platelets; Coronary Vessels; Dogs; Female; Guinea Pigs; Heart; Humans; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Neutrophils; Norepinephrine; Phenethylamines; Rats; Receptors, Purinergic; Theophylline; Vasodilator Agents; Xanthines