KF17837 IS AN A(2) ADENOSINE RECEPTOR ANTAGONIST IN-VIVO

The goal of this study was to determine whether (E)-l,3-dipropyl-7-methyl-8-(3,4-dimethoxystyryl)xanthine (KF17837) is a useful pharmacological probe for investigating in the rat the in vivo physiological roles of A2 adenosine receptors. In anesthetized rats, bradycardic responses to N6-cyclopentyladenosine and hypotensive responses to 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido adenosine (CGS21680C) were used to assess Al receptor and A2 receptor activation, respectively. After obtaining control responses to N6-cyclopentyladenosine and CGS21680C, the rats received infusions of either vehicle or one of two dosage levels of KF17837, a compound recently demonstrated to be a potent and selective A2 receptor antagonist in vitro. KF17837 was infused for 4 hr and, at various times during the infusions, bradycardic and hypotensive responses to N6-cyclopentyladenosine and CGS21680C, respectively, were elicited. Infusion of either 1 0 or 30 mug kg-1 min-1 (2.4 or 7.4 mg kg-1 4 hr-1) of KF17837 did not significantly affect the bradycardic responses to N6-cyclopentyladenosine. By contrast, 1 0 mug kg-1 min-1 of KF17837 attenuated and 30 mug kg-1 min-1 of KF17837 nearly abolished hypotensive responses to CGS21680C. In a second study, pretreatment with KF17837 (30 mug kg-1 min-1) did not affect the hypotensive response to either PGI2 (3 mug kg-1 min-1) or acetylcholine (1 00 mug kg-1 min-1); however, it attenuated the hypotensive response to adenosine (300 mug kg-1 min-1). In a third study, hypotension was induced and maintained with an infusion of adenosine (300 mug kg-1 min-1). Subsequent initiation of an infusion of KF17837 (30 mug kg-1 min-1) completely reversed the adenosine-induced hypotension. This study suggests that in vivo KF17837 has relative selectivity for the A2 receptor and may be a useful pharmacological probe for elucidating the role of endogenous adenosine-A2 receptor interactions in vivo in the rat.