The ex vivo effects of hypoxanthine-tricyclano, a synthetic adenosine analogue, on rat left and right atria.

Abstract

Hypoxanthine-tricyclano is a synthetic adenosine analogue, in which adenine and ribose have been replaced by hypoxanthine and a morpholino-derived tricyclic moiety, respectively. We investigated whether hypoxanthine-tricyclano could influence atrial inotropy and/or chronotropy, two important functions regulated by the A1 receptor, the main adenosine receptor type of the supraventricular myocardium. Paced left atria and spontaneously beating right atria, isolated from male, 30-35 weeks old, Wistar rats, were used. The ino- and chronotropic effects of adenosine and hypoxanthine-tricyclano (separately and together) were assessed in the absence and presence of 8-cyclopentyl-1,3-dipropylxanthine (CPX), a selective, orthosteric, reversible A1 adenosine receptor antagonist. We found that adenosine exerted a strong negative inotropic effect (similar in left and right atria). However, hypoxanthine-tricyclano elicited a moderate positive inotropic effect (also similar in all atria). In right atria, adenosine evoked a robust negative chronotropic effect, whereas hypoxanthine-tricyclano produced a slight positive chronotropy. CPX blunted the effects of both adenosine and hypoxanthine-tricyclano, although this antagonism was strong (and significant) for adenosine, while smaller (and non-significant) for hypoxanthine-tricyclano. Both effects of hypoxanthine-tricyclano were easily surmountable with adenosine. Thus, hypoxanthine-tricyclano may act as a week, orthosteric, reversible, inverse and low-affinity agonist of the A1 receptor, although alternative mechanisms of action cannot be excluded.