Sensitization by chronic diazepam treatment of A(2A) adenosine receptor-mediated relaxation in rat pulmonary artery

The effects of a 10-day i.p. treatment of rats with diazepam on responses t o subtype selective adenosine receptor agonists were studied 3 h, 2 and s d ays after termination of diazepam treatment in isolated cardiovascular tiss ues possessing distinct adenosine receptors. After longlasting diazepam exp osure, the relaxation elicited by the specific A(2A) receptor agonist CGS 2 1680 was enhanced in rat main pulmonary arteries (a tissue containing A(2A) adenosine receptors). The increased sensitivity of A(2A) receptors observe d 3 h and 2 days after withdrawal of diazepam was completely restored by th e 8th day of the wash-out period. N-6-cyclopentyladenosine (CPA)-induced su ppression in mechanical activity of electrically stimulated rat atrial myoc ardium (a tissue containing A(1) adenosine receptors) was not altered follo wing diazepam treatment. In order to reveal the possible role of inhibition of membrane adenosine transport in the effects of diazepam (a moderate inh ibitor of membrane adenosine transport), the action of a 10-day treatment w ith dipyridamole or S-(p-nitrobenzyl)-6-thioinosine (NBTI; prototypic adeno sine uptake inhibitors) was also studied. Dipyridamole or NBTI treatment, l ike diazepam, increased the responsiveness of rat pulmonary artery to CGS 2 1680, but did not influence the cardiodepressive effect of CPA in electrica lly driven left atrial myocardium. The CGS 21680-induced relaxations were s ignificantly antagonized by 10 nM ZM 241385 (a selective A(2A) adenosine re ceptor antagonist) in vessels of diazepam-treated rats. The relaxation resp onses to verapamil were unaltered in pulmonary arteries obtained from anima ls chronically treated with diazepam, dipyridamole or NBTI. These results s uggest that chronic diazepam treatment is able to enhance the A(2A) adenosi ne receptor-mediated vascular functions, but does not modify the responses mediated via A(1) receptors of rat myocardium, where nucleoside transport i nhibitory sites of membrane are of a very low density. It is possible that sensitization of A(2A) adenosine receptor mediated vasorelaxation is due to a long-lasting inhibition of membrane adenosine transporter during diazepa m treatment, (C) 1998 Elsevier Science Inc.