Effects of selective A1 and A2 adenosine receptor agonists on cardiovascular tissues

Abstract

We investigated the negative chronotropic and vasodilating properties of new selective A₁ and A₂ 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 At agonist of those currently available in producing negative chronotropic effects (EC₅₀ = 8.2 nM). The A1 antagonist 8-cyclopentyl-1,3-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 A₁ receptors as measured in the rat brain by [³H]-N⁶-cyclohexyladenosine (³[H]-CHA) binding. The A₂ selective agonist 2-hexynyl-NECA showed vasodilating properties comparable with those observed with the reference compounds, CGS 21680 and NECA. EC₅₀ 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 A₂ receptors as measured in the rat striatum by ³[H]-CGS 21680 binding. These data further support that A₁ receptors are involved in depressing cardiac activity and A₂ receptors in inducing vasorelaxation.