Role of A₁ adenosine receptors in regulation of vascular tone

The vascular response to adenosine and its analogs is mediated by four adenosine receptors (ARs), namely, A₁, A_2A, A _2B, and A₃. A_2AARs and/or A_2BARs are involved in adenosine-mediated vascular relaxation of coronary and aortic beds. However, the role of A₁ARs in the regulation of vascular tone is less well substantiated. The aim of this study was to determine the role of A₁ARs in adenosine-mediated regulation of vascular tone. A ₁AR-knockout [A₁AR^(-/-)] mice and available pharmacological tools were used to elucidate the function of A₁ARs and the impact of these receptors on the regulation of vascular tone. Isolated aortic rings from A₁AR^(-/-) and wild-type [A ₁AR^(+/+)] mice were precontracted with phenylephrine, and concentration-response curves for adenosine and its analogs, 5′-N-ethyl-carboxamidoadenosine (NECA, nonselective), 2-chloro-A ⁶-cyclopentyladenosine (CCPA, A₁AR selective), 2-(2-carboxyethyl)phenethyl amino-5′-N-ethylcarboxamido-adenosine (CGS-21680, A_2A selective), and 2-chloro-N⁶-3- obenzyladenosine-5′-N-methyluronamide (Cl-IBMECA, A₃ selective) were obtained to determine relaxation. Adenosine and NECA (0.1 μM) caused small contractions of 13.9 ± 3.0 and 16.4 ± 6.4%, respectively, and CCPA at 0.1 and 1.0 μM caused contractions of 30.8 ± 4.3 and 28.1 ± 3.9%, respectively, in A₁AR^(+/+) rings. NECA- and CCPA-induced contractions were eliminated by 100 nM of 1,3-dipropyl-8- cyclopentylxanthine (DPCPX, selective A₁AR antagonist). Adenosine, NECA, and CGS-21680 produced an increase in maximal relaxation in A ₁AR^(-/-) compared with A₁AR^(+/+) rings, whereas Cl-IBMECA did not produce contraction in either A ₁AR^(+/+) or A₁A₁R^(-/-) rings. CCPA-induced contraction at 1.0 μM was eliminated by the PLC inhibitor U-73122. These data suggest that activation of A₁ARs causes contraction of vascular smooth muscle through PLC pathways and negatively modulates the vascular relaxation mediated by other adenosine receptor subtypes.