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Role of A₁ adenosine receptors in regulation of vascular tone

¹Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina; and ²National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Submitted 12 July 2004 ; accepted in final form 5 November 2004

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. A₁AR-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 [A₁AR^(+/+)] mice were precontracted with phenylephrine, and concentration-response curves for adenosine and its analogs, 5'-N-ethyl-carboxamidoadenosine (NECA, nonselective), 2-chloro-N⁶-cyclopentyladenosine (CCPA, A₁AR selective), 2-(2-carboxyethyl)phenethyl amino-5'-N-ethylcarboxamido-adenosine (CGS-21680, A_2A selective), and 2-chloro-N⁶-3-iodobenzyladenosine-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 A₁AR^(–/–) compared with A₁AR^(+/+) rings, whereas Cl-IBMECA did not produce contraction in either A₁AR^(+/+) or A₁AR^(–/–) 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.

A₁ adenosine receptor; knockout mice; smooth muscle

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