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1 Department of Pharmacology and Toxicology, East Carolina University, Brody School of Medicine, Greenville, NC, USA
2 NIDDK, NIH, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: mustafas{at}mail.ecu.edu.
The vascular response to adenosine and its analogues is mediated by four adenosine receptors (AR) namely, A1, A2A, A2B, and A3. A2AAR and/or A2BAR are involved in adenosine-mediated vascular relaxation in coronary and aortic beds. However, the role of A1AR in the regulation of vascular tone is less well substantiated. The aim of this study was to determine the role of A1AR in adenosine-mediated regulation of vascular tone. An A1AR knockout (A1AR-/-) mice and available pharmacological tools were used to elucidate the function of A1AR and the impact of this receptor 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 analogues, 5'-N-ethyl-carboxamidoadenosine (NECA, nonselective), 2-chloro-N6cyclopentyladenosine (CCPA, A1AR-selective), 2-(2carboxyethyl)phenethyl amino-5'-N-ethylcarboxamido-adenosine (CGS21680, A2A-selective), and 2-chloro-N6-3-iodobenzyladenosine-5'-N-methyluronamide (Cl-IBMECA, A3-selective) were obtained to determine relaxation. Adenosine and NECA (0.1µM) caused a small contraction of 13.9%±3.0 and 16.4%±6.4, respectively in A1AR+/+ rings. CCPA at 0.1µM and 1.0µM caused contraction of 30.8%±4.3 and 28.1%±3.9 in A1AR+/+, respectively. NECA- and CCPA-induced contractions were eliminated by 100nM of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, selective A1AR-antagonist). Adenosine, NECA, and CGS21680 produced an increase in maximal relaxation in A1AR-/- compared to A1AR+/+ rings while Cl-IB-MECA did not produce contraction in either A1AR+/+ or A1AR-/- rings. CCPA-induced contraction at 1.0µM was eliminated by the PLC inhibitor U73122. These data suggest that the activation of A1AR causes contraction of the vascular smooth muscle through PLC pathway and negatively modulates the vascular relaxation mediated by other adenosine receptor subtypes.
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