title: A role for the A3 adenosine receptor in determining tissue levels of cAMP and blood pressure: studies in knock-out mice.
abstract: Adenosine administration has been reported to lower blood pressure by activating specific membrane receptors. The rat and human heart and aorta have been previously found to express both A2-type adenosine receptors, which activate adenylyl cyclase, and A3 adenosine receptors (A3AR), which inhibit adenylyl cyclase. In the current study, we used A3 adenosine receptor (A3AR) knock-out mice to examine the hypothesis that the relative levels of the A2-type adenosine receptors and A3AR determine the steady-state levels of cAMP in the cells and may affect blood pressure. We found that the A3AR knock-out mice express normal levels of the A1- and A2-type adenosine receptors. In situ hybridization demonstrated that the level of A3AR is high in the vascular smooth muscle layer of aortas derived from wild-type mice, but is not detectable in the knock-out mice. The steady-state level of cAMP is elevated in the aorta and heart of knock-out mice, as compared to wild-type mice, but is not altered in platelets, where A3AR is not expressed naturally. A3AR knock-out mice possess a blood pressure comparable to this in wild-type mice. However, when challenged with adenosine, the knock-out mice display a further increase in cAMP levels in the heart and vascular smooth muscle and a significant decrease in blood pressure, as compared to wild-type mice. In contrast, the effect of adenosine on ADP-induced platelet aggregation is similar in both types of mice. These studies indicate that the A3AR affects the steady-state level of cAMP in the tissues where it is naturally expressed, and that it influences the blood pressure in response to adenosine.
authors.affiliation: Department of Biochemistry and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: K
authors.initials: K
authors.lastname: Makaritsis
authors.forename: C E
authors.initials: CE
authors.lastname: Francis
authors.forename: H
authors.initials: H
authors.lastname: Gavras
authors.forename: K
authors.initials: K
authors.lastname: Ravid
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001792:Blood Platelets / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000032:analysis*; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D015539:Platelet Activation; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D000242:Cyclic AMP; D000241:Adenosine