Abstract
Adenosine clearly regulates coronary blood flow (CBF); however, contributions of specific adenosine receptor (AR) subtypes (A1, A2A, A2B, A3) to CBF in swine have not been determined. ARs generally decrease (A1, A3) or increase (A2A, A2B) cyclic adenosine monophosphate, a major mediator of vasodilation. We hypothesized that A1 antagonism potentiates coronary vasodilation and coronary stent deployment in dyslipidemic Ossabaw swine elicits impaired vasodilation to adenosine that is associated with increased A1/A2A expression. The left main coronary artery was accessed with a guiding catheter allowing intracoronary infusions. After placement of a flow wire into the left circumflex coronary artery the responses to bolus infusions of adenosine were obtained. Steady-state infusion of AR-specific agents was achieved by using a small catheter fed over the flow wire in control pigs. CBF was increased by the A2-nonselective agonist 2-phenylaminoadenosine (CV1808) in a dose-dependent manner. Baseline CBF was increased by the highly A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), but not changed by other AR-specific agents. The nonselective A2 antagonist 3,7-dimethyl-1-propargylxanthine and A2A-selective antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) abolished adenosine-induced CBF, whereas A2B and A3 antagonism had no effect. Dyslipidemia and stenting decreased adenosine-induced CBF ∼70%, whereas A1, A2A, and A2B mRNA were up-regulated in dyslipidemic versus control >5-fold and there was no change in the ratio of A1/A2A protein in microvessels distal to the stent. In control Ossabaw swine A1 antagonism by DPCPX positively regulated basal CBF. Impaired adenosine-induced CBF after stenting in dyslipidemia is most likely caused by the altered balance between A1 and A2A signaling, not receptor expression.
Footnotes
This work was supported by the National Institutes of Health National Center for Research Resources [Grant RR013223] (to M.S.), the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL062552] (to M.S.); Boston Scientific, Inc.; Research Animal Angiography Laboratory of Indiana Center for Vascular Biology and Medicine; Purdue-Indiana University Comparative Medicine Program; Fortune-Fry Ultrasound Research Fund; an Indiana University School of Medicine Translational Research Fellowship (to J.M.E. and Z.P.N.); National Institutes of Health Translational Research Fellowship [Grant UL1-RR025761] (to Z.P.N.); and an American Heart Association Predoctoral Fellowship (to X.L.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.170803.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- CBF
- coronary blood flow
- A1
- adenosine A1 receptor
- A2A
- adenosine A2A receptor
- A2B
- adenosine A2B receptor
- A3
- adenosine A3 receptor
- AR
- adenosine receptor
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine
- DMPX
- 3,7-dimethyl-1-propargylxanthine
- CCPA
- 2-chloro-N(6)-cyclopentyladenosine
- IVUS
- intravascular ultrasound
- APV
- average peak velocity
- HDL
- high-density lipoprotein
- LDL
- low-density lipoprotein
- PCR
- polymerase chain reaction
- ZM241385
- 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol
- MRS1706
- N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide
- MRS1220
- N-[9-chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-yl]benzene acetamide
- CV1808
- 2-phenylaminoadenosine.
- Received May 27, 2010.
- Accepted September 16, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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