Adenosine receptor regulation of coronary blood flow in ossabaw miniature swine

Xin Long, Eric A. Mokelke, Zachary P. Neeb, Mouhamad Alloosh, Jason M. Edwards, Michael Sturek

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)781-787
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume335
Issue number3
DOIs
StatePublished - Dec 2010

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Miniature Swine
Purinergic P1 Receptors
Adenosine
Swine
Vasodilation
Dyslipidemias
varespladib methyl
Stents
Coronary Vessels
Catheters
Adenosine A1 Receptors
Microvessels
Phenol
Cyclic AMP
Messenger RNA

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Adenosine receptor regulation of coronary blood flow in ossabaw miniature swine. / Long, Xin; Mokelke, Eric A.; Neeb, Zachary P.; Alloosh, Mouhamad; Edwards, Jason M.; Sturek, Michael.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 335, No. 3, 12.2010, p. 781-787.

Research output: Contribution to journalArticle

Long, Xin ; Mokelke, Eric A. ; Neeb, Zachary P. ; Alloosh, Mouhamad ; Edwards, Jason M. ; Sturek, Michael. / Adenosine receptor regulation of coronary blood flow in ossabaw miniature swine. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 335, No. 3. pp. 781-787.
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