title: Blunted coronary vasodilator response to uridine adenosine tetraphosphate in post-infarct remodeled myocardium is due to reduced P1 receptor activation.
abstract: We previously demonstrated that uridine adenosine tetraphosphate (Up4A) exerts a potent vasodilator effect in the healthy porcine coronary vasculature. Since the coronary microvascular effects of Up4A after myocardial infarction (MI) are unknown, the present study investigated the response to Up4A in coronary microvessels from post-MI remodeled porcine myocardium, and the involvement of purinergic receptor subtypes. Coronary small arteries (diameter ∼150 μm) were dissected from the apex of Sham-operated swine and swine in which MI had been produced 5 weeks earlier by transient (2h) occlusion of the left circumflex coronary artery, and mounted on Mulvany wire myographs. Up4A (10(-9)-10(-5)M) produced coronary vasodilation that was reduced in MI as compared to Sham-operated swine. Up4A-induced vasodilation was reduced by P1 blockade with 8-phenyltheophylline in Sham-operated swine and to a lesser extent in MI, while the attenuation by the A2A receptor blocker SCH58261 was similar in Sham-operated and MI swine. Up4A-induced vasodilation remained unaffected by non-selective P2 receptor antagonist PPADS, but was attenuated by selective P2X1 and P2Y1 receptor antagonists MRS2159 and MRS2179, albeit to a similar extent in Sham-operated and MI swine. These responses were paralleled by similar mRNA expression levels of A2A, P2X1 and P2Y1 receptors in MI compared to slaughterhouse control swine. Finally, attenuation of Up4A-induced coronary vasodilation by nitric oxide synthase inhibition was not attenuated in MI as compared to Sham-operated swine. In conclusion, blunted coronary vasodilation in response to Up4A in MI swine is most likely due to reduced activation of P1, rather than P2, receptors and does not involve a loss of NO bioavailability.
authors.affiliation: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, The Netherlands.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Daphne
authors.initials: D
authors.lastname: de Wijs-Meijler
authors.forename: Inge
authors.initials: I
authors.lastname: Lankhuizen
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.forename: Vera
authors.initials: V
authors.lastname: Jankowski
authors.forename: A H
authors.initials: AH
authors.lastname: Jan Danser
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D015226:Dinucleoside Phosphates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000096:biosynthesis; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D015226:Dinucleoside Phosphates; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D011743:Pyrimidines; D011983:Receptors, Purinergic; D018047:Receptors, Purinergic P1; D014230:Triazoles; D014665:Vasodilator Agents; C529314:uridine adenosine tetraphosphate; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000244:Adenosine Diphosphate; D013806:Theophylline; C028322:8-phenyltheophylline
keywords: Coronary microcirculation; Myocardial infarction; Purinergic receptor; Up(4)A