title: Mechanisms involved in increased sensitivity to adenosine A(2A) receptor activation and hypoxia-induced vasodilatation in porcine coronary arteries.
abstract: Hypoxia-induced coronary vasorelaxation is a compensatory mechanism increasing blood flow. We hypothesized that hypoxia shares pathways with adenosine and causes vasorelaxation through the adenosine A(2A) receptor and force suppression by increasing cAMP and phosphorylated heat shock protein (HSP)20. Adenosine receptors in porcine left anterior descending coronary arteries (LAD) were examined by RT-PCR and isometric tension recording in myographs. Vasorelaxation was induced by adenosine, 1% oxygen, or both in the absence or presence of ZM241385, an adenosine A(2A) receptor antagonist. cAMP was determined by ELISA and p-HSP20/HSP20 and p-MLC/MLC were determined by immunoblotting and densitometric analyses. In coronary arteries exposed to 1% oxygen, there was increased sensitivity to adenosine, the adenosine A2 selective agonist NECA, and the adenosine A(2A) selective receptor agonist CGS21680. ZM241385 shifted concentration-response curves for CGS21680 to the right, whereas the adenosine A1 antagonist DPCPX, the adenosine A2B receptor antagonist MRS1754 and the adenosine A3 receptor antagonist MRS1523 failed to reduce vasodilatation induced by CGS21680. 1% oxygen or adenosine increased cAMP accumulation and HSP20 phosphorylation without changing T850-MYPT1 and MLC phosphorylation. ZM241385 failed to change 1% oxygen-induced vasodilation, cAMP accumulation, HSP20 phosphorylation and MLC phosphorylation. The PKA inhibitor Rp-8-CPT-cAMPS significantly reduced vasorelaxation induced by 1% oxygen or CGS21680. Our findings suggest that the increased sensitivity to adenosine, NECA, and CGS21680 at 1% oxygen involves adenosine A(2A) receptors. Adenosine and 1% oxygen induce vasorelaxation in PGF2α-contracted porcine coronary arteries partly by force suppression caused by increased cAMP and phosphorylation of HSP20.
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, MEMBRANES, University of Aarhus, Denmark. Electronic address: erh@farm.au.dk.
authors.forename: Elise R
authors.initials: ER
authors.lastname: Hedegaard
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, MEMBRANES, University of Aarhus, Denmark; Department of Rheumatology, Aarhus University Hospital, Denmark.
authors.forename: Berit D
authors.initials: BD
authors.lastname: Nielsen
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, MEMBRANES, University of Aarhus, Denmark.
authors.forename: Susie
authors.initials: S
authors.lastname: Mogensen
authors.affiliation: Cardiovascular Division, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rembold
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, MEMBRANES, University of Aarhus, Denmark; Department of Cardiology, Örebro University Hospital, Sweden.
authors.forename: Ole
authors.initials: O
authors.lastname: Frøbert
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, MEMBRANES, University of Aarhus, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D015237:Dinoprost / Q000494:pharmacology; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D010100:Oxygen / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013552:Swine; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D050886:HSP20 Heat-Shock Proteins; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D015237:Dinoprost; D000242:Cyclic AMP; D000241:Adenosine; D010100:Oxygen
keywords: Coronary; Force suppression; HSP20; Hypoxia; MLC; Vasorelaxation; cAMP