Mechanisms involved in increased sensitivity to adenosine A(2A) receptor activation and hypoxia-induced vasodilatation in porcine coronary arteries
2014 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 723, 216-226 p.Article in journal (Refereed) Published
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-HSP20/1-ISP20 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 112 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 A(1) antagonist DPCPX, the adenosine A(2B) receptor antagonist MRS1754 and the adenosine A(3) 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 PGF(2 alpha)-contracted porcine coronary arteries partly by force suppression caused by increased cAMP and phosphorylation of HSP20.
Place, publisher, year, edition, pages
Elsevier, 2014. Vol. 723, 216-226 p.
HSP20, MLC, CAMP, Hypoxia, Coronary, Vasorelaxation, Force suppression
Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:oru:diva-56438DOI: 10.1016/j.ejphar.2013.11.029ISI: 000330574600029PubMedID: 24309216ScopusID: 2-s2.0-84893769209OAI: oai:DiVA.org:oru-56438DiVA: diva2:1082361
FunderEU, FP7, Seventh Framework Programme
Danish Medical Research Council
Danish Heart Association
Ulf Simonsen is part of LiPhos (Living Photonics: Monitoring light propagation through cells)2017-03-162017-03-162017-03-16Bibliographically approved