title: Endothelial dysfunction of coronary resistance vessels in apoE-/- mice involves NO but not prostacyclin-dependent mechanisms.
abstract: OBJECTIVE
  We have analyzed the extent of endothelial dysfunction in cardiac resistance vessels of hyperlipidaemic apoE-/- mice and explored whether NO and/or prostacyclin dependent pathways are involved.
  
  
  METHODS
  Coronary resistance was measured in isolated perfused hearts from WT and apoE-/- mice. To discriminate between NO and PGI(2)-dependent flow responses, we made use of the finding that acetylcholine (ACh) predominantly activates the prostaglandin pathway whereas bradykinin (Bk) mainly acts via NO in murine cardiac resistance vessels.
  
  
  RESULTS
  Basal coronary flow as well as the ACh induced vasodilation (0.1-1 microM) were not different between WT and apoE-/- hearts (flow increase+100%). Similarly, vasodilation in response to the prostacyclin mimetic iloprost reached the same levels. In contrast, the Bk-stimulated [3.3 microM Bk] coronary flow was reduced from 31.6+/-4.2 in WT to 19.2+/-2.7 ml min(-1) g(-1) in apoE-/- hearts. NOS inhibition by ethylisothiourea (ETU, 10 microM) reduced basal as well as Bk-stimulated coronary flow in WT and apoE-/- hearts to the same extent. RT-PCR and Western analysis demonstrated that neither eNOS expression nor protein levels were reduced. Similarly, the flow response to the NO donor SNAP (0.3-33 microM) was not altered suggesting that soluble guanylyl cyclase was not affected. Intracoronary application of superoxide dismutase augmented the Bk-induced vasodilation of apoE-/- hearts almost back to WT levels (26.6+/-3.3 ml min(-1) g(-1)). In line with this finding the NADPH induced O(2)(-) formation was enhanced in cardiac extracts from apoE-/- hearts.
  
  
  CONCLUSIONS
  apoE-/- hearts develop a hemodynamically relevant endothelial dysfunction at the level of coronary resistance vessels most likely via inactivation of bioavailable NO by superoxide anions. The function of the prostacyclin system is not altered.
authors.affiliation: Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, Postfach 101007, 40001 Düsseldorf, Germany. axel.goedecke@uni-duesseldorf.de
authors.forename: Axel
authors.initials: A
authors.lastname: Gödecke
authors.forename: Martin
authors.initials: M
authors.lastname: Ziegler
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Ding
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schrader
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000097:blood; D003331:Coronary Vessels; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism*; D016285:Iloprost / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D013482:Superoxide Dismutase / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D004008:Diclofenac; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D016285:Iloprost; D000241:Adenosine; D000109:Acetylcholine; D001920:Bradykinin