Document Detail

Endothelial dysfunction of coronary resistance vessels in apoE-/- mice involves NO but not prostacyclin-dependent mechanisms.
MedLine Citation:
PMID:  11744035     Owner:  NLM     Status:  MEDLINE    
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. CONCLUSION: 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.
Axel Gödecke; Martin Ziegler; Zhaoping Ding; Jürgen Schrader
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cardiovascular research     Volume:  53     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2002 Jan 
Date Detail:
Created Date:  2001-12-17     Completed Date:  2002-05-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  253-62     Citation Subset:  IM    
Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, Postfach 101007, 40001 Düsseldorf, Germany.
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MeSH Terms
Acetylcholine / pharmacology
Adenosine / pharmacology
Analysis of Variance
Apolipoproteins E / genetics,  physiology*
Bradykinin / pharmacology
Cholesterol, LDL / blood
Coronary Vessels
Cyclooxygenase Inhibitors / pharmacology
Diclofenac / pharmacology
Dose-Response Relationship, Drug
Endothelium, Vascular / metabolism*
Enzyme Inhibitors / pharmacology
Epoprostenol / metabolism*
Hypercholesterolemia / genetics,  metabolism*
Iloprost / pharmacology
Mice, Inbred C57BL
Mice, Mutant Strains
Nitric Oxide / metabolism*
Nitric Oxide Synthase / antagonists & inhibitors
Superoxide Dismutase / pharmacology
Vascular Resistance / drug effects
Vasodilator Agents / pharmacology
omega-N-Methylarginine / pharmacology
Reg. No./Substance:
0/Apolipoproteins E; 0/Cholesterol, LDL; 0/Cyclooxygenase Inhibitors; 0/Enzyme Inhibitors; 0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 15307-86-5/Diclofenac; 17035-90-4/omega-N-Methylarginine; 35121-78-9/Epoprostenol; 51-84-3/Acetylcholine; 58-61-7/Adenosine; 58-82-2/Bradykinin; 78919-13-8/Iloprost; EC Oxide Synthase; EC Dismutase

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