Document Detail


The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles.
MedLine Citation:
PMID:  16715115     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1. We characterized the vasoactive effects of OR-1896, the long-lived metabolite of the inodilator levosimendan, in coronary and skeletal muscle microvessels. 2. The effect of OR-1896 on isolated, pressurized (80 mmHg) rat coronary and gracilis muscle arteriole (approximately 150 microm) diameters was investigated by videomicroscopy. 3. OR-1896 elicited concentration-dependent (1 nM-10 microM) dilations in coronary (maximal dilation: 66+/-6%, relative to that in Ca2+-free solutions; pD2: 7.16+/-0.42) and gracilis muscle arterioles (maximal dilation: 73+/-4%; pD2: 6.71+/-0.42), these dilations proving comparable to those induced by levosimendan (1 nM-10 microM) in coronary (maximal dilation: 83+/-6%; pD2: 7.06+/-0.14) and gracilis muscle arterioles (maximal dilation: 73+/-12%; pD2: 7.05+/-0.1). 4. The maximal dilations in response to OR-1896 were significantly (P<0.05) attenuated by the nonselective K+ channel inhibitor tetraethylammonium (1 mM) in coronary (to 34+/-9%) and gracilis muscle arterioles (to 28+/-6%). 5. Glibenclamide (5 or 10 microM), a selective ATP-sensitive K+ channel (KATP) blocker, elicited a greater reduction of OR-1896-induced dilations in skeletal muscle arterioles than in coronary microvessels. 6. Conversely, the selective inhibition of the large conductance Ca2+-activated K+ channels (BK(Ca)) with iberiotoxin (100 nM) significantly reduced the OR-1896-induced maximal dilation in coronary arterioles (to 21+/-6%), but was ineffective in skeletal muscle arterioles (72+/-8%). 7. Accordingly, OR-1896 elicits a substantial vasodilation in coronary and skeletal muscle arterioles, by activating primarily BK(Ca) and K(ATP) channels, respectively, and it is suggested that OR-1896 contributes to the long-term hemodynamic effects of levosimendan.
Authors:
Nóra Erdei; Zoltán Papp; Piero Pollesello; István Edes; Zsolt Bagi
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-05-22
Journal Detail:
Title:  British journal of pharmacology     Volume:  148     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-07-03     Completed Date:  2006-12-26     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  696-702     Citation Subset:  IM    
Affiliation:
Division of Clinical Physiology, Institute of Cardiology, University of Debrecen, Debrecen H-4004, Hungary.
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MeSH Terms
Descriptor/Qualifier:
Acetamides
Animals
Arterioles / drug effects*
Coronary Vessels / drug effects
Hydrazones / pharmacokinetics*,  pharmacology*
Large-Conductance Calcium-Activated Potassium Channels / metabolism*,  physiology
Male
Muscle, Skeletal / drug effects
Potassium Channels / metabolism*,  physiology
Pyridazines / pharmacokinetics*,  pharmacology*
Rats
Rats, Wistar
Vasodilation / drug effects*
Vasodilator Agents / pharmacology*
Chemical
Reg. No./Substance:
0/Acetamides; 0/Hydrazones; 0/Large-Conductance Calcium-Activated Potassium Channels; 0/N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; 0/Potassium Channels; 0/Pyridazines; 0/Vasodilator Agents; 0/mitochondrial K(ATP) channel; 349552KRHK/simendan
Comments/Corrections

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