Document Detail

Nonspecific inhibition of nitric oxide synthesis evokes endothelin-dependent increases in myocardial contractility.
MedLine Citation:
PMID:  19735735     Owner:  NLM     Status:  MEDLINE    
The role of endogenous nitric oxide (NO) in modulating myocardial contractility is still unclear, in part because of unknown, secondary effects of blocking NO release. We hypothesized that the nonspecific inhibition of nitric oxide synthase (NOS) enhances endothelin-1 (ET-1) effects, which can play a role in ET-A receptor-dependent myocardial contractile responses. The myocardial contractility was estimated from the slope of the left ventricular end-systolic pressure-diameter relationship in closed-chest, pentobarbital-anesthetized dogs. Group 1 (n = 7) was the saline-treated control, while in groups 2 (n = 7) and 3 (n = 7) N-nitro-l-arginine (NNA, 4 mg kg(-1)), a nonselective NOS blocker, was administered with or without pretreatment with the ET-A receptor antagonist ETR-P1/fl peptide (100 nmol kg(-1) iv). Plasma ET-1, nitrite/nitrate (NO(x)) and blood superoxide levels were measured, and myocardial ET-1 content and xanthine oxidoreductase (XOR) activity were determined from myocardial biopsies. The infusion of NNA over 120 min decreased the plasma NO(x), significantly elevated the plasma ET-1 and blood superoxide levels, and in parallel greatly increased the left ventricular contractility as compared with the untreated controls [47.5 vs 30 mm Hg mm(-1)]. The myocardial ET-1 content decreased simultaneously, while the XOR activity and blood superoxide level were significantly elevated. These effects, including NNA-induced positive inotropy, were significantly suppressed by pretreatment with ETR-P1/fl peptide. These results demonstrate that a diminished NO synthesis leads to a preponderant ET-1 effect, which increases myocardial contractility through an ET-A receptor-dependent mechanism.
Mikl??s Cz??bel; J??zsef Kaszaki; G??bor Moln??r; S??ndor Nagy; Mih??ly Boros
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Publication Detail:
Type:  Journal Article     Date:  2009-09-06
Journal Detail:
Title:  Nitric oxide : biology and chemistry / official journal of the Nitric Oxide Society     Volume:  21     ISSN:  1089-8611     ISO Abbreviation:  Nitric Oxide     Publication Date:    2009 Nov-Dec
Date Detail:
Created Date:  2009-11-16     Completed Date:  2010-01-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9709307     Medline TA:  Nitric Oxide     Country:  United States    
Other Details:
Languages:  eng     Pagination:  201-9     Citation Subset:  IM    
Institute of Surgical Research, University of Szeged, Hungary.
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MeSH Terms
Endothelin-1 / metabolism*,  pharmacology
Enzyme Inhibitors / pharmacology
Heart / drug effects,  physiology*
Hemodynamics / drug effects
Myocardial Contraction*
Myocardium / metabolism*
Nitric Oxide / antagonists & inhibitors,  physiology*
Nitric Oxide Synthase / antagonists & inhibitors,  metabolism
Nitroarginine / pharmacology
Xanthine Dehydrogenase / metabolism
Reg. No./Substance:
0/Endothelin-1; 0/Enzyme Inhibitors; 10102-43-9/Nitric Oxide; 2149-70-4/Nitroarginine; EC Oxide Synthase; EC Dehydrogenase

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