Document Detail

Chronic nitric oxide synthase blockade desensitizes the heart to the negative metabolic effects of nitric oxide.
MedLine Citation:
PMID:  16831448     Owner:  NLM     Status:  MEDLINE    
The consequences of chronic nitric oxide synthase (NOS) blockade on the myocardial metabolic and guanylyl cyclase stimulatory effects of exogenous nitric oxide (NO) were determined. Thirty-three anesthetized open-chest rabbits were randomized into four groups: control, NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4 )M), NOS blocking agent N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg/day) for 10 days followed by a 24 hour washout and L-NAME for 10 days followed by a 24 hour washout plus SNAP. Myocardial O(2) consumption was determined from coronary flow (microspheres) and O(2) extraction (microspectrophotometry). Cyclic GMP and guanylyl cyclase activity were determined by radioimmunoassay. There were no baseline metabolic, functional or hemodynamic differences between control and L-NAME treated rabbits. SNAP in controls caused a reduction in O(2) consumption (SNAP 5.9+/-0.6 vs. control 8.4+/-0.8 ml O(2)/min/100 g) and a rise in cyclic GMP (SNAP 18.3+/-3.8 vs. control 10.4+/-0.9 pmol/g). After chronic L-NAME treatment, SNAP caused no significant changes in O(2) consumption (SNAP 7.1+/-0.8 vs. control 6.4+/-0.7) or cyclic GMP (SNAP 14.2+/-1.8 vs. control 12.1+/-1.3). In controls, guanylyl cyclase activity was significantly stimulated by SNAP (216.7+/-20.0 SNAP vs. 34.4+/-2.5 pmol/mg/min base), while this increase was blunted after L-NAME (115.9+/-24.5 SNAP vs. 24.9+/-4.7 base). These results demonstrated that chronic NOS blockade followed by washout blunts the response to exogenous NO, with little effect on cyclic GMP or myocardial O(2) consumption. This was related to reduced guanylyl cyclase activity after chronic L-NAME. These results suggest that, unlike many receptor systems, the NO-cyclic GMP signal transduction system becomes downregulated upon chronic inhibition.
Tomer Davidov; Harvey R Weiss; James Tse; Peter M Scholz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-06-08
Journal Detail:
Title:  Life sciences     Volume:  79     ISSN:  0024-3205     ISO Abbreviation:  Life Sci.     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-09-18     Completed Date:  2006-11-02     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0375521     Medline TA:  Life Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  1674-80     Citation Subset:  IM    
Heart and Brain Circulation Laboratory, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, USA.
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MeSH Terms
Blood Flow Velocity / drug effects
Cyclic GMP / metabolism*
Enzyme Inhibitors / pharmacology
Guanylate Cyclase / metabolism
Heart / drug effects,  physiology*
Heart Ventricles / chemistry,  drug effects,  metabolism
Hemodynamics / drug effects
Myocardium / metabolism*
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide / metabolism*
Nitric Oxide Donors / pharmacology
Nitric Oxide Synthase / antagonists & inhibitors*
Oxygen / analysis
Oxygen Consumption / drug effects,  physiology*
Penicillamine / analogs & derivatives,  pharmacology
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Nitric Oxide Donors; 0/S-nitro-N-acetylpenicillamine; 10102-43-9/Nitric Oxide; 50903-99-6/NG-Nitroarginine Methyl Ester; 52-67-5/Penicillamine; 7665-99-8/Cyclic GMP; 7782-44-7/Oxygen; EC Oxide Synthase; EC Cyclase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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