Document Detail

Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.
MedLine Citation:
PMID:  21645517     Owner:  NLM     Status:  MEDLINE    
The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''
An L Moens; Elizabeth A Ketner; Eiki Takimoto; Tim S Schmidt; Charles A O'Neill; Michael S Wolin; Nicholas J Alp; Keith M Channon; David A Kass
Related Documents :
8334757 - Effect of control of hypertension on progressive renal failure.
3536587 - Regulation of arterial pressure: role of pressure natriuresis and diuresis.
15812257 - Ambulatory blood pressure variations relative to sitting or standing position in renal ...
7644627 - Normal renal artery spectral doppler waveform: a closer look.
3897477 - Safe use of peep in patients with severe head injury.
10536557 - Effect of rocuronium compared with succinylcholine on intraocular pressure during rapid...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-30
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  51     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-19     Completed Date:  2012-01-06     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  564-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Ltd. All rights reserved.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Analysis of Variance
Biopterin / analogs & derivatives*,  metabolism,  pharmacokinetics,  therapeutic use
Cardiotonic Agents / pharmacokinetics,  therapeutic use*
Dose-Response Relationship, Drug
Heart Failure / drug therapy*,  etiology,  physiopathology
Hypertrophy, Left Ventricular / drug therapy*,  etiology,  physiopathology
Mice, Inbred C57BL
Myocardium / pathology
Random Allocation
Superoxides / metabolism
Ventricular Function, Left
Ventricular Remodeling / drug effects*
Grant Support
090532//Wellcome Trust; HL-59480/HL/NHLBI NIH HHS; HL-89297/HL/NHLBI NIH HHS; P50 HL084946-03/HL/NHLBI NIH HHS; R01 HL089297/HL/NHLBI NIH HHS; R01 HL089297-02/HL/NHLBI NIH HHS; RG/07/003/23133//British Heart Foundation
Reg. No./Substance:
0/Cardiotonic Agents; 11062-77-4/Superoxides; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 6779-87-9/7,8-dihydrobiopterin

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

Previous Document:  Sociosexuality moderates the association between testosterone and relationship status in men and wom...
Next Document:  Dynamic modulation of Ca2+ sparks by mitochondrial oscillations in isolated guinea pig cardiomyocyte...