Document Detail


A hydroxylated analog of the beta-adrenoceptor antagonist, carvedilol, affords exceptional antioxidant protection to postischemic rat hearts.
MedLine Citation:
PMID:  8902527     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The antioxidant and cardioprotective effects of the beta-adrenoceptor antagonist, carvedilol, and its hydroxylated analog. BM-910228, were compared using the postischemic rat heart model. Hearts were infused with either agent (0.01, 0.10, or 10 nM final, or drug-free infusate) for 10 min prior to 30 min global ischemia, and also during the initial 15 min of reperfusion. Recovery of postischemic hemodynamic parameters (left ventricular systolic and developed pressures, mean diastolic pressure, cardiac output, coronary flow rate, and cardiac pressure-volume work), and the extent of postischemic tissue lactate dehydrogenase (LDH) loss, lipid hydroperoxide (LOOH) formation, and lipid peroxidation (LPO)-derived free radical production were assessed and compared among the treatment groups. The depressive pharmacological properties (beta- and alpha-blockade) of both agents masked the extent of postischemic hemodynamic recovery, except at the lowest dose (10 pM) of the analog, which provided significant improvements in systolic and developed pressures, and cardiac work. Treatment with both agents provided significant dose-dependent reductions in postischemic LOOH formation and lipid alkoxyl radical production, as determined by electron spin resonance spectroscopy and alpha-phenyl-tert-butylnitrone. (PBN) spin trapping (PBN/alkoxyl adduct hyperfine splitting alpha N = 13.63 G and alpha H = 1.93 G). Although both agents reduced oxidative injury, the hydroxylated analog was clearly the superior antioxidant (equipotent at doses two to three orders of magnitude lower) compared to the parent compound. This was also reflected with respect to three orders of magnitude lower) compared to the parent compound. This was also reflected with respect to drug-mediated improvement in myocardial preservation (reduced LDH release), which paralleled the antioxidant protective effects. Because neither agent displayed significant primary radical scavenging ability at doses (< or = 10 nM), which did provide substantial inhibition of postischemic LOOH and alkoxyl formation, our data suggest that the antioxidant properties of carvedilol and its analog are mediated primarily through a LPO chair-breaking mechanism. Moreover, the significant antioxidant protection afforded by the analog BM-910228 at subnanomolar levels places this agent into an exclusive category reserved for exceptionally potent antioxidants.
Authors:
J H Kramer; W B Weglicki
Related Documents :
12499877 - Improved myocardial function with the addition of pinacidil to custadiol.
17458647 - Cardioprotection induced by olprinone, a phosphodiesterase iii inhibitor, involves phos...
8748227 - Protective effect of the superoxide scavenger euk8 against ultrastructural alterations ...
22348547 - Noninvasive positive pressure ventilation for post-pneumonectomy severe hypoxemia: a ca...
24481287 - Feasibility and mortality of airway balloon dilation in a live rabbit model.
19853337 - Intradialytic hypertension: a less-recognized cardiovascular complication of hemodialysis.
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Free radical biology & medicine     Volume:  21     ISSN:  0891-5849     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  1996  
Date Detail:
Created Date:  1997-02-18     Completed Date:  1997-02-18     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  813-25     Citation Subset:  IM    
Affiliation:
Department of Medicine, George Washington University Medical Center, Washington, District of Columbia 20037, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / therapeutic use*
Alcohols / metabolism
Animals
Antioxidants*
Carbazoles / chemistry,  therapeutic use*
Dose-Response Relationship, Drug
Electron Spin Resonance Spectroscopy
Free Radical Scavengers
Free Radicals
Hemodynamics / drug effects
Hydroxyl Radical / metabolism
L-Lactate Dehydrogenase / metabolism
Lipid Peroxidation
Male
Myocardial Reperfusion Injury / prevention & control*
Propanolamines / chemistry,  therapeutic use*
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
R01-HL36418/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Alcohols; 0/Antioxidants; 0/BM 910228; 0/Carbazoles; 0/Free Radical Scavengers; 0/Free Radicals; 0/Propanolamines; 0/alkoxyl radical; 0K47UL67F2/carvedilol; 3352-57-6/Hydroxyl Radical; EC 1.1.1.27/L-Lactate Dehydrogenase

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


Previous Document:  Aminoguanidine and its pro-oxidant effects on an experimental model of protein glycation.
Next Document:  Attack of cefotaxime by different radicals: comparison of the effects.