Document Detail

Modulation of the NO/cGMP pathway reduces the vasoconstriction induced by acellular and PEGylated haemoglobin.
MedLine Citation:
PMID:  18241681     Owner:  NLM     Status:  MEDLINE    
Activation of the NO/cGMP pathway modulates smooth muscle cells relaxation and hence vasoconstriction, a major hindrance for the use of cell-free haemoglobin (Hb) as blood substitute, despite conjugation with 5-kDa maleimide poly(ethylene)-glycol (PEG) reduces vasoconstriction in vivo. We aimed at assessing how a recently developed PEGylated-Hb (Deoxy-PEGHb) and manipulation of the NO/cGMP pathway enable modulation of vasoconstriction in isolated rat hearts. Hearts were Langendorff-perfused with oxygenated Krebs-Henseleit (15 ml/min) while monitoring the coronary pressure (CPP) after injection (1 min) of 50 nM norepinephrine followed by a 1 microM Hb or Deoxy-PEGHb bolus, without altering the flow. Deoxy-PEGHb induced less vasoconstriction than Hb. Although the presence of PEG could contribute to vasoconstriction, Deoxy-PEGHb did not contain appreciable amounts of free PEG. Whereas reducing endothelial NO release by 0.2 mM L-NAME increased vasoconstriction, abolishing NO scavenging by Hb using its cyanomet derivative almost completely blunted it. Furthermore, maintaining intracellular cyclic GMP by inhibiting phosphodiesterase-5 with 0.02 mM sildenafil enabled control of Hb-induced vasoconstriction. We conclude that, although PEG-Hb represents a possible approach to limit Hb-induced vasoconstriction, manipulating the NO/cGMP pathway may provide a powerful way to circumvent this problem.
Anna Caretti; Monica Fantacci; Dario Caccia; Michele Perrella; Kenneth C Lowe; Michele Samaja
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-01-05
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1784     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-23     Completed Date:  2008-12-31     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1428-34     Citation Subset:  IM    
Dipartimento di Medicina, Chirurgia e Odontoiatria, University of Milan, Italy.
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MeSH Terms
Blood Pressure / drug effects
Coronary Vessels / drug effects,  physiology
Cyclic GMP / physiology*
Endotoxins / toxicity
Heart / drug effects,  physiology,  physiopathology*
Hemoglobins / adverse effects,  therapeutic use*
Muscle Relaxation / physiology
Muscle, Smooth / blood supply,  physiology
Nitric Oxide / physiology*
Perfusion / methods
Polyethylene Glycols / adverse effects*
Rats, Sprague-Dawley
Vasoconstriction / drug effects,  physiology*
Reg. No./Substance:
0/Endotoxins; 0/Hemoglobins; 0/Polyethylene Glycols; 10102-43-9/Nitric Oxide; 7665-99-8/Cyclic GMP

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