Non-Anticoagulant Heparin Increases Endothelial Nitric Oxide Synthase Activity: Role of Inhibitory Guanine Nucleotide Proteins
| Autor: | Robert L. Hannan, James V. Sitzmann, Eileen M. Redmond, Paul A. Cahill, Adam K. Myers, Navin K. Kapur, Peter C. Kouretas, Young D. Kim, Richard J. Hendrickson |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Time Factors Endothelium medicine.drug_class Blotting Western Aorta Thoracic In Vitro Techniques Pharmacology Pertussis toxin Potassium Chloride Nitric oxide Rats Sprague-Dawley chemistry.chemical_compound GTP-Binding Proteins Enos medicine Citrulline Animals Virulence Factors Bordetella Endothelial dysfunction Molecular Biology Cells Cultured Edetic Acid Dose-Response Relationship Drug biology Heparin Anticoagulant biology.organism_classification medicine.disease Acetylcholine Rats NG-Nitroarginine Methyl Ester medicine.anatomical_structure Pertussis Toxin chemistry Biochemistry Cattle Endothelium Vascular Nitric Oxide Synthase Cardiology and Cardiovascular Medicine Deoxycholic Acid medicine.drug |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 30:2669-2682 |
| ISSN: | 0022-2828 |
| Popis: | Heparin, which is widely used clinically, has recently been shown to have specific properties affecting the vascular endothelium. We hypothesized that heparin stimulates endothelial nitric oxide synthase (eNOS) activity by a mechanism independent of its anticoagulant properties and dependent on an inhibitory guanine nucleotide regulatory protein (Gi). We determined the effect of both heparin and N-acetyl heparin (Non-Hep), a heparin derivative without anticoagulant properties, on eNOS activity in cultured bovine aortic endothelial cells and on endothelium-dependent relaxation in isolated vascular rings. The eNOS activity was determined by measuring both citrulline and nitric oxide (NO) metabolite formation. Heparin and Non-Hep dose-dependently increased basal eNOS activity (ED50 1.0 microgram/ml or 0.15 U/ml), an effect that was significantly inhibited by pertussis toxin (100 ng/ml), a Gi-protein inhibitor. Agonist-stimulated (acetylcholine, 10 microM) eNOS activity was potentiated following pre-treatment with both heparin and Non-Hep and reversed by pertussis toxin. Heparin and Non-Hep induced a dose-dependent relaxation in preconstricted thoracic aortic rings, an effect that was significantly inhibited by pertussis toxin, endothelial inactivation (following treatment with sodium deoxycholate) and NG-nitro-L-arginine-methyl ester (L-NAME). We conclude that heparin and non-anticoagulant heparin induce endothelium-dependent relaxation following activation of eNOS by a mechanism involving a Gi-protein. Administration of heparin derivatives without anticoagulant properties may have therapeutic implications for the preservation of eNOS in conditions characterized by endothelial dysfunction. |
| Databáze: | OpenAIRE |
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