%0 Journal Article %1 KHK+98 %A Kouretas, P.C. %A Hannan, R.L. %A Kapur, N.K. %A Hendrickson, R. %A Redmond, E.M. %A Myers, A.K. %A Kim, Y.D. %A Cahill, P.A. %A Sitzmann, J.V. %D 1998 %J J Mol Cell Cardiol %K Heparin %N 12 %P 2669-82 %T Non-anticoagulant heparin increases endothelial nitric oxide synthase activity: role of inhibitory guanine nucleotide proteins. %V 30 %X 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.

@article{KHK+98, abstract = {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.}, added-at = {2010-08-12T21:05:52.000+0200}, author = {Kouretas, P.C. and Hannan, R.L. and Kapur, N.K. and Hendrickson, R. and Redmond, E.M. and Myers, A.K. and Kim, Y.D. and Cahill, P.A. and Sitzmann, J.V.}, authoraddress = {Department of Physiology and Biophysics, Georgetown University Medical Center, Washington DC 20007, USA.}, biburl = {https://www.bibsonomy.org/bibtex/2d43e3c80d0e59b91c7ecedc4f956e5f4/referrator}, interhash = {34e801da9259e04c0462334aebf1ba21}, intrahash = {d43e3c80d0e59b91c7ecedc4f956e5f4}, journal = {J Mol Cell Cardiol}, keywords = {Heparin}, language = {eng}, medline = {J Mol Cell Cardiol 1998 Dec;30(12):2669-82.}, number = 12, pages = {2669-82}, timestamp = {2010-08-12T21:05:52.000+0200}, title = {Non-anticoagulant heparin increases endothelial nitric oxide synthase activity: role of inhibitory guanine nucleotide proteins.}, volume = 30, year = 1998 }