title: Heparin inhibits angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways.
abstract: Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistance arteries through modulating the Rho-A/Rho kinase pathway. Vascular contractility was studied by using pressurized, resistance-sized mesenteric arteries from mice. Rho-A activation was measured by pull-down assay, and myosin light chain or PKA phosphorylation by immunoblotting. We found that heparin significantly attenuated vasoconstriction induced by Ang II but not that by KCl. The combined effect of Ang II with heparin was almost abolished by a specific Rho kinase inhibitor Y27632. Ang II stimulated Rho-A activation and myosin light chain phosphorylation, both responses were antagonized by heparin. Moreover, the inhibitory effect of heparin on Ang II-induced vasoconstriction was reversed by Rp-cAMPS (cAMP-dependent PKA inhibitor), blunted by ODQ (soluble guanylate cyclase inhibitor), and mimicked by a cell-permeable cGMP analogue, 8-Br-cGMP, but not by a cAMP analogue. PKC and Src kinase were not involved. We conclude that heparin inhibits Ang II-induced vasoconstriction through Rho-A/Rho kinase- and cGMP/PKA-dependent pathways.
authors.affiliation: Research Center for Molecular Physiology, Children's Research Institute, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie-Zukauskas
authors.forename: Jharna
authors.initials: J
authors.lastname: Das
authors.forename: Billie Lou
authors.initials: BL
authors.lastname: Short
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Patricio E
authors.initials: PE
authors.lastname: Ray
mesh_terms: D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000187:drug effects / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000577:Amides; D000925:Anticoagulants; D018994:Myosin Light Chains; D011725:Pyridines; D000804:Angiotensin II; C108830:Y 27632; D006493:Heparin; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein; D006152:Cyclic GMP