title: cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries.
abstract: cGMP is considered the only mediator synthesized by soluble guanylyl cyclase (sGC) in response to nitric oxide (NO). However, purified sGC can synthesize several other cyclic nucleotides, including inosine 3',5'-cyclic monophosphate (cIMP). The present study was designed to determine the role of cIMP in hypoxic contractions of isolated porcine coronary arteries. Vascular responses were examined by measuring isometric tension. Cyclic nucleotides were assayed by HPLC tandem mass spectroscopy. Rho kinase (ROCK) activity was determined by measuring the phosphorylation of myosin phosphatase target subunit 1 using Western blot analysis and an ELISA kit. The level of cIMP, but not that of cGMP, was elevated by hypoxia in arteries with, but not in those without, endothelium [except if treated with diethylenetriamine (DETA) NONOate]; the increases in cIMP were inhibited by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ). Hypoxia (Po2: 25-30 mmHg) augmented contractions of arteries with and without endothelium if treated with DETA NONOate; these hypoxic contractions were blocked by ODQ. In arteries without endothelium, hypoxic augmentation of contraction was also obtained with exogenous cIMP. In arteries with endothelium, hypoxic augmentation of contraction was further enhanced by inosine 5'-triphosphate, the precursor for cIMP. The augmentation of contraction caused by hypoxia or cIMP was accompanied by increased phosphorylation of myosin phosphatase target subunit 1 at Thr(853), which was prevented by the ROCK inhibitor Y-27632. ROCK activity in the supernatant of isolated arteries was stimulated by cIMP in a concentration-dependent fashion. These results demonstrate that cIMP synthesized by sGC is the likely mediator of hypoxic augmentation of coronary vasoconstriction, in part by activating ROCK.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China;
authors.forename: Zhengju
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China;
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Wenzhou Medical University, Wenzhou; Zhejiang, China;
authors.forename: Lei
authors.initials: L
authors.lastname: Ying
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China;
authors.forename: Dou
authors.initials: D
authors.lastname: Dou
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China; Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, China;
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China;
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China;
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China;
authors.forename: Han
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China;
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China; and.
authors.forename: Susan Wai-Sum
authors.initials: SW
authors.lastname: Leung
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China; and State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China; ygao@bjmu.edu.cn.
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology*; D007289:Cyclic IMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013552:Swine; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D018160:Receptors, Cytoplasmic and Nuclear; D014662:Vasoconstrictor Agents; D007289:Cyclic IMP; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: endothelium; hypoxic vasoconstriction; inosine 3′,5′-cyclic monophosphate; soluble guanylyl cyclase