cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries.

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.
AuthorsZhengju Chen, Xu Zhang, Lei Ying, Dou Dou, Yanhui Li, Yun Bai, Juan Liu, Limei Liu, Han Feng, Xiaoxing Yu, Susan Wai-Sum Leung, Paul M Vanhoutte, Yuansheng Gao
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 307 Issue 3 Pg. H328-36 (Aug 1 2014) ISSN: 1522-1539 [Electronic] United States
PMID24906916 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 the American Physiological Society.
Chemical References
  • Enzyme Inhibitors
  • Nitric Oxide Donors
  • Receptors, Cytoplasmic and Nuclear
  • Vasoconstrictor Agents
  • Cyclic IMP
  • rho-Associated Kinases
  • Myosin-Light-Chain Phosphatase
  • Guanylate Cyclase
  • soluble guanylyl cyclase
  • Animals
  • Cell Hypoxia
  • Coronary Vessels (drug effects, enzymology)
  • Cyclic IMP (metabolism)
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular (enzymology)
  • Enzyme Activation
  • Enzyme Inhibitors (pharmacology)
  • Guanylate Cyclase (antagonists & inhibitors, metabolism)
  • Myosin-Light-Chain Phosphatase (metabolism)
  • Nitric Oxide Donors (pharmacology)
  • Phosphorylation
  • Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, metabolism)
  • Signal Transduction (drug effects)
  • Swine
  • Up-Regulation
  • Vasoconstriction (drug effects)
  • Vasoconstrictor Agents (pharmacology)
  • rho-Associated Kinases (antagonists & inhibitors, metabolism)

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