title: The calcium ionophore A23187 induces endothelium-dependent contractions in femoral arteries from rats with streptozotocin-induced diabetes.
abstract: OBJECTIVE
  To study the importance of endothelium-derived contracting factors (EDCFs) in arteries of rats with type I diabetes.
  
  
  METHODS
  Rat femoral arteries were collected four or twelve weeks after induction of diabetes with streptozotocin. Rings, with or without endothelium, were suspended in organ chambers for isometric tension measurement. COX protein levels were determined by Western blotting.
  
  
  RESULTS
  Four weeks after the injection of streptozotocin, the endothelium-dependent relaxations (during contractions to phenylephrine) to A23817 were attenuated, but the endothelium-dependent contractions (quiescent preparations) to the ionophore were augmented. Indomethacin and S18886 prevented the endothelium-dependent contractions, while dazoxiben reduced them in rings from streptozotocin-treated rats, suggesting that thromboxane A2, activating TP- receptors, is involved. Twelve weeks after the injection of streptozotocin, the changes in endothelium-dependent relaxations and contractions to A23187 were even more noticeable. The protein expression of COX-1 was increased in femoral arteries of the diabetic rats. Valeryl salicylate and SC560 inhibited the contractions, suggesting that the EDCFs are produced by COX-1. At that time, a combination of S18886 with EP1-blockers was required to abolish the contractions, suggesting that the EDCFs involved act at both TP- and EP-receptors. Rings without endothelium from streptozotocin-treated rats exhibited a reduced maximal contraction to potassium chloride and U46619, combined with hyper-responsiveness to the latter, suggesting that more prolonged diabetes also alters the responsiveness of vascular smooth muscle.
  
  
  CONCLUSIONS
  The production of EDCFs is progressively increased in the course of type I diabetes. Eventually, the disease also damages vascular smooth muscle.
authors.affiliation: Department of Pharmacology, The University of Hong Kong, Hong Kong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: M
authors.initials: M
authors.lastname: Feletou
authors.forename: D D
authors.initials: DD
authors.lastname: Ku
authors.forename: R Y K
authors.initials: RY
authors.lastname: Man
authors.forename: P M
authors.initials: PM
authors.lastname: Vanhoutte
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005263:Femoral Artery / Q000187:drug effects / Q000503:physiopathology; D007476:Ionophores / Q000494:pharmacology*; D008565:Membrane Proteins / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D007476:Ionophores; D008565:Membrane Proteins; D018078:Receptors, Prostaglandin E; D017482:Receptors, Thromboxane; D000001:Calcimycin; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D002118:Calcium