title: Circumferential stretching of saphenous vein smooth muscle enhances vasoconstrictor responses by Rho kinase-dependent pathways.
abstract: OBJECTIVE
  Surgical preparation and/or pulsatile arterial perfusion of saphenous vein increases the sensitivity of vein rings to calcium mobilising agonists such as phenylephrine. We have investigated the mechanism(s) underlying this effect.
  
  
  METHODS
  We have used an ex vivo flow circuit, with simulated arterial or venous flows (mean pressure 100 and 20 mmHg, respectively), to investigate the sensitivity of human saphenous vein to phenylephrine, 5-hydroxytryptamine (5-HT) and KCl, using organ chamber pharmacology.
  
  
  RESULTS
  After 90 min of pulsatile arterial perfusion the mean maximum tension induced by KCl had increased from 4.7 to 11.1 g (n=5), by phenylephrine had increased from 4.4 to 10.2 g (n=8) and by 5-HT had increased from 4.4 to 6.7 g (n=10), all P<0.01. Phenylephrine did not augment the tension in vein rings maximally precontracted with KCl (n=4). The EC(50) for KCl was unchanged after pulsatile arterial perfusion (n=5), but for phenylephrine and 5-HT there were significant reductions from 14+/-5 to 2+/-1 microM (n=8) and from 1.0+/-0.4 to 0.20+/-0.06 microM (n=10), respectively. The rate of contraction (in response to 3 microM phenylephrine) increased from 0.11 g/min to 0.37 g/min, P<0.02, after arterial perfusion (n=4). These changes in contractile properties (to phenylephrine) were endothelium-independent, evident within 5 min of simulated arterial perfusion. The changes in contractile properties could be abrogated by external stenting of the vein (to attenuate circumferential deformation) or inclusion in the perfusate of a vasodilator, e.g., cromakalim (5 microM) or the selective Rho kinase inhibitor Y-27632 (20 microM). The heightened sensitivity and contractility to phenylephrine was maintained after inclusion of adenosine (100 microM), gadolinium (10 microM) or cycloheximide (10 microM) in the vein perfusate.
  
  
  CONCLUSIONS
  The circumferential deformations imposed by simulated arterial perfusion alter the vasomotor responses of saphenous vein smooth muscle. These effects are independent of new protein synthesis or the activation of stretch activated cation channels. The Rho kinase pathway appears to mediate the signalling mechanisms leading to increased agonist-induced tension and the increased sensitivity to vasoconstrictors.
authors.affiliation: Department of Vascular Surgery, Imperial College at Charing Cross Hospital, St Dunstan's Road, London W6 8RP, UK. e.mcgregor@ic.ac.uk
authors.forename: Emma
authors.initials: E
authors.lastname: McGregor
authors.forename: Martin
authors.initials: M
authors.lastname: Gosling
authors.forename: David K
authors.initials: DK
authors.lastname: Beattie
authors.forename: Duncan M P
authors.initials: DM
authors.lastname: Ribbons
authors.forename: Alun H
authors.initials: AH
authors.lastname: Davies
authors.forename: Janet T
authors.initials: JT
authors.lastname: Powell
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011673:Pulsatile Flow; D011725:Pyridines / Q000494:pharmacology; D012501:Saphenous Vein; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D015607:Stents; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019806:Cromakalim; C108830:Y 27632; D010656:Phenylephrine; D012701:Serotonin; D011189:Potassium Chloride; D003513:Cycloheximide; D005682:Gadolinium; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000241:Adenosine