title: Somatostatin sst5 inhibition of receptor mediated regeneration of rat aortic vascular smooth muscle cells.
abstract: 1. The aim of the present study was to determine the effect of somatostatin (SRIF) on mitogen-induced regeneration of rat aortic vascular smooth muscle cells (VSMC) and for comparison Chinese hamster ovary (CHO)-K1 cells expressing human recombinant sst5 receptors (CHOsst5), following partial denudation of a confluent cell monolayer. Regeneration was assessed by measuring areas of recovery into the denuded area and by counting total cell numbers. 2. In VSMC, SRIF (0.1 nM - 1 microM) had no effect on the basal levels of regeneration but caused a concentration-dependent inhibition (pIC50 8.0-8.6) of the stimulated regeneration induced by submaximal concentrations of basic fibroblast growth factor (bFGF, 10 ng ml[-1]), platelet-derived growth factor-BB (PDGF, 5 ng ml[-1]) or endothelin-1 (ET-1, 100 nM). SRIF (pIC50 8.8) also inhibited bFGF-induced regeneration of CHOsst5 cells. 3. In VSMC, the inhibitory action of SRIF on the regeneration induced by bFGF (10 ng ml[-1]) was due to an anti-proliferative effect, rather than an effect on cell migration, as SRIF (0.1 nM - 1 microM) abolished bFGF-induced increases in total cell numbers. The bFGF-induced increase in cell numbers was also abolished by actinomycin D (0.1 microg ml[-1]). 4. The sst5 receptor-selective agonist, L-362,855 (pIC50 10.5), was about 100 times more potent than SRIF at inhibiting bFGF-induced regeneration of both VSMC and CHOsst5 cells whilst the sst2 receptor-selective agonist, BIM-23027 (pIC50 6.8), was approximately 20 times weaker than SRIF. 5. The sst5 receptor antagonist, BIM-23056 (100 nM), antagonized SRIF-induced inhibition of bFGF-induced regeneration in both VSMC and CHOsst5 cells (estimated pKB values 8.8 and 8.3, respectively). 6. SRIF-induced inhibition of bFGF-induced regeneration of VSMC and CHOsst5 cells was abolished by pretreating cells with pertussis toxin (100 ng ml[-1]) for 20 h. 7. These findings suggest that SRIF-induced inhibition of the proliferation of rat aortic VSMC is mediated via activation of receptors which are similar to human sst5 receptors. Furthermore this inhibitory effect is transduced via pertussis toxin-sensitive Gi/Go proteins.
authors.affiliation: Glaxo Institute of Applied Pharmacology and Department of Pharmacology, University of Cambridge.
authors.forename: H
authors.initials: H
authors.lastname: Lauder
authors.forename: L A
authors.initials: LA
authors.lastname: Sellers
authors.forename: T P
authors.initials: TP
authors.lastname: Fan
authors.forename: W
authors.initials: W
authors.lastname: Feniuk
authors.forename: P P
authors.initials: PP
authors.lastname: Humphrey
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects*; D016466:CHO Cells; D002455:Cell Division; D002478:Cells, Cultured; D006224:Cricetinae; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: C091737:BIM 23056; D009842:Oligopeptides; D017481:Receptors, Somatostatin; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D016222:Fibroblast Growth Factor 2; D013004:Somatostatin; C094573:somatostatin receptor 5; D037342:Pertussis Toxin