title: Doxazosin blocks the angiotensin II-induced smooth muscle cell DNA synthesis in the media, but not in the neointima of the rat carotid artery after balloon injury.
abstract: OBJECTIVE
  Infusion of angiotensin II (AngII) during the third and fourth week after balloon injury of the left common carotid artery of the rat induces smooth muscle cell (SMC) DNA synthesis. In this study we wanted to investigate whether alpha 1-adrenoreceptors are involved in AngII-induced SMC DNA synthesis in the neointima.
  
  
  METHODS
  Adult male Wistar Kyoto rats were subcutaneously infused for 2 weeks with AngII and the alpha 1-adrenoreceptor antagonist doxazosin during the 3rd and the 4th week after balloon injury of the left common carotid artery. Control groups received AngII, 0.9% NaCl, AngII + 50% dimethylsulfoxide (DMSO, the solvent of doxazosin), doxazosin or 50% dimethylsulfoxide. Each rat received 5-bromo-2'-deoxyuridine in a separate osmotic minipump to label DNA-synthesizing SMC. Systolic blood pressures were measured in all groups.
  
  
  RESULTS
  Angiotensin II caused an increase in systolic blood pressure, whereas addition of doxazosin did not affect the increase in SBP caused by AngII. In the media of the non-injured carotid artery, AngII increased SMC DNA synthesis, as the BrdUrd labeling fraction increased from 0.2 +/- 0.1% (mean +/- s.e.m.) in the NaCl group towards 3.4 +/- 0.6% in the AngII group. Coinfusion with doxazosin reduced the AngII-induced increase in BrdUrd labeling fraction from 3.2 +/- 0.8% in the AngII + DMSO group towards 0.6 +/- 0.2% in the AngII+doxazosin group. A similar effect of doxazosin was found in the media of the injured left carotid artery, in which coinfusion with doxazosin also reduced the BrdUrd labeling fraction from 2.6 +/- 0.8% in the AngII+DMSO group towards 0.3 +/- 0.1% in the AngII+doxazosin group. In the neointima of the injured left carotid artery, AngII increased the BrdUrd labeling fraction from 11.7 +/- 1.6% in the NaCl group towards 28.0 +/- 3.4% in the AngII group. Coinfusion with doxazosin did not influence the AngII-induced SMC DNA synthesis, since the BrdUrd labeling fraction in the neointima of the AngII+doxazosin group was 22.5 +/- 2.9%, whereas the neointimal BrdUrd labeling fraction in the AngII+DMSO group was 22.9 +/- 2.3%. Little effect was found on the medial cross-sectional area. The neointimal cross-sectional area was increased as a result of infusion of AngII (0.12 +/- 0.01 mm2 vs. 0.18 +/- 0.01 mm2), and coinfusion of doxazosin did not reduce the AngII-induced increase in neointimal cross-sectional area (0.18 +/- 0.03 mm2).
  
  
  CONCLUSIONS
  These data suggest that alpha 1-adrenoreceptors are not involved in AngII-induced neointimal SMC DNA synthesis and cross-sectional area, but only play a role in the media of the carotid artery.
authors.affiliation: Department of Pathology, University of Limburg, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: van Kleef
authors.forename: J F
authors.initials: JF
authors.lastname: Smits
authors.forename: S M
authors.initials: SM
authors.lastname: Schwartz
authors.forename: M J
authors.initials: MJ
authors.lastname: Daemen
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D020212:Carotid Artery Injuries; D002404:Catheterization; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011921:Rats, Inbred WKY; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000804:Angiotensin II; D004247:DNA; D017292:Doxazosin