title: Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease.
abstract: BACKGROUND
  Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.
  
  
  METHODS
  Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology.
  
  
  RESULTS
  ETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% +/- 23%; P < 0.05) and in the patients with angina pectoris (199% +/- 6%; P < 0.05), than in the healthy controls (100% +/- 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ETA receptors. AT1 and, to a lesser extent, AT2 receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT1 receptor expression was higher in both the angina pectoris (128% +/- 25%; P < 0.05) and in the CABG patients (203% +/- 41%; P < 0.05), as compared to the healthy controls (100% +/- 25%). The increased AT1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).
  
  
  CONCLUSIONS
  The results demonstrate, for the first time, upregulation of ETB and AT1 receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.
authors.affiliation: Department of Medicine, Lund University Hospital, Lund, Sweden. ivan.dimitrijevic@med.lu.se
authors.forename: Ivan
authors.initials: I
authors.lastname: Dimitrijevic
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Edvinsson
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Chen
authors.forename: Malin
authors.initials: M
authors.lastname: Malmsjö
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Kimblad
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000368:Aged; D000787:Angina Pectoris / Q000209:etiology / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D057912:Angiotensin II Type 2 Receptor Blockers; D001158:Arteries / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D001026:Coronary Artery Bypass; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D009213:Myography; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000098:blood supply*; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D019332:Endothelin-1; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D000804:Angiotensin II; C073402:PD 123319
references.citation: Trends Pharmacol Sci. 1999 May;20(5):210-7
references.pmid: 10354617
references.citation: Basic Clin Pharmacol Toxicol. 2004 Dec;95(6):266-72
references.pmid: 15569271
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C82-97
references.pmid: 16870827
references.citation: Br J Clin Pharmacol. 2004 Jan;57(1):27-36
references.pmid: 14678337
references.citation: Pathol Int. 2000 Dec;50(12):929-36
references.pmid: 11123758
references.citation: Curr Hypertens Rep. 2005 Feb;7(1):52-60
references.pmid: 15683587
references.citation: Arterioscler Thromb Vasc Biol. 1998 Sep;18(9):1433-9
references.pmid: 9743232
references.citation: Acta Physiol Scand. 1983 Jan;117(1):49-61
references.pmid: 6858705
references.citation: Eur J Pharmacol. 1997 Jun 18;329(1):69-77
references.pmid: 9218686
references.citation: Annu Rev Physiol. 1999;61:391-415
references.pmid: 10099694
references.citation: J Biol Chem. 1992 Sep 15;267(26):18797-804
references.pmid: 1326535
references.citation: Vascul Pharmacol. 2005 Jun;43(1):19-29
references.pmid: 15955745
references.citation: BMC Cardiovasc Disord. 2008 Sep 08;8:21
references.pmid: 18778461
references.citation: Endocrinology. 2006 Dec;147(12):5914-20
references.pmid: 16980435
references.citation: J Biol Chem. 1994 Apr 1;269(13):10112-8
references.pmid: 8144511
references.citation: Atherosclerosis. 1999 Sep;146(1):93-100
references.pmid: 10487491
references.citation: J Cardiovasc Pharmacol. 1995;26 Suppl 3:S494-6
references.pmid: 8587456
references.citation: Heart. 1999 Mar;81(3):278-84
references.pmid: 10026353
references.citation: Am J Respir Cell Mol Biol. 2000 Mar;22(3):323-32
references.pmid: 10696069
references.citation: J Cardiovasc Pharmacol. 1996 Jan;27(1):147-53
references.pmid: 8656649
references.citation: Ann Thorac Surg. 1996 Oct;62(4):1222-8
references.pmid: 8823128
references.citation: J Biol Chem. 1993 Feb 15;268(5):3463-70
references.pmid: 8429023
references.citation: Hypertension. 2007 Feb;49(2):341-6
references.pmid: 17159079
references.citation: Am J Med. 2002 Oct 1;113(5):409-18
references.pmid: 12401536
references.citation: Biochem Biophys Res Commun. 1992 Dec 15;189(2):994-1000
references.pmid: 1472072
references.citation: J Mol Cell Cardiol. 1996 Feb;28(2):243-52
references.pmid: 8729057
references.citation: Circulation. 2003 Apr 8;107(13):1783-90
references.pmid: 12665485
references.citation: Nutr Rev. 2007 Dec;65(12 Pt 2):S253-9
references.pmid: 18240558
references.citation: Nature. 1988 Mar 31;332(6163):411-5
references.pmid: 2451132
references.citation: Pharmacol Res. 2004 Dec;50(6):561-8
references.pmid: 15501693
references.citation: Circulation. 1997 Jan 7;95(1):5-7
references.pmid: 8994406
references.citation: Eur J Pharmacol. 1995 Dec 20;287(3):279-85
references.pmid: 8991802
references.citation: Stroke. 2008 Nov;39(11):3015-21
references.pmid: 18688013
references.citation: J Urol. 1997 Nov;158(5):1966-72
references.pmid: 9334651
references.citation: Eur J Pharmacol. 1999 Jul 9;376(3):223-32
references.pmid: 10448880
references.citation: J Am Coll Cardiol. 1999 Mar 15;33(4):932-8
references.pmid: 10091818
references.citation: Ann Card Anaesth. 2008 Jan-Jun;11(1):6-14
references.pmid: 18182753
references.citation: Circulation. 1996 Feb 15;93(4):646-51
references.pmid: 8640990
references.citation: Hypertension. 1997 Jul;30(1 Pt 1):35-41
references.pmid: 9231818
references.citation: Cardiovasc Res. 2000 Oct;48(1):158-67
references.pmid: 11033118