Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease.
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.
Dimitrijevic
Ivan
I
Department of Medicine, Lund University Hospital, Lund, Sweden. ivan.dimitrijevic@med.lu.se
Edvinsson
Marie-Louise
ML
Chen
Qingwen
Q
Malmsjö
Malin
M
Kimblad
Per-Ola
PO
Edvinsson
Lars
L
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
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
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