Antihypertensive effect of an endothelin receptor antagonist in DOCA-salt spontaneously hypertensive rats.
1. Endothelin-1 gene expression is enhanced in aorta and mesenteric arteries, and possibly other vessels, of deoxycorticosterone acetate (DOCA)-salt hypertensive rats but is normal or reduced in spontaneously hypertensive rats (SHR). Bosentan, a mixed ETA/ETB endothelin receptor antagonist, blunts the development of elevated blood pressure of DOCA-salt hypertensive rats but not in SHR. In this study we investigated whether treatment of DOCA-salt SHR with bosentan would result in blunted rise in blood pressure. 2. SHR, aged 13 weeks, were implanted with silastic containing DOCA and offered 1% saline to drink. Systolic blood pressure was measured by the tail-cuff method. Endothelin-1 mRNA abundance in aorta and mesenteric arteries was measured by Northern blot analysis. Content of immunoreactive endothelin in blood vessels was measured by radioimmunoassay. 3. Systolic blood pressure rose less in bosentan-treated DOCA-salt SHR (to 223 +/- 2 mmHg) in comparison to the untreated rats (241 +/- 1), a small but significant difference (P < 0.001). However, blood pressure of bosentan-treated DOCA-salt SHR was still higher than in age-matched SHR. Endothelin-1 mRNA abundance and content of immunoreactive endothelin were increased in the aorta and the mesenteric arterial bed of DOCA-salt SHR, and were unaffected by treatment with bosentan. 4. These data support the hypothesis of a role of endothelin-1 in blood pressure elevation in this hypertensive model with malignant hypertension. They also support the hypothesis that an antihypertensive effect of the mixed ETA/ETB endothelin receptor antagonist, bosentan, is found when experimental hypertensive animals exhibit enhanced endothelin-1 gene expression in blood vessels.
Schiffrin
E L
EL
MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Québec, Canada.
Sventek
P
P
Li
J S
JS
Turgeon
A
A
Reudelhuber
T
T
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D000077300:Bosentan; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000032:analysis* / Q000097:blood; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis* / Q000097:blood; D011863:Radioimmunoassay; D051381:Rats; D011918:Rats, Inbred SHR; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; D003900:Desoxycorticosterone; D000077300:Bosentan