ANTIHYPERTENSIVE EFFECT OF AN ENDOTHELIN RECEPTOR ANTAGONIST IN DOCA-SALT SPONTANEOUSLY HYPERTENSIVE RATS

1 Endothelin-1 gene expression is enhanced in aorta and mesenteric art eries, and possibly other vessels, of deoxycorticosterone acetate (DOC A)-salt hypertensive rats but is normal or reduced in spontaneously hy pertensive rats (SHR). Bosentan, a mixed ET(A)/ET(B) endothelin recept or antagonist, blunts the development of elevated blood pressure of DO CA-salt hypertensive rats but not in SHR. In this study we investigate d whether treatment of DOCA-salt SHR with bosentan would result in blu nted rise in blood pressure. 2 SHR, aged 13 weeks, were implanted with silastic containing DOCA and offered 1% saline to drink. Systolic blo od pressure was measured by the tail-cuff method. Endothelin-1 mRNA ab undance in aorta and mesenteric arteries was measured by Northern blot analysis. Content of immunoreactive endothelin in blood vessels was m easured by radioimmunoassay. 3 Systolic blood pressure rose less in bo sentan-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 st ill higher than in age-matched SHR. Endothelin-1 mRNA abundance and co ntent of immunoreactive endothelin were increased in the aorta and the mesenteric arterial bed of DOCA-salt SHR, and were unaffected by trea tment with bosentan. 4 These data support the hypothesis of a role of endothelin-1 in blood pressure elevation in this hypertensive model wi th malignant hypertension. They also support the hypothesis that an an tihypertensive effect of the mixed ET(A)/ET(B) endothelin receptor ant agonist, bosentan, is found when experimental hypertensive animals exh ibit enhanced endothelin-1 gene expression in blood vessels.