No abstract

To investigate the potential pathogenic role of endothelin in blood pressure elevation and vascular hypertrophy in renovascular hypertensive rats, which present twofold elevations in endothelin-1 mRNA abundance in blood vessels, the response of blood pressure and vascular structure to chronic treatment with the endothelin receptor antagonist bosentan was evaluated. One-kidney, one clip (1K,1C) and two kidney, one clip (2K,1C) Goldblatt hypertensive rats were treated for 2 wk with bosentan (100 mg.kg-1.day-1) in their chow, and systolic blood pressure was measured by the tail-cuff method. Vascular structure was studied in small arteries mounted on a wire myograph. Treatment with bosentan did not result in a significant change in systolic blood pressure or in the structure of small coronary, renal cortical, mesenteric, or femoral arteries in 1K, 1C or in 2K, 1C hypertensive rats. In conclusion, modest (twofold) elevations of endothelin-1 gene expression in blood vessels in renovascular hypertension are not associated with hypotensive responses or regression of vascular hypertrophy during treatment with endothelin antagonists in contrast to what is found in deoxycorticosterone acetate salt hypertensive rats, which exhibit very dramatic increases in endothelin-1 expression (five-to eightfold) and do respond to endothelin antagonism with blood pressure lowering and regression of vascular hypertrophy. These small elevations of vascular endothelin-1 gene expression thus do not appear to indicate the presence of an endothelin component in blood pressure elevation in renovascular hypertension in 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-l 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.