Vascular remodeling and endothelin antagonism in hypertension

Endothelin-1 is a potent vasoconstrictor peptide which is also endowed with hypertrophic properties. Endothelin-1 gene expression is enhanced in blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats and in DOCA-salt spontaneously hypertensive rats (SHR) but not in SHR. Rats treated with salt and/or DOCA showed that increased abundance of endothelin-1 mRNA and greater content of immunoreactive endothelin-1 were present only in DOCA-salt hypertensive rats, even when blood pressure of other rats rose up to a systolic pressure of 180 mmHg. Vascular morphometry of all groups of rats was closely correlated with systolic blood pressure except in DOCA-salt hypertensive rats, in which vascular morphometric parameters were excessive for the level of blood pressure. In contrast, vascular morphometry of DOCA-salt hypertensive rats treated with the endothelin antagonist bosentan correlated closely with blood pressure. DOCA-salt SHR, which also exhibited vascular endothelin-1 overexpression, responded to bosentan with lowering of blood pressure. In SHR, which do not overexpress endothelin in blood vessels, bosentan did not blunt development of hypertension in young SHR nor affect blood pressure of adult SHR. These data support the hypothesis that endothelin-1 gene overexpression in blood vessels may cause blood pressure-independent vascular hypertrophy in some hypertensive models, and in these participate in the pathogenesis of blood pressure elevation. They also suggest that a blood pressure lowering response to endothelin antagonism is found in hypertensive rats which exhibit enhanced endothelin expression in blood vessels