Enhanced expression of the endothelin-1 gene in blood vessels of DOCA-salt hypertensive rats: correlation with vascular structure.

Endothelin (ET)-1 is a potent vasoconstrictor peptide which is also endowed with hypertrophic and mitogenic properties. Enhanced ET-1 gene expression in blood vessels of rats with hypertension induced by deoxycorticosterone acetate (DOCA)-salt has been previously demonstrated. The objective of this study was: (1) to investigate the individual effects of salt and DOCA, and of the development of hypertension in DOCA-salt-hypertensive rats, on ET-1 gene expression in blood vessels; and (2) to correlate the presence of enhanced ET expression and the severity of vascular hypertrophy. By providing salt and/or DOCA to rats which were or were not unilaterally nephrectomized, groups of rats with variable degrees of blood pressure elevation were generated. Increased abundance of ET-1 mRNA and a greater content of immunoreactive ET-1 were found with progression of hypertension in aorta and the mesenteric arterial bed only in unilaterally nephrectomized DOCA-salt-treated rats (DOCA-salt-hypertensive rats). Vascular expression of ET-1 was not enhanced in other DOCA-or salt-treated rats, even when blood pressure rose to a mean systolic pressure of 180 mm Hg. The wet weight of aorta and the mesenteric arterial bed, the media thickness, the media cross-sectional area, and the media-to-lumen ratio of mesenteric small arteries of all groups of rats exhibited a close correlation with systolic blood pressure. In DOCA-salt-hypertensive rats after 5 weeks, in which overexpression of ET-1 was maximal, the vascular morphometric parameters were excessive for the level of systolic blood pressure. However, in DOCA-salt-hypertensive rats treated with the combined ETA/ETBET receptor antagonist bosentan, vascular morphometry correlated closely with blood pressure, even though blood pressure was only slightly lower than than of untreated DOCA-salt-hypertensive rats. These data support the hypothesis that ET-1 gene overexpression in blood vessels may accentuate vascular hypertrophy in some forms of hypertension.