We have previously shewn that the endothelin content in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats is increased. We designed this study to examine, using the new orally active nonselective endothelin receptor antagonist bosentan, whether this increase in vascular endothelin may contribute to elevated blood pressure and vascular hypertrophy in DOCA-salt hypertensive rats. Rats received bosentan (100 mg/kg body wt per day) for 3 weeks mixed with their food. Systolic blood pressure of DOCA-salt hypertensive rats rose to 197±5 mm Hg, and that of bosentantreated DOCA-salt hypertensive rats was 177±4 mm Hg (P<.01). Mesenteric resistance arteries were studied on a wire myograph. The media width, ratio of media width to lumen diameter, and cross-sectional area of the media of resistance arteries of bosentan-treated DOCA-salt hypertensive rats E ndothelins comprise a family of potent vasoconstrictor peptides 1 ' 2 endowed, as other similar peptides, with mitogenic properties. 3 The role of endothelins in hypertension is unclear. Endothelin-1 (ET-1) is one of the best-studied and possibly one of the more important members of this family of peptides in peripheral tissues. Several studies have demonstrated that the circulating concentrations of ET-1 exhibit little or no increase in most models of hypertension in animals or in human essential hypertension. "7 It has also been shown that the effects of ET-1 on blood vessels in experimental models of hypertension and in essential hypertensive humans are either normal or blunted.814 Thus, it has been difficult to postulate a role of ET-1 in hypertension.We have recently demonstrated that in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat the content of immunoreactive ET-1 is increased in aorta and mesenteric arteries despite normal circulating levels.15 Thus, endothelin secretion may occur abluminally, 16 and exaggerated vascular production may not result in elevated plasma levels. Histochemical staining for endothelin was enhanced in endothe- © 1994 American Heart Association, Inc.were significantly smaller than those of untreated DOCA-salt hypertensive rats. The lumen diameter and cross-sectional area of the media of vessels of bosentan-treated rats were not different from those of uninephrectomized control rats. Vasoconstrictor responses, which were altered in DOCA-salt hypertensive rats, approached control in the bosentan-treated rats. We conclude that these results with a nonselective endothelin receptor antagonist may suggest a role for endothelin in the elevation of blood pressure and vascular hypertrophy and remodeling in DOCA-salt hypertensive rats. Hal cells in these vessels. 15 In a subsequent study we found that the abundance of mRNA for ET-1 was significantly increased between three and five times in vessels of DOCA-salt hypertensive rats. 17 In contrast to DOCA-salt hypertensive rats, spontaneously hypertensive rats (SHR) did not exhibit an increased endothelin content in vascular tissues. 15 We were also impressed ...

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced in the endothelium of blood vessels that may play an important role in the control of local blood flow and could be involved in the pathogenesis of hypertension. We investigated immunoreactive ET-1 (ir-ET-1) levels in acid extracts from blood vessels of deoxycorticosterone acetate (DOCA)-salt and spontaneously hypertensive rats. We found that segments of thoracic aorta and the mesenteric vascular bed contain significantly more ir-ET-1 (11.84±0.84 and 17.30±1.89 fmol, respectively) than uninephrectomized control rats (1.78±0.20 and 9.19+0.63 fmol, respectively; p<0.001). High performance liquid chromatography showed that ir-ET-1 of blood vessels of DOCA-salt hypertensive rats eluted in the same position as synthetic ET-1. Significantly increased ir-ET-1 was localized by immunohistochemistry in endothelial cells of aorta and large and small mesenteric arteries of DOCA-salt hypertensive rats. In contrast to the latter, in spontaneously hypertensive rats, vascular content of ir-ET-1 was similar to that of blood vessels of Wistar-Kyoto control rats, at both 6 and 16 weeks of age. High levels of vascular ET-1 may explain the downregulation of vascular endothelin receptors previously described in DOCA-salt hypertensive rats. Furthermore, this suggests that ET-1 may be involved in the maintenance of high blood pressure in mineralocorticoid hypertension. ET-1 is a 21-amino acid peptide produced primarily in endothelial cells' but also in vascular smooth muscle cells.3 Locally produced ET-1 exerts its effects in an autocrine and paracrine fashion to constrict blood vessels by acting on smooth muscle. Through its effect on endothelial cells, it induces the production of endothelium-derived relaxing factor and prostacyclin, which relax underlying smooth muscle cells. 4 The balance between these responses may contribute to the control of blood pressure. 5 The role of ET-1 in hypertension, however, remains unclear. Plasma ET-1 levels in different models of hypertension in the rat and in essential hypertension in humans have been found to be similar or slightly higher in comparison to normotensive controls.6 -9 Recently, we have shown that arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive

This study demonstrates a relationship between inflammation/ROS and arterial calcification in CKD and contributes to understanding of the complex pathways that mediate arterial calcification in CKD patients.