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Abstract-We investigated the involvement of actions mediated by endothelin-A (ET A ) and endothelin-B (ET B ) receptors in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Two weeks after the start of DOCA-salt treatment, rats were given ABT-627 (10 [mg/kg]/d), a selective ET A receptor antagonist; A-192621 (30 [mg/kg]/d), a selective ET B receptor antagonist; or their vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Treatment with DOCA and salt for 2 weeks led to a mild but significant hypertension; in vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3 to 4 weeks. Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was histochemically evaluated at 4 weeks, there were significant increases in wall thickness, wall area, and wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with uninephrectomized control rats. The development of vascular hypertrophy was markedly suppressed by ABT-627. In contrast, treatment with A-192621 significantly exaggerated these vascular changes. In vehicle-treated DOCA-salt rats, renal blood flow and creatinine clearance decreased, and urinary excretion of protein, blood urea nitrogen, fractional excretion of sodium, and urinary N-acetyl-␤-glucosaminidase activity increased. Such damage was overcome by treatment with ABT-627 but not with A-192621; indeed, the latter agent led to worsening of the renal dysfunction. Histopathologic examination of the kidney in vehicle-treated DOCA-salt rats revealed tubular dilatation and atrophy as well as thickening of small arteries. Such damage was reduced in animals given ABT-627, whereas more severe histopathologic changes were observed in A-192621-treated animals. These results strongly support the view that ET A receptor-mediated action plays an important role in the pathogenesis of DOCA-salt-induced hypertension. On the other hand, it seems likely that the ET B receptor-mediated action protects against vascular and renal injuries in this model of hypertension. A selective ET A receptor antagonist is likely to be useful for treatment of subjects with mineralocorticoid-dependent hypertension, whereas ET B -selective antagonism alone is detrimental to such cases. (Hypertension. 1999;33:759-765.)Key Words: receptors, endothelin Ⅲ hypertension, DOCA-salt Ⅲ renal function Ⅲ vascular hypertrophy T here is accumulating evidence indicating that endothelin-1 (ET-1) plays an important role in the development and/or maintenance of hypertension in animal models such as the deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rat 1-6 and Dahl salt-sensitive rat. 7,8 This view is based on findings indicating that acute administration of an endothelin-A (ET A )-selective receptor antagonist or nonselective ET A /ET B receptor antagonist to DOCAsal...

Sesamin, a major lignan in sesame seeds and oil, has been known to lower blood pressure in several types of experimental hypertensive animals. A recent study demonstrated that sesamin metabolites had in vitro radical-scavenging activities. Thus, we determined whether the antioxidative effect of sesamin metabolites modulate the vascular tone and contribute to the in vivo antihypertensive effect of sesamin. We used four demethylated sesamin metabolites: SC-1m (piperitol), SC-1 (demethylpiperitol), SC-2m [(1R,2S,5R,6S)-6-(4-hydroxy-3-methoxyphenyl)-2-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo [3,3,0]octane], and SC-2 [(1R,2S,5R, 6S)-2,6-bis (3,4-dihydroxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane]. SC-1, SC-2m, and SC-2, but not SC-1m, exhibited potent radicalscavenging activities against the xanthine/xanthine oxidaseinduced superoxide production. On the other hand, SC-1m, SC-1, and SC-2m produced endothelium-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings, whereas SC-2 had no effect. The SC-1m-and SC-1-induced vasorelaxations were markedly attenuated by pretreatment with a nitric oxide synthaseNeither SC-1m nor SC-1 changed the expression level of endothelial NOS protein in aortic tissues. The antihypertensive effects of sesamin feeding were not observed in chronically NO-ARG-treated rats or in deoxycorticosterone acetate-salt-treated endothelial NOS-deficient mice. These findings suggest that the enhancement of endothelium-dependent vasorelaxation induced by sesamin metabolites is one of the important mechanisms of the in vivo antihypertensive effect of sesamin.Endothelium-derived nitric oxide (NO) is a potent vasodilator. NO synthesized by endothelial NO synthase (eNOS) diffuses into the smooth muscle cells and stimulates the soluble guanylate cyclase (sGC), leading to increased cGMP production and smooth muscle relaxation (Moncada and Higgs, 1993). Several findings have suggested that excess superoxide (O 2 . ) produced in vascular cells interacts with NO, induces the abnormality of vascular tonus regulation, and results in the development of hypertension (Rajagopalan et al., 1996;Jung et al., 2004). In addition, Laursen et al. (1997) reported that both the development of hypertension and the altered endothelium-dependent vascular relaxation were improved by the treatment with membrane-targeted forms of superoxide dismutase in angiotensin II-induced hypertensive rats. Thus, it seems likely that the suppression of oxidative stress improves the NO bioavailability and prevents the development of hypertension and end-organ damage (Zhou et al., 2003;Schmieder, 2005). Sesamin ( Fig. 1) is one of the lignans found in high concentration in sesame seeds and oil. We have obtained evidence that dietary sesamin efficiently suppressed the development and maintenance of hypertension in deoxycorticoArticle, publication date, and citation information can be found at

Sesamin is one of the lignans contained abundantly in sesame oil. Previous studies have indicated that sesamin inhibits lipid metabolism, such as desaturation in polyunsaturated fatty acid biosynthesis 1) and cholesterol absorption. 2) In recent studies, we have demonstrated the antihypertensive effect of sesamin using several types of experimental hypertensive models. [3][4][5] The most efficient antihypertensive activity was observed in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat model. Moreover, a development of cardiovascular hypertrophy in these animals was attenuated by the sesamin-feeding. 3)There is accumulating evidence indicating that an oxidative stress in vascular tissues is closely related to the development of hypertensive diseases. 6) Nakazono et al. 7) have shown that blood pressure of spontaneously hypertensive rats (SHR) was decreased markedly by administration of heparinbinding superoxide dismutase (SOD) which bound to vascular endothelial cells. In angiotensin II-induced hypertensive rats, both the development of hypertension and the altered endothelium-dependent vascular relaxation were improved by the treatment with membrane-targeted forms of SOD. 8)These findings suggest that vascular superoxide (O 2 Ϫ ) production is increased in several animal models of hypertension and contributes to the development and/or maintenance of their high blood pressure and endothelial dysfunction.Most recently, we noted that the increased vascular O 2 Ϫ production in DOCA-salt hypertensive animals was normalized almost completely by the feeding of sesamin-containing diet. 9) On the other hand, a previous in vitro study has shown that stretching vascular smooth muscle cells results in increased O 2 Ϫ production, 10) thereby suggesting that the high blood pressure by itself may increase the vascular O 2 Ϫ production. Therefore the possibility that dietary sesamin-induced decreases in vascular O 2 Ϫ production may result from a decrease in blood pressure cannot be ruled out. Thus in the present study, we further evaluated the relationship between the antihypertensive effect of sesamin and its antioxidative activity in DOCA-salt hypertensive rats. MATERIALS AND METHODSMaterials Sesamin was prepared from refined sesame oil and purified as described previously.11) Sesamin-containing diets (0.1, 1 w/w% in commercial normal diet, NMF) were obtained from Oriental Yeast Co., Ltd. (Tokyo, Japan). Reserpine and hydralazine hydrochloride were purchased from Tokyo Kasei Kogyo Co. (Tokyo, Japan). All other reagents used were obtained from Sigma Chemical Co. (St. Louis, Missouri, U.S.A.) and Nacalai Tesque (Kyoto, Japan).Animal Experiments Male Sprague-Dawley rats (6 weeks old) (SLC, Inc., Hamamatsu, Japan), were anesthetized with sodium pentobarbital (40 mg/kg, i.p.), and the right kidney was removed via a right flank incision. After a 1-week postsurgical recovery period, rats were separated into a sham-operated group and a DOCA-salt group. Each group was further divided into five groups: i) normal diet gro...