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

We examined the renoprotective effects of l-carnosine (␤-alanyl-l-histidine) on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. In vehicle (0.9% saline)-treated rats, renal sympathetic nerve activity (RSNA) was significantly augmented during the renal ischemia, and renal function was markedly decreased at 24 h after reperfusion. Intracerebroventricular injection of l-carnosine (1.5 and 5 pmol/rat) to ischemic ARF rats dose-dependently suppressed the augmented RSNA during ischemia and the renal injury at 24 h after reperfusion. N-␣-Acetyl-l-carnosine [N-acetyl-␤-alanyl-l-histidine; 5 pmol/rat intracerebroventricular (i.c.v.)], which is resistant to enzymatic hydrolysis by carnosinase, did not affect the renal injury, and l-histidine (5 pmol/rat i.c.v.), a metabolite cleaved from l-carnosine by carnosinase, ameliorated the I/R-induced renal injury. Furthermore, a selective histamine H 3 receptor antagonist, thioperamide (30 nmol/rat i.c.v.) eliminated the preventing effects by l-carnosine (15 nmol/rat intravenously) on ischemic ARF. In contrast, a selective H 3 receptor agonist, R-␣-methylhistamine (5 pmol/rat i.c.v.), prevented the I/R-induced renal injury as well as l-carnosine (5 pmol/rat) did. These results indicate that l-carnosine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppressing the enhanced RSNA during ischemia. In addition, the present findings suggest that the renoprotective effect of l-carnosine on ischemic ARF is induced by its conversion to l-histidine and l-histamine and is mediated through the activation of histamine H 3 receptors in the central nervous system.

Estrogens attenuate renal injury induced by ischemia/reperfusion (I/R), an effect that is related to nitric oxide production in the post-ischemic kidney. The compound 17beta-estradiol (E(2)-beta) acting via estrogen receptors (ERs) is known to activate endothelial nitric oxide synthase (eNOS) through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. We determined if this pathway contributes to the renoprotective effect of E(2)-beta in the uninephrectomized ischemia reperfusion rat model of acute renal injury. Treatment with E(2)-beta suppressed the I/R-induced increases in blood urea nitrogen, plasma creatinine, urine flow, and fractional excretion of sodium while augmenting creatinine clearance, renal blood flow, and urine osmolality, indicating attenuation of renal injury. Phosphorylation of Akt and eNOS protein was significantly increased 30-60 min after reperfusion in estradiol-treated compared to vehicle-treated rats. The protective effects of E(2)-beta and protein phosphorylation were reversed by the PI3K inhibitor wortmannin or the ER antagonist tamoxifen. Furthermore, the E(2)-beta-induced renoprotective effects were not seen in eNOS knockout mice with renal injury. We conclude that the E(2)-beta-induced renoprotective effect is due to activation of the PI3K/Akt pathway followed by increased eNOS phosphorylation in the post-ischemic kidney.