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...

ET(B)-mediated actions are protective in the pathogenesis of DOCA-salt-induced hypertension. Enhanced ET-1 production and ET(A)-mediated actions are responsible for the increased susceptibility to DOCA-salt hypertension and tissue injuries in ET(B) receptor-deficient rats.

We investigated the effects of ABT-627, a selective ETA-receptor antagonist, and A-192621, a selective ETB-receptor antagonist, on ischemic acute renal failure (ARF) in rats. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min, 2 weeks after the contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion and thereafter tended to recover gradually. ABT-627 (1 mg/kg, i.v.) administration before ischemia markedly attenuated the renal dysfunction induced by the ischemia/reperfusion, whereas A-192621 (3 mg/kg, i.v.) pretreatment was without effect. Histopathological examination of the kidney of untreated ARF rats revealed severe renal damage such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion. Histologically evident damage was improved by pretreatment with ABT-627, but not with A-192621. Daily oral administration of ABT-627 (10 mg/kg per day), but not A-192621 (30 mg/kg per day), given after the ischemia/reperfusion period also exerted protective effects. These findings clearly indicate that endothelin, acting via the ETA receptor, participates in the pathogenesis of ischemic ARF. Thus, selective ETA-receptor antagonism may be useful in the treatment of human ischemic ARF, whereas selective blockade of the ETB receptor will probably be ineffective.

Effects of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl- 1-1-phenyl- 1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt), a novel endothelin converting enzyme (ECE) inhibitor, on ischemic acute renal failure (ARF) in rats were examined in comparison with those of phosphoramidon, a conventional ECE inhibitor. ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in ARF rats markedly decreased at 24 h after reperfusion. Intravenous bolus injection of SM-19712 (3, 10, 30 mg/kg) prior to the occlusion attenuated dose-dependently the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were dose-dependently attenuated by SM-19712. Protective effects of phosphoramidon (10 mg/kg) on ARF-induced functional and tissue damages were less potent than that of the same dose of SM-19712. Endothelin-1 (ET-1) content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after reperfusion, and this elevation was completely suppressed by the higher dose of SM-19712. Our findings support the view that renal ET-1 plays an important role in the development of ischemia/reperfusion-induced renal injury. SM-19712 may be useful in the treatment of ischemic ARF.