Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

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Abstract
The biosynthesis of endothelin‐1 is increased in the diabetic state. So this peptide may cause diabetic vascular complications. We tested this possibility by chronically administering J‐104132, a potent orally active mixed antagonist of endothelin A and B (ETA/ETB) receptors to streptozotocin (STZ)‐induced diabetic rats and focusing on changes in endothelial function. The acetylcholine (ACh)‐induced endothelium‐dependent relaxation was impaired in diabetic rats and this impairment was significantly attenuated following chronic administration of J‐104132 (10 mg kg−1, p.o., daily for 4 weeks). In an in vitro experiment using aortae from diabetic rats, the ACh‐induced relaxation was not changed by the presence of J‐104132 (3×10−9 M). The expression levels of the mRNA for endothelial nitric oxide synthase was comparable among aortae from the three groups (control, diabetic and chronically J‐104132‐treated diabetic). The amount of superoxide anion was significantly greater in aortae from diabetic rats than in controls. Chronic J‐104132 treatment significantly decreased the level of superoxide anion in diabetic rats. The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was significantly increased in STZ‐induced diabetic rats and this increase was completely prevented by chronic administration of J‐104132. These results suggest that in STZ‐induced diabetic rats, ET‐1 may be directly involved in impairing endothelium‐dependent relaxation via increased superoxide‐anion production. British Journal of Pharmacology (2002) 135, 1935–1942; doi:10.1038/sj.bjp.0704659