Effects of chronic administration of the novel endothelin antagonist J-104132 on endothelial dysfunction in streptozotocin-induced diabetic rat.
1. 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 (ET(A)/ET(B)) receptors to streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. 2. 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). 3. In an in vitro experiment using aortae from diabetic rats, the ACh-induced relaxation was not changed by the presence of J-104132 (3 x 10(-9) M). 4. 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). 5. 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. 6. 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. 7. 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.
Kanie
Noriyasu
N
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Kamata
Katsuo
K
D000109:Acetylcholine / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D026901:Membrane Transport Proteins; D009126:Muscle Relaxation / Q000187:drug effects; D009252:NADPH Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology; D013481:Superoxides / Q000032:analysis / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D065128:Endothelin Receptor Antagonists; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D011725:Pyridines; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D014280:Triglycerides; D013481:Superoxides; D009599:Nitroprusside; D009580:Nitroblue Tetrazolium; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; C119319:J 104132; D000109:Acetylcholine