| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
We evaluated the pathological role of ET_B receptors in DOCA-salt-induced hypertension, cardiovascular hypertrophy and renal damage, using the spotting-lethal (sl) rat which carries a naturally occurring deletion in ET_B receptor gene. When homozygous (sl/sl) and wild-type (+/+) rats were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than wild-type rats. Chronic treatment with ABT-627, an ET_A receptor antagonist, completely suppressed DOCA-salt-induced hypertension in both groups. Renal dysfunction and histologial damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous, compared with wild-type rats. Renal and vaslcular injuries were significantly improved by ABT-627. In DOCA-salt-induced hypertension. Enhanced ET-1 production and ET_A-mediated actions are responsible for the increased susceptivity to DOCA-salt hypertention and tissue injuries in ET_B receptor-defici
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ent rats
Using same animals, we also evaluated the role of endothelin ET\B-receptor-mediated action in the development and maintenance of ischemic acute renal failure (ARF). Animals were subjected to ischemic ARF by clamping the renal pedicle for 45 min followed by reperfusion. At 24 h after the reperfusion, renal glomerular dysfunction and histological damage were markedly and equally observed both in homozygous and wild-type groups, and these renal njury gradually recovered. When the ischemia/reperfusion-induced renal injury was examined at 7 days after the reperfusion, the recovery in homozygous ARF rats obviously delayed compared with the cases in wild-type animals. Increment of renal endothelin-1 content after the ischemia/reperfusion was more marked in homozygous than in wild-type rats. Thus, ET_B-receptor-mediated actoins do not play an important role in the development of ischemic ARF, but may be involoved in the recovery process from the ischemia/reperfusion-induced renal injury Less
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