Effects of endothelin receptor antagonism and angiotensin-converting enzyme inhibition on cardiac and renal remodeling in the rat.
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY(1998)
摘要
The effects of a nonpeptide, orally active mixed endothelin (ET) ETA/ETB receptor antagonist, SB 217242, and an angiotensin-converting enzyme (ACE) inhibitor, ramipril, were evaluated after inter-renal aortic banding in the rat. Separate sham, vehicle, and treatment groups were compared in each study. In vehicle-treated animals in the ramipril group, aortic banding for 4 weeks produced significant cardiac hypertrophy (247 +/- 5 mg/100 g bw vs. 305 +/- 11 mg/100 g bw; p < 0.001), right (upstream) renal hypertrophy (380 6 mg/100 g bw vs. 559 28 mg/100 g bw; p < 0.001), and significant left (downstream) renal atrophy (405 4 mg/100 g bw vs. 192 25 mg/100 g bw; p < 0.001). Continuous ramipril treatment (1 mg/kg p.o. once daily), begun 3 days before aortic banding, inhibited cardiac hypertrophy (305 11 mg/100 g bw vs. 266 7 mg/100 g bw; p < 0.05) but did not alter renal hypertrophy or atrophy. In a similarly designed study, SB 217242 (30 mg/kg p.o. b.i.d.) had no effect on the development of cardiac hypertrophy (298 7 mg/100 g bw vs. 310 12 mg/100 g bw) or renal hypertrophy (561 15 mg/100 g bw vs. 575 19 mg/100 g bw), but abolished the development of renal atrophy (158 16 mg/100 g bw vs. 395 19 mg/100 g bw; p < 0.001). [I-125]ET-1 radioligand binding experiments indicated that the density of both ETA and ETB receptors was increased dramatically (three- to fourfold) in the atrophic kidney cortex compared to sham or hypertrophic kidneys, In situ hybridization studies indicate an upregulation of ETB receptor mRNA in the glomeruli of atrophic kidneys within 5 days of aortic banding. In conclusion, an angiotensin-dependent mechanism may mediate cardiac hypertrophy associated with aortic banding, whereas ET-dependent mechanisms may mediate an atrophic response in the hypoperfused kidney, perhaps through an interaction with upregulated ETA and/or ETB receptors.
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关键词
ACE inhibitor,cardiac hypertrophy,endothelin receptor antagonist,ramipril,renal atrophy,renal hypertrophy,SB 217242
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