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Cardiovascular Aging

Long-term AT₁ receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats

¹The Hypertension and Vascular Research Center, ²General Surgery, ³Department of Physiology and Pharmacology and ⁴Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 13 April 2007 ; accepted in final form 2 July 2007

Fischer-344 (F344) rats exhibit proteinuria and insulin resistance in the absence of hypertension as they age. We determined the effects of long-term (1 yr) treatment with the angiotensin (ANG) II type 1 (AT₁) receptor blocker L-158,809 on plasma and urinary ANG peptide levels, systolic blood pressure (SBP), and indexes of glucose metabolism in 15-mo-old male F344 rats. Young rats at 3 mo of age (n = 8) were compared with two separate groups of older rats: one control group (n = 7) and one group treated with L-158,809 (n = 6) orally (20 mg/l) for 1 yr. SBP was not different between control and treated rats but was higher in young rats. Serum leptin, insulin, and glucose levels were comparable between treated and young rats, whereas controls had higher glucose and leptin with a similar trend for insulin. Plasma ANG I and ANG II were higher in treated than untreated young or older rats, as evidence of effective AT₁ receptor blockade. Urinary ANG II and ANG-(1-7) were higher in controls compared with young animals, and treated rats failed to show age-related increases. Protein excretion was markedly lower in treated and young rats compared with control rats (young: 8 ± 2 mg/day vs. control: 129 ± 51 mg/day vs. treated: 9 ± 3 mg/day, P < 0.05). Long-term AT₁ receptor blockade improves metabolic parameters and provides renoprotection. Differential regulation of systemic and intrarenal (urinary) ANG systems occurs during blockade, and suppression of the intrarenal system may contribute to reduced proteinuria. Thus, insulin resistance, renal injury, and activation of the intrarenal ANG system during early aging in normotensive animals can be averted by renin-ANG system blockade.

angiotensin type 1 receptor blockade; glucose metabolosim; aging

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