Enhanced angiotensin II-mediated central sympathoexcitation in streptozotocin-induced diabetes: Role of superoxide anion

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Abstract

Studies have shown that the superoxide mechanism is involved in angiotensin II (ANG II) signaling in the central nervous system. We hypothesized that ANG II activates sympathetic outflow by stimulation of superoxide anion in the paraventricular nucleus (PVN) of streptozotocin (STZ)-induced diabetic rats. In α-chloralose- and urethane-anesthetized rats, micro-injection of ANG II into the PVN (50, 100, and 200 pmol) produced dose-dependent increases in renal sympathetic nerve activity (RSNA), arterial pressure (AP), and heart rate (HR) in control and STZ-induced diabetic rats. There was a potentiation of the increase in RSNA (35.0 ± 5.0 vs. 23.0 ± 4.3%, P < 0.05), AP, and HR due to ANG II type I (AT1) receptor activation in diabetic rats compared with control rats. Blocking endogenous AT1 receptors within the PVN with AT1 receptor antagonist losartan produced significantly greater decreases in RSNA, AP, and HR in diabetic rats compared with control rats. Concomitantly, there were significant increases in mRNA and protein expression of AT1 receptor with increased superoxide levels and expression of NAD(P)H oxidase subunits p22phox, p47phox, and p67 phox in the PVN of rats with diabetes. Pretreatment with losartan (10 mg·kg-1·day-1 in drinking water for 3 wk) significantly reduced protein expression of NAD(P)H oxidase subunits (p22 phox and p47phox) in the PVN of diabetic rats. Pretreatment with adenoviral vector-mediated overexpression of human cytoplasmic superoxide dismutase (AdCuZnSOD) within the PVN attenuated the increased central responses to ANG II in diabetes (RSNA: 20.4 ± 0.7 vs. 27.7 ± 2.1%, n = 6, P < 0.05). These data support the concept that superoxide anion contributes to an enhanced ANG II-mediated signaling in the PVN involved with the exaggerated sympathoexcitation in diabetes.

Original languageEnglish (US)
Pages (from-to)R311-R320
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume300
Issue number2
DOIs
StatePublished - Feb 2011

Keywords

  • Central nervous system
  • Renin-angiotensin system
  • Sympathetic nerve activity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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