Nitric Oxide May Prevent Hypertension Early in Diabetes by Counteracting Renal Actions of Superoxide

Abstract

Abstract-The dependence of blood pressure on a balance between superoxide and nitric oxide may be amplified in diabetes. We have shown that the first occurrence of sustained hyperglycemia in type I diabetes causes hypertension when induced in rats that have had nitric oxide synthesis blocked chronically (L-NAME, 10 g/kg per minute IV). This study used tempol (18 mol/kg per hour IV) to test the hypothesis that superoxide mediates that hypertensive response. Induction of diabetes in untreated rats had no significant effect on mean arterial pressure (MAP, measured 18 h/d), and glomerular filtration rate (GFR) increased significantly during the 2 weeks of diabetes. Chronic infusion of L-NAME in a separate group of rats increased baseline MAP from Ϸ90 mm Hg to a stable level of Ϸ120 mm Hg after 6 days of infusion, and induction of diabetes (streptozotocin, 40 mg/kg IV) in those rats caused a rapid, progressive increase in MAP that averaged 156Ϯ5 mm Hg by day 14 of diabetes that was associated with a decrease in GFR and 4-fold increase in isoprostane excretion. Tempol infusion was begun on day 2 of diabetes in a subgroup of those rats, and the progressive hypertensive response was prevented, with MAP averaging 134Ϯ10 mm Hg by day 14. In addition, the normal renal hyperfiltration response was restored by tempol and the increase in isoprostane did not occur. Thus, the hypertension and decrease in GFR caused by onset of diabetes in rats without a functioning nitric oxide system was prevented by chronic administration of the superoxide dismutase mimetic tempol. Key Words: blood pressure Ⅲ glomerular filtration rate Ⅲ diabetes mellitus Ⅲ nitric oxide Ⅲ L-NAME T here is good evidence for opposing actions of superoxide and nitric oxide in the chronic control of arterial pressure under physiological and pathophysiologic states.1-9 Most of this evidence suggests that there is a balance between the blood pressure-lowering effects of nitric oxide and the hypertensive actions of superoxide that involves direct and indirect chemical interaction as well as physiological interaction at effector sites. Shifts in that balance can have wide-ranging effects, and there could be a more critical and tenuous balance between the two in the control of blood pressure in diabetes because of the neurohumoral and direct effects of hyperglycemia and the added stress imparted by renal fluid and electrolyte losses caused by poor glycemic control. Studying the interaction between nitric oxide and superoxide has been complicated, however, by evidence that production of both may be increased in diabetes 1,2,5,8,9 but that nitric oxide synthesis becomes impaired over time. 9,10 We recently tested the hypothesis that nitric oxide was critical for preventing hypertension very early in diabetes. 11,12 This was based on our previous work that suggested endothelium-dependent vasodilation was not impaired during the first week of type I diabetes 13 and that angiotensin (Ang) II increased significantly during that same period. 14 We found that blocking nitric ...

Ghrelin Improves Renal Function in Mice with Ischemic Acute Renal Failure

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Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

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Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

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