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      A Nitric Oxide-Generating Beta-Blocking Agent Prevents Renal Injury in the Rat Remnant Kidney Model

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          Background: The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether β-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis. Methods: Nipradilol, a β-blocker with an ONO<sub>2</sub> group (5, 10 or 15 mg/kg/day) and propranolol, a β-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro- L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (U<sub>NOx</sub>) and cyclic GMP (U<sub>cGMP</sub>). Results: Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced U<sub>NOx</sub> in comparison with the sham-operated rats. Nipradilol increased U<sub>NOx</sub> and U<sub>cGMP</sub> significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced U<sub>NOx</sub>. The addition of nipradilol increased U<sub>NOx</sub> and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect. Conclusion: These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The β-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents.

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          Identification of the enzymatic mechanism of nitroglycerin bioactivation.

          Nitroglycerin (glyceryl trinitrate, GTN), originally manufactured by Alfred Nobel, has been used to treat angina and heart failure for over 130 years. However, the molecular mechanism of GTN biotransformation has remained a mystery and it is not well understood why "tolerance" (i.e., loss of clinical efficacy) manifests over time. Here we purify a nitrate reductase that specifically catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from GTN, leading to production of cGMP and relaxation of vascular smooth muscle both in vitro and in vivo, and we identify it as mitochondrial aldehyde dehydrogenase (mtALDH). We also show that mtALDH is inhibited in blood vessels made tolerant by GTN. These results demonstrate that the biotransformation of GTN occurs predominantly in mitochondria through a novel reductase action of mtALDH and suggest that nitrite is an obligate intermediate in generation of NO bioactivity. The data also indicate that attenuated biotransformation of GTN by mtALDH underlies the induction of nitrate tolerance. More generally, our studies provide new insights into subcellular processing of NO metabolites and suggest new approaches to generating NO bioactivity and overcoming nitrate tolerance.
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            The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies.

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              Hypertension associated with early stage kidney disease


                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                February 2003
                20 February 2003
                : 93
                : 2
                : p42-p50
                Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
                68529 Nephron Physiol 2003;93:p42–p50
                © 2003 S. Karger AG, Basel

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                Figures: 2, Tables: 4, References: 47, Pages: 1
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