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Effects of acute and chronic L-arginine treatment in experimental hyperuricemia

Laura G. Sánchez-Lozada,¹ Edilia Tapia,¹ Rubén López-Molina,¹ Tomás Nepomuceno,¹ Virgilia Soto,² Carmen Ávila-Casado,² Takahiko Nakagawa,³ Richard J. Johnson,³ Jaime Herrera-Acosta,^1, and Martha Franco¹

Departments of ¹Nephrology and ²Pathology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico; and ³Department of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida

Submitted 12 May 2006 ; accepted in final form 18 December 2006

Experimental hyperuricemia (HU) results in preglomerular arteriolopathy, cortical vasoconstriction, and glomerular hypertension. Recently, uric acid has been shown to induce endothelial dysfunction. We therefore studied the effect of acute and chronic administration of L-arginine (a substrate for endothelial nitric oxide synthase) on the renal hemodynamic and vascular structural alterations induced by HU. To induce HU, oxonic acid (OA; 750 mg·kg^–1·day^–1) was administered in male Sprague-Dawley rats. To study the acute effect of arginine, nine rats received L-arginine (L-Arg; 15 mg·kg^–1·min^–1) during micropuncture. To elucidate the chronic effect of L-Arg, OA + 1% L-Arg (n = 8) and OA + 2.5% L-Arg (n = 6; drinking water) were evaluated throughout the 5-wk period. Eight normal control (N), and eight OA, rats were also studied. Kidneys were fixed by perfusion and afferent arteriole morphology was evaluated. HU rats developed the renal functional and structural alterations described and had suppressed urinary excretion of NO₂^–/NO₃^–. Acute stimulation of nitric oxide (NO) synthesis markedly increased urinary NO₂^–/NO₃^–, lowered systemic blood pressure, and relieved cortical vasoconstriction despite a significant increment of glomerular hypertension and afferent arteriole damage. Increasing doses of chronic L-Arg were associated with increasing excretion of urinary NO₂^–/NO₃^–, reduction of systemic hypertension, and prevention of cortical vasoconstriction (2.5% L-Arg). In addition, both doses prevented glomerular hypertension and preglomerular arteriolopathy. Thus an acute relief of renal vasoconstriction in the setting of afferent arteriole damage cannot reverse glomerular hypertension, likely due to impairment in preglomerular autoregulation. On the other hand, chronic L-Arg preserved arteriolar structures probably mediated by the antiproliferative effect of NO on vascular smooth muscle cells.

endothelial dysfunction; renal cortical vasoconstriction; glomerular hypertension; arteriolopathy

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