Hyperuricemia Attenuates Aortic Nitric Oxide Generation, through Inhibition of Arginine Transport, in Rats

Abstract

Objectives: Hyperuricemia provokes endothelial dysfunction (ECD). Decreased endothelial nitric oxide synthase (eNOS) activity is an important source of ECD. Cationic amino acid transporter-1 (CAT-1) is the specific arginine transporter for eNOS. We hypothesize that hyperuricemia inhibits arginine uptake. Methods: Experiments were performed in freshly harvested aortas from untreated animals and rats fed with oxonic acid (hyperuricemia), and compared to hyperuricemic rats treated with either allopurinol, benzbromarone or arginine. Results: Arginine transport was significantly decreased in hyperuricemia. Benzbromarone and arginine prevented the decrease in arginine transport in hyperuricemic rats while allopurinol did not. Arginine transport was significantly decreased in control rats treated with allopurinol. Blood pressure response to acetylcholine was significantly attenuated in hyperuricemic rats, an effect which was prevented in all other experimental groups. L-NAME inhibitable cGMP response to carbamyl-choline was significantly decreased in hyperuricemic rats and this was completely prevented by both benzbromarone and arginine, while allopurinol partially prevented the aforementioned phenomenon. Hyperuricemia induced a significant increase in protein nitration that was prevented by benzbromarone, allopurinol, and arginine. Protein abundance of CAT-1, PKCα, and phosphorylated PKCα remained unchanged in all experimental groups. Conclusions: In hyperuricemia, the decrease in aortic eNOS activity is predominantly the result of attenuated arginine uptake.

Effect of rosuvastatin on hyperuricemic rats and the protective effect on endothelial dysfunction

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The Impact of Uric Acid on Long-term Mortality in Patients with Asymptomatic Carotid Atherosclerotic Disease

“…28 The entry of uric acid into cells is associated with a reduction in NO bioavailability, which leads to smooth muscle cell constriction. This effect of uric acid is caused by blocking the uptake of L-arginine, 29 stimulating the degradation of L-arginine through arginase, 30 and by the direct inactivation of NO through uric acid itself. 31 In this context, increased levels of SUA have been shown to cause arteriolar vasoconstriction and glomerular hypertension in rats.…”

The role of uric acid in the pathogenesis of human cardiovascular disease

“…While the antioxidant effects of uric acid can protect endothelial cells from external oxidative stress, most studies show that the entry of uric acid into cells is associated with a reduction in NO bioavailability via a variety of mechanisms, including by blocking uptake of L-arginine,109 stimulating L-arginine degradation via arginase,110 and by scavenging of NO from uric acid-generated oxidants100 or by uric acid itself 95. Endothelial dysfunction, as noted by a reduction in NO metabolites, has also been shown in the hyperuricaemic rat, and early supplementation of L-arginine can block the systemic hypertension and renal haemodynamic effects in this model 31 111.…”