OXIDATIVE STRESS INDUCED RENAL D1 RECEPTOR DYSFUNCTION CAUSES SALT SENSITIVE HYPERTENSION IN SPRAGUE DAWLEY RATS

Abstract

Renal dopamine, via activation of D1 receptors plays a role in maintaining sodium homeostasis and blood pressure during increased sodium intake. Animal models of Salt sensitive hypertension are associated with defective renal D1 receptor function and increased oxidative stress. The objective of the present study was to determine whether oxidative stress associated with high salt intake will produce hypertension resulting from defective renal D1 receptor function. Male Sprague Dawley rats were divided into four groups and received tap water (vehicle), 30mM L-buthionine sulfoximine (BSO), an oxidant, 1% NaCl (high salt), and BSO plus NaCl in drinking water for ten days. Compared to vehicle, BSO treatment caused elevated levels of renal tubular malondialdehyde, reduced levels of glutathione, increased urinary excretion of 8-isoprostane and decreased D1 receptor numbers and coupling to G proteins. Furthermore, SKF-38393, a D1 receptor agonist, failed to inhibit Na, K-ATPase in proximal tubules and was unable to promote sodium excretion. Animals provided with high salt alone did not show any increase in oxidative stress or defect in D1 receptor function. Concomitant administration of BSO and high salt caused significant increase in renal tubular oxidative stress, abrogation of D1 receptor function and showed marked decrease in basal sodium excretion and significant increase in blood pressure. It appears that during high salt intake oxidative stress induced D1 receptor dysfunction leads to salt retention and hypertension. These phenomena may explain, in part, the mechanism for salt sensitive hypertension associated with oxidative stress. [Supported in part by NIH grant DK-58743]