DOPAMINERGIC SYSTEMS IN HYPERTENSIVE

Georgetown University, Washington DC

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Abstract

DESCRIPTION (verbatim from the application): In kidney, dopamine (DA) and Dl DA receptors regulate sodium excretion. The spontaneously hypertensive rat, SHR, and the DOCA- (deoxycorticosone acetate) salt rats are established animal models of hypertension. We have shown that Dl DA receptors in SHR are dysfunctional, being unable to couple to the G protein effector systems. The goal of this study is to analyze the linkage between oxidative stress, Dl DA receptors and hypertension in both SHR and the DOCA-salt rat models of hypertension. We have found increased oxidative stress in SHR kidney, compared to the normotensive rats, the Wistar-Kyoto (WKY) rat and Sprague-Dawley. Lipid peroxidation (LP) is increased, with release of toxic aldehydic products. One of these products, 4-hydroxynonenal, can directly modulate Dl DA receptors in WKY rat proximal tubule (PT) membranes, leading to loss of receptor coupling and function. Thus, increased oxidative stress and LP may be an important means by which the Dl DA receptor becomes dysfunctional. Other imbalances in the redox state of SHR PTs and kidney include: both elevated and depressed levels of nitric oxide synthase isoforms, increased NO production, depressed glutathione peroxidase activity and increased expression of Cu-Zn-superoxide dismutase and catalase. Using isolated tissues from SHR and DOCA-salt rat, and from their normotensive controls, we will analyze in detail the nature of the alterations in the redox state of the kidney from these animals, and will study the underlying mechanisms in PT cell culture systems. We will treat the SHR with different blockers of the renin-angiotensin system (RAS), which normalizes blood pressure, and will examine the effects of these blockers on the various indices of oxidative stress (LP, antioxidant enzymes, nitrite production and nitric oxide synthase levels). It is likely that RAS blockers will normalize the redox state of the SHR kidney, and that upon such normalization, Dl DA receptor function may also be normalized, restoring the ability of DA and the Dl DA receptors to excrete sodium.