This project focuses on the role of dopamine (DA) and DA1 receptors in the control of renal tubular Na+ transport in hypertension. Abnormalities in the kidney are important factors in the pathogenesis and/or maintenance of elevated blood pressure in various animal models of hypertension. The young spontaneously hypertensive rat (SHR) has increased Na+ reabsorption, elevated renal concentrations of DA, and a decreased natriuretic response to exogenous and endogenous DA. The Dahl Salt Sensitive rat (DSS), also has increased renal Na+ reabsorption, decreased renal DA concentration, a failure to mobilize renal DA in response to a Na+ load, and an stimulation rather than inhibition of renal Na+/K+ATPase activity when compared to the Dahl Salt Resistant rat (DSR). Therefore the SHR and DSS represent two models of hypertension with different renal DA levels but with defective tubular DA1 effects. DA may act as an intrarenal natriuretic hormone. DA decreases Na+ transport in the proximal convoluted tubule (PCT) and in the cortical collecting duct (CCD). However, the mechanism for the natriuretic properties of DA and its possible role in hypertension remain to be determined. We hypothesize that our recently discovered defect in the tubular dopaminergic system is an important mechanism for the increased Na+ retention in hypertension. Furthermore, DA regulates Na+ flux by interaction through DA1 cell surface receptors linked to the activation of adenylate cyclase (AC) and inhibition of Na+/K+ATPase activity. We will study the renal tubular dopaminergic system (where DA1 receptors have been localized), by measuring the release of DA in PCT and proximal tubular cells, by characterization of DA1 cell surface receptors, linkage to an intracellular second messenger, and finally the effect of DA on proximal tubular Na+ transport. The consequences of these renal tubular dopaminergic defects can lead to hypertension. Salt loading accelerated the development of hypertension in SHR when peripheral synthesis of DA was inhibited. Whether these models of hypertension have human counterparts remains to be determined. A renal dopaminergic abnormality may not be unique to animal models of hypertension; derangements in the renal dopaminergic system have also been demonstrated in patients with essential hypertension. A subset of thee patients (the salt sensitive hypertensive which has normal basal urinary DA) do not increase urinary DA, retain sodium, and increase their blood pressure in response to a salt load. These experiments will focus mainly on the two animal models of hypertension, the spontaneously hypertensive rat of the Okamoto-Aoki strain and the Dahl salt sensitive rat and their normotensive controls.
