Dopamine (DA), an intrarenal natriuretic hormone in normotensive animals, decreases Na+ transport indirectly through hemodynamic mechanisms and directly by inhibiting Na+ transport in the proximal convoluted tubule (PCT) and in the distal nephron (medullary thick ascending limb of Henle (mTAL), cortical collecting duct, CCD). DA1 receptors linked to the activation of adenylate cyclase (AC) inhibit NA+/H+ antiport at brush border membranes of PCT. They also stimulate phospholipase C (PLC) activity and inhibit Na+/K+ ATPase activity at basolateral membranes. We hypothesize that defects in the renal tubular dopaminergic system are important mechanisms in the Na+ retention of the young hypertensive animal. (After hypertension is established, compensatory mechanisms, e.g. pressure natriuresis, may override and mask this dopaminergic defect). The DA1 abnormalities in hypertension include defective renal DA1 receptor/or signal transduction, leading to a diminished AC stimulation. Since the DA1 mechanism is defective, DA via alpha and beta adrenoceptors may stimulate rather than inhibit Na+/K+ ATPase activity. The net result is an increase in renal Na+ reabsorption. Chronic suppression of DA synthesis outside the central nervous system causes Na+ retention and induces hypertension in normotensive rats. DA1 blockade will have similar effects. In hypertensive rats where renal DA1 activity is impaired, DA1 inhibition will accelerate the development of hypertension by alterations in systemic vascular resistance (including the kidney); renal Na+ retention will also occur. These effects are increased by NaCl intake. The increased renal nerve activity in hypertension may dampen renal dopaminergic effects.
The specific aims are: I. To determine the effect of chronic suppression of DA activity on renal DA1 receptors, second messengers, water, Na+ and K+ balance, renal function, and blood pressure. DA1 receptors, AC, Na+/K+ATPase, PLC and protein kinase C activities will be measured in proximal tubular cells (brush border and basolateral membranes) and distal tubular cells. Transport effects will be measured by amiloride sensitive 22Na+ uptake in proximal tubular brush border membrane vesicles and ouabain inhibitable 86Rb uptake in proximal and distal tubular cells. In addition, effects on total renal function, renal and systemic vascular resistances will be studied. Two approaches will be used: a) selective DA1 blockade and b) decreased DA synthesis. II. To determine the effect of the chronic elevation of renal DA by the chronic administration of a DA prodrug, gludopa on DA1 receptors, second messengers, water, Na+ and K+ balance, renal function, and blood pressure. The variables to be measured will be the same as those described in Protocol I. III. To determine the interaction between DA and renal nerves. The acute renal effects of DA agonists and antagonists will be compared in innervated and chronically denervated kidneys. In addition, DA1 receptors, AC, and Na+/K+ ATPase activity will be measured in PCT, mTAL and CCD. These studies should lead to a better understanding of the role of DA in the control of renal Na+ handling and blood pressure.
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