Pergamon o3o6-~23(94)oo~-7 Gen. Pharmac. Vol. 26, No. 4, pp. 727-735, 1995 Copyright© 1995Elsevier ScienceLtd Printed in Great Britain.All rights reserved 0306-3623/95 $9.50+ 0.00 Chronic Manipulation of Dietary Salt Modulates Renal Physiology and Kidney Dopamine Receptor Subtypes: Functional and Autoradiographic Studies N. A. SHARIF,*t J. L. NUNES, K. D. LAKE, D. L. McCLELLAND, S. F. CORKINS, I. LAKATOS, R. P. ROSENKRANZ, R. L. WHITING and R. M. EGLEN Institute of Pharmacology, Syntex Discovery Research, Palo Alto, CA 94303, U.S.A. (Received 2 September 1994) Abstract--1. Compared to rats maintained on the normal NaCI (0.33%) diet, animals maintained on the low NaCI (0%) diet for 4 weeks exhibited increased plasma aldosterone and chloride and decreased urinary sodium excretion. 2. Rats maintained on the high NaCI (8%) diet for 4 weeks showed increased systolic blood pressure, water intake, urine volume, sodium and dopamine excretion and decreased plasma aldosterone and glomerular filtration rate. 3. Administration of SCH 23390 (10mg/kg, po), but not domperidone to the high salt diet rats attenuated the diuretic effect, indicating the involvement of DA~ rather than DA2 receptors. The dopamine decarboxylase inhibitor, carbidopa (30 mg/kg, i.p.), also reduced the high salt-induced diuresis. 4. Kidney sections from rats fed the low NaC1 diet showed a 63-100% decrease (P < 0.001-0.02) in cortical ~nd medullary DAt and DA2 binding sites, while rats fed the high NaCI diet demonstrated only a 70% decrease (P < 0.01-0.02) in cortical DA~ binding, without affecting DA2 binding. 5. These data indicate that chronic modification of dietary salt profoundly affects the sodium, water and dopamine excretion and leads to selective modulation of renal dopamine receptor subtypes. Key Words: Dopamine receptors, kidney, autoradiography, salt consumption INTRODUCTION Dopamine acts as an endogenous neurotransmitter in the mammalian central nervous system (CNS) and peripheral organs (Seeman, 1980; Goldberg and Kohli, 1983). At least five receptor subtyl~es, D~-D 5 encoded by five different genes, mediate the central actions of dopamine (see Gingrich and Caron, 1993; Sibley and Monsma, 1992 for reviews), while 2 subtypes, DA~ and DA2, are involved in the periphery (Lokhandwala and Hegde, 1990; Kohli et al., 1991; Brodde, 1990; Gingrich and Caron, 1993; Sibley and Monsma, 1992 for reviews). Disturbances in the dopaminergic transmission in the CNS are *To whom all correspondence should be addressed. tPresent address: Alcon Labs Inc. (R2-19), 6201 South FreeWay, Fort Worth, TX 76134, U.S.A. Tel: (817)5686115; Fax: (817)551 4584. responsible for many neurological and psychiatric disorders such as Parkinson's disease, Huntington's chorea, schizophrenia and drug-induced psychosis (Seeman, 1980; Gingrich and Caron, 1993; Sibley and Monsma, 1992). In addition, there is increasing evidence suggesting a CNS-mediated regulation of renal physiology (Wyss and Donovan, 1984; Morgunov and Baines, 1985; Huang et al., 1987, 1988; Lichardus et al., 1987; Hansell et al., 1988), blood pressure (Stumpe et al., 1977) and thirst (Fitzsimons and Settler, 1975). DAI and DA 2 receptors in peripheral tissues such as the vasculature, renal tubules, renal juxta- glomerular cells and adrenal cortex appear to mediate various effects including vasodilation, diuresis, natriuresis, stimulation of renin release, and inhibition of aldosterone release (Lokhandwala and Hegde, 1990; Brodde, 1990; Kohli et al., 1991; Lee, 727