The pathogenesis and maintenance of some forms of hypertension may be due to an abnormality of the renal dopaminergic system. The renal dopaminergic abnormality which leads to sodium retention may be due to at least two possible mechanisms: 1) there may be an abnormality in renal natriuretic D-1 receptor or renal antinatriuretic D-2 receptor in the kidneys of SHR; 2) the second abnormality may be due to decreased renal production of dopamine leading to sodium retention and hypertension. The reported defects in central dopaminergic control of blood pressure may not be the cause of the elevation in blood pressure but rather compensatory mechanisms. Direct studies of dopaminergic functions in the anterior and intermediate lobe of the pituitary gland suggest an increased rather than a decreased dopaminergic activity in SHR. (Previous studies of """"""""central"""""""" dopaminergic activity have relied on measurements of serum prolactin). We propose to study SHR of varying ages before and after the onset of hypertension and their normotensive Wistar Kyoto (WKY) controls, and another hypertensive model, the Dahl salt sensitive rat (DSS) and its control, the Dahl salt resistant rat (DRR). Central dopaminergic activity will be directly assessed by measuring dopamine levels, prolactin content, and biosynthesis, POMC biosynthesis and MSH under basal conditions and in response to the D-2 agonist bromocryptine. Dopamine receptors will be characterized and adenylate cyclase activity measured in both the SHR and WKY in the following tissues: intermediate lobe, anterior lobe, striatum, renal cortical tubules, medullary tubules, and glomeruli. Adenylate cyclase activity will be measured in the basal and stimulated state. In SHR and WKY as well as the alternate model, DSS and DRR, the effects of salt intake on the renal tubular and glomerular receptors, plasma urinary and renal catecholamine and serum prolactin levels will be measured. In some of the studies the effect of normalization of blood pressure on the above variables will also be determined. Finally, the effects of dopamine-1 or dopamine-2 agonists and blockers on renal sodium excretion will be determined in the unilaterally denervated model. By profiling brain activity and renal activity of dopamine receptors and correlating this with peripheral dopamine, norepinephrine and epinephrine levels in two different models of hypertension, it should be possible to sort out cause and effect and glean additional insights into the essential role of dopamine in hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033498-05
Application #
3345448
Study Section
(SRC)
Project Start
1984-09-30
Project End
1989-09-29
Budget Start
1988-09-30
Budget End
1989-09-29
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Felder, R A; Seikaly, M G; Cody, P et al. (1990) Attenuated renal response to dopaminergic drugs in spontaneously hypertensive rats. Hypertension 15:560-9
Kinoshita, S; Ohlstein, E H; Felder, R A (1990) Dopamine-1 receptors in rat proximal convoluted tubule: regulation by intrarenal dopamine. Am J Physiol 258:F1068-74
Felder, C C; McKelvey, A M; Gitler, M S et al. (1989) Dopamine receptor subtypes in renal brush border and basolateral membranes. Kidney Int 36:183-93
Felder, R A; Felder, C C; Eisner, G M et al. (1989) The dopamine receptor in adult and maturing kidney. Am J Physiol 257:F315-27
Felder, C C; Blecher, M; Jose, P A (1989) Dopamine-1-mediated stimulation of phospholipase C activity in rat renal cortical membranes. J Biol Chem 264:8739-45
Kinter, M; Singh, S; Felder, R A (1989) Quantitation of selective dopaminergic drugs in plasma by gas chromatography-mass spectrometry following solid-phase extraction. J Chromatogr 496:201-8
Kinoshita, S; Sidhu, A; Felder, R A (1989) Defective dopamine-1 receptor adenylate cyclase coupling in the proximal convoluted tubule from the spontaneously hypertensive rat. J Clin Invest 84:1849-56
Felder, R A; Garland, D S (1989) POMC biosynthesis in the intermediate lobe of the spontaneously hypertensive rat. Am J Hypertens 2:618-24
Felder, R A; Robillard, J; Eisner, G M et al. (1989) Role of endogenous dopamine on renal sodium excretion. Semin Nephrol 9:91-3
Jose, P A; Holloway, R R; Campbell, T W et al. (1988) Dopamine blockade attenuates the natriuresis of saline loading in the adrenalectomized rat. Nephron 48:54-7

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