Dopamine D(3) receptors and salt-dependent hypertension.
Alterations in the dopaminergic system may contribute to the pathogenesis of hypertension. Dopamine D(3) receptors have been shown to be involved in the regulation of sodium balance and hemodynamics in rodents. For determining the role of D(3) receptors in salt-dependent hypertension, clearance experiments were performed in anesthetized salt-sensitive (DS) and salt-resistant (DR) Dahl rats that were fed a standard diet with either normal (0.2%) or high (4%) sodium content for 21 to 26 d, which induced hypertension in DS but not in DR rats. The D(3) receptor agonist R(+)-7-hydroxydipropyl-aminotetralin (7-OH-DPAT) increased GFR by up to 35% and urinary sodium excretion by up to 4.4-fold in DR rats that were on both normal and high-sodium diet. 7-OH-DPAT-induced natriuresis also was observed in DS rats that were on normal diet but not in hypertensive DS rats that were on high-salt diet. No GFR response to 7-OH-DPAT was found in DS rats, irrespective of sodium diet. The diminished functional response to D(3) receptor stimulation in DS rats was associated with a significantly lower [(3)H]-7-OH-DPAT binding to renal membrane protein when comparing DS with DR rats. Consequently, DR rats were treated with BSF 135170, a novel, highly selective D(3) receptor antagonist, for 29 d. Whereas no change in systolic BP was observed during normal diet, high sodium intake significantly increased BP by almost 40 mmHg. In summary, both expression and function of the renal dopamine D(3) receptor are impaired in salt-sensitive Dahl rats. Together with the induction of salt-dependent hypertension in genetically salt-resistant Dahl rats by D(3) receptor blockade, the data strongly suggest that the deficiency in dopamine D(3) receptors represents an important pathophysiological factor in the development of salt-dependent hypertension.
Luippold
Gerd
G
Department of Pharmacology, University of Tübingen, Tübingen, Germany.
Zimmermann
Claudia
C
Department of Pharmacology, University of Tübingen, Tübingen, Germany.
Mai
Matthias
M
Department of Pharmacology, University of Tübingen, Tübingen, Germany.
Kloor
Doris
D
Department of Pharmacology, University of Tübingen, Tübingen, Germany.
Starck
Dorothea
D
Department of Pharmacology, Knoll AG, Ludwigshafen, Germany.
Gross
Gerhard
G
Department of Pharmacology, Knoll AG, Ludwigshafen, Germany.
Mühlbauer
Bernd
B
Department of Pharmacology, University of Tübingen, Tübingen, Germany.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004032:Diet; D018491:Dopamine Agonists / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D051381:Rats; D020303:Rats, Inbred Dahl; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D050637:Receptors, Dopamine D3; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology
D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D008565:Membrane Proteins; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; D012965:Sodium Chloride; C031349:7-hydroxy-2-N,N-dipropylaminotetralin