Selective inhibition of the renal dopamine subtype D(1a) receptor induces antinatriuresis in conscious rats

Abstract

Both dopamine D1-like (D(1A) and D(1B)) and D2-like (D2, D3, and D4) receptor subfamilies are present in the kidney. Blockade of the intrarenal D1-like receptor family is associated with natriuresis and diuresis. Because the D(1A) and D(1B) receptor subtypes are not distinguishable by currently available dopaminergic agents, their functional role remains undefined. In the present study, the effect of selective inhibition of the renal D(1A) receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) was investigated in conscious uninephrectomized rats. After renal interstitial administration of Texas red-labeled D(1A) receptor AS-ODN, intense fluorescent signal was localized in the renal tubular epithelium and vasculature. In rats on normal salt intake, AS-ODN injected interstitially into the kidney reduced daily urinary sodium excretion (1.4±0.04 versus 0.8±0.2 mEq/d, n=5, P<0.05) and urine output (16.9±3.8 versus 12.5±3.6 mL/d, n=5, P<0.05). In rats on high sodium intake, continuous renal interstitial administration of D(1A) receptor AS- ODN transiently decreased daily urinary sodium excretion (5.4±0.5 versus 4.2±0.3 mEq/d, n=7, P<0.01) and urine output (27.6±4.5 versus 18.1±1.8 mL/d, n=7, P<0.01). Neither vehicle nor sense oligodeoxynucleotide had significant effects. Systolic blood pressure remained unchanged. The renal D(1A) receptor protein was significantly decreased by 35% and 46% at the end of the study in AS-ODN-treated rats on normal and high salt intake, respectively, whereas the D(1B) receptor and β-actin were not affected. These results provide the first direct evidence that the renal D(1A) receptor subtype plays an important role in the control of sodium excretion.