Selective Inhibition of the Renal Dopamine Subtype D 1A Receptor Induces Antinatriuresis in Conscious Rats

Abstract

Abstract —Both dopamine D 1 -like (D 1A and D 1B ) and D 2 -like (D 2 , D 3 , and D 4 ) receptor subfamilies are present in the kidney. Blockade of the intrarenal D 1 -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.