Selective inhibition of the renal dopamine subtype D-1A receptor induces antinatriuresis in conscious rats

Both dopamine D-1-like (D-1A and D-1B) and D-2-like (D-2, D-3, and D-4) rec eptor 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 av ailable dopaminergic agents, their functional role remains undefined. In th e present study, the effect of selective inhibition of the renal D-1A recep tor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) was inve stigated in conscious uninephrectomized rats. After renal interstitial admi nistration of Texas red-labeled D-1A receptor AS-ODN, intense fluorescent s ignal was localized in the renal tubular epithelium and vasculature. In rat s on normal salt intake, AS-ODN injected interstitially into the kidney red uced 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 administrati on of D,, receptor AS-ODN transiently decreased daily urinary sodium excret ion (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 oligo deoxynucleotide had significant effects. Systolic blood pressure remained u nchanged. 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 beta-actin were n ot affected. These results provide the first direct evidence that the renal D-1A receptor subtype plays an important role in the control of sodium exc retion.