Defective renal dopamine D-1-like receptor signal transduction in obese hypertensive rats

It is reported that dopamine promotes renal sodium excretion via activation of D-1-like dopamine receptors located on the proximal tubules. In spontan eously hypertensive rats the natriuretic and diuretic response to exogenous ly administered and endogenously produced dopamine is reduced, which result s from a diminished dopamine-induced inhibition of the enzyme, Na+,K+-ATPas e. The present study was designed to examine dopamine-receptor mediated inh ibition of Na+,K+-ATPase and its associated signal transduction pathway in the proximal tubules of Zucker obese and lean control rats. The obese anima ls were hypertensive, hyperinsulinaemic and hyperglycaemic compared with th e lean rats. While dopamine caused inhibition of Na+,K+-ATPase activity in lean rats, this effect was significantly attenuated in the obese animals. T here was significant reduction in D-1-like receptor numbers in the basolate ral membranes of obese rats compared with lean rats with no change in the a ffinity to the ligand [H-3]SCH 23390 between the two groups of rats. Dopami ne failed to stimulate G proteins as measured by [S-35]GTP gamma S binding in the obese rats. Also, dopamine was unable to cause phospholipase-C activ ation in obese rats, but it did activate phospholipase-C in lean rats. Thes e results show that reduction in D-1-like receptor numbers and a defect in receptor-G protein coupling may account for the inability of dopamine to ac tivate the D-1-like receptor-coupled signal transduction pathway and cause inhibition of Na+,K+-ATPase in the obese hypertensive rats.