Defective renal dopamine D1-like receptor signal transduction in obese hypertensive rats.
It is reported that dopamine promotes renal sodium excretion via activation of D1-like dopamine receptors located on the proximal tubules. In spontaneously hypertensive rats the natriuretic and diuretic response to exogenously administered and endogenously produced dopamine is reduced, which results from a diminished dopamine-induced inhibition of the enzyme, Na+,K+-ATPase. The present study was designed to examine dopamine-receptor mediated inhibition of Na+,K+-ATPase and its associated signal transduction pathway in the proximal tubules of Zucker obese and lean control rats. The obese animals were hypertensive, hyperinsulinaemic and hyperglycaemic compared with the lean rats. While dopamine caused inhibition of Na+,K+-ATPase activity in lean rats, this effect was significantly attenuated in the obese animals. There was significant reduction in D1-like receptor numbers in the basolateral membranes of obese rats compared with lean rats with no change in the affinity to the ligand [3H]SCH 23390 between the two groups of rats. Dopamine failed to stimulate G proteins as measured by [35S]GTPgammaS binding in the obese rats. Also, dopamine was unable to cause phospholipase-C activation in obese rats, but it did activate phospholipase-C in lean rats. These results show that reduction in D1-like receptor numbers and a defect in receptor-G protein coupling may account for the inability of dopamine to activate the D1-like receptor-coupled signal transduction pathway and cause inhibition of Na+,K+-ATPase in the obese hypertensive rats.
Lokhandwala
M F
MF
Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Houston 77204-5511, USA.
Hussain
T
T
D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000378:metabolism / Q000502:physiology*; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015544:Inositol 1,4,5-Trisphosphate; D000254:Sodium-Potassium-Exchanging ATPase