(Hypertension. 1999;34:1091-1096.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Defective Dopamine Receptor Function in Proximal Tubules of Obese Zucker Rats
From the Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Tex.
Correspondence to Tahir Hussain, PhD, Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Houston TX 77204-5515. E-mail THussain{at}jetson.uh.edu
Abstract—Some of the
pathophysiological consequences of obesity include
insulin resistance, increased renal sodium reabsorption, and the
development of hypertension. Dopamine promotes renal sodium excretion
via activation of D1-like receptors present on the
proximal tubules. Reduced dopamine-induced natriuresis and a defect in
D1-like receptor function have been reported in the
proximal tubules of hypertensive animals. The present study
investigated D1-like dopamine receptors and associated G
proteins as the initial signaling components in the proximal tubular
basolateral membranes of obese Zucker and control lean Zucker rats. We
found that the obese rats were hyperinsulinemic,
hyperglycemic, and hypertensive compared with the lean rats. Dopamine
produced concentration-dependent inhibition of Na,K-ATPase activity in
the proximal tubules of lean rats, whereas the inhibitory
effect of dopamine was reduced in obese rats. The D1-like
receptors measured by [3H]SCH 23390 binding revealed an
45% decrease in Bmax without a change in
Kd in the basolateral membranes of obese
rats compared with lean rats. Although we found an increase in
Gq/11
and no change in Gs in the
basolateral membranes of obese rats, dopamine and SKF 38393 failed to
stimulate G proteins as measured by [35S]GTP
S binding
in obese rats, suggesting a receptor–G protein coupling defect. We
conclude that decrease in D1-like dopamine receptor binding
sites and diminished activation of G proteins, resulting perhaps from
defective coupling, led to the reduced inhibition by dopamine of
Na,K-ATPase activity in the proximal tubules of obese Zucker rats. Such
a defect in renal dopamine receptor function may contribute to sodium
retention and development of hypertension in obese rats.
Key Words: kidney • sodium pump • hypertension, obesity • insulin resistance • obesity
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