Bromocriptine regulates angiotensin II response on sodium pump in proximal tubules.
-Dopamine and angiotensin II (Ang II) receptors have been reported to exhibit an interaction in renal proximal tubules. The present study was designed to investigate the regulation by a D2-like dopamine receptor of Ang II-mediated stimulation of Na,K-ATPase activity in the renal proximal tubules. Ang II (10(-13) to 10(-9) mol/L) stimulated Na,K-ATPase activity in the proximal tubules that was completely abolished when the tubules were pretreated with the D2-like receptor agonist bromocriptine (1 micromol/L) for 30 minutes. The effect of bromocriptine on Ang II response was prevented by domperidone (1 micromol/L), a D2-like dopamine receptor antagonist. Similarly, the inhibition of forskolin (1 micromol/L)-induced cAMP accumulation caused by Ang II (10 pmol/L) was also abolished in bromocriptine-pretreated tubules. Basal and forskolin-stimulated cAMP was not significantly different in bromocriptine-treated tubules compared with the control. [3H]-Ang II binding sites (angiotensin type 1 [AT1] receptors) were reduced by approximately 65% in bromocriptine-treated proximal tubules, a result that was further substantiated by Western blot analysis revealing a 50% decrease in AT1 receptors in bromocriptine-treated tubules compared with the control. Western blot analysis of G proteins revealed a 2-fold increase in Gsalpha and a 20% decrease in Gialpha1 and Gialpha2 in the bromocriptine-treated proximal tubules. Bromocriptine (1 micromol/L) alone stimulated Na,K-ATPase activity during the first 30 minutes of incubation, and thereafter the stimulation fell to the basal level. Similarly, bromocriptine-mediated inhibition of cAMP lasted only up to 20 minutes. The data suggest that preactivation of D2-like dopamine receptors abolishes Ang II-mediated stimulation of Na,K-ATPase activity and inhibition of cAMP accumulation. This phenomenon may be a consequence of a decrease in AT1 receptors and alterations in G protein levels in the proximal tubules. We propose that such a regulation of Ang II response by bromocriptine is the result of heterologous desensitization of the D2-like receptor system.
Hussain
T
T
Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Houston, Tex 77204-5511, USA.
Abdul-Wahab
R
R
Kotak
D K
DK
Lokhandwala
M F
MF
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D015259:Dopamine Agents / Q000494:pharmacology*; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000032:analysis; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000032:analysis; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D015259:Dopamine Agents; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D001971:Bromocriptine; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase