Aberrant D1 and D3 dopamine receptor transregulation in hypertension.
Dopamine plays a role in the regulation of blood pressure by inhibition of sodium transport in renal proximal tubules (RPTs) and relaxation of vascular smooth muscles. Because dopamine receptors can regulate and interact with each other, we studied the interaction of D(1) and D(3) receptors in immortalized RPT cells and mesenteric arteries from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), and in human coronary artery smooth muscle cells (CASMCs). In WKY rats, the D(1)-like agonist, fenoldopam, increased D(3) receptor protein in a time-dependent and concentration-dependent manner (EC(50)=4.5x10(-9) M, t(1/2)=15.8 hours). In SHRs, fenoldopam (10(-5) M) actually decreased the expression of D(3) receptors. D(1) and D(3) receptor co-immunoprecipitation was increased by fenoldopam (10(-7) M/24 h) in WKY rats but not in SHRs. The effects of fenoldopam in CASMCs were similar as those in WKY RPT cells (ie, fenoldopam increased D(1) and D(3) receptor proteins). Both D(3) (PD128907, Emax=80%+/-6%, pED(50)=5+/-0.1) and D(1)-like receptor (fenoldopam, Emax=81%+/-8%, pED(50)=5+/-0.2, n=12) agonists relaxed mesenteric arterial rings. Co-stimulation of D(1) and D(3) receptors led to additive vasorelaxation in WKY rats, but not in SHRs. D(1) and D(3) receptors interact differently in WKY and SHRs. Altered interactions between D(1) and D(3) receptors may play a role in the pathogenesis of genetic hypertension, including human hypertension, because these receptors also interact in human vascular smooth muscle cells.
Zeng
Chunyu
C
Department of Pediatrics, PHC-2, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, DC 20007, USA. cyzeng1@hotmail.com
Wang
Dan
D
Asico
Laureano D
LD
Welch
William J
WJ
Wilcox
Christopher S
CS
Hopfer
Ulrich
U
Eisner
Gilbert M
GM
Felder
Robin A
RA
Jose
Pedro A
PA
D000818:Animals; D002460:Cell Line; D003331:Coronary Vessels / Q000166:cytology; D018491:Dopamine Agonists / Q000494:pharmacology; D018818:Fenoldopam / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D011233:Precipitin Tests; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D014664:Vasodilation
C493593:DRD3 protein, human; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D018818:Fenoldopam