title: Dopamine D3 receptor-mediated inhibition of Na+/H+ exchanger activity in normotensive and spontaneously hypertensive rat proximal tubular epithelial cells.
abstract: This study evaluated the response of the Na(+)/H(+) exchanger (NHE) to dopamine D(1)- and D(2)-like receptor stimulation in immortalized renal proximal tubular epithelial cells and freshly isolated renal proximal tubules from the spontaneously hypertensive rat (SHR) and their normotensive controls (Wistar Kyoto rats; WKY). Stimulation of D(1)-like receptors with SKF 38393 attenuated NHE activity in WKY cells (IC(50)=151 nM), but not in SHR cells. Stimulation of D(2)-like receptors with quinerolane (IC(50)=120 nM) attenuated NHE activity in SHR cells, but not in WKY cells. Forskolin was equipotent in SHR and WKY cells in inhibiting NHE activity. The effect of SKF 38393 was abolished by overnight treatment of WKY cells with cholera toxin (CTX, 500 ng ml(-1)), but not with pertussis toxin (PTX, 100 ng ml(-1)). The effect of quinerolane (1 microm) was abolished by overnight treatment of SHR cells with PTX, but not with CTX. The D(3) receptor agonist 7-OH-DPAT (IC(50)=0.8 microM) attenuated NHE activity in SHR cells only. This effect was abolished by S-sulpiride and by overnight treatment with PTX. The D(4) receptor agonist RBI 257 did not affect NHE activity. The 7-OH-DPAT inhibited NHE activity in freshly isolated renal proximal tubules from 4- and 12-week-old SHR and 12-week-old WKY, but not in freshly isolated renal proximal tubules from 4-week-old WKY. It is concluded that D(3) receptors coupled to a G(i/o) protein play a role in the handling of tubular Na(+), namely through inhibition of the NHE activity, this being of particular relevance in the SHR, which fail to respond to D(1)-like dopamine receptor stimulation.
authors.affiliation: Institute of Pharmacology and Therapeutics, Faculty of Medicine, Porto 4200-319, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Pedrosa
authors.forename: Pedro
authors.initials: P
authors.lastname: Gomes
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hopfer
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004298:Dopamine / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D050637:Receptors, Dopamine D3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D004298:Dopamine; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017923:Sodium-Hydrogen Exchangers; C493595:Drd3 protein, rat; C044846:SKF83566