Renal D3 dopamine receptor stimulation induces natriuresis by endothelin B receptor interactions

Abstract

Dopaminergic and endothelin systems participate in the control blood pressure by regulating sodium transport in the renal proximal tubule. Disruption of either the endothelin B receptor (ETB) or D(3) dopamine receptor gene in mice produces hypertension. To examine whether these two receptors interact we studied the Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats by selectively infusing reagents into the right kidney of anesthetized rats. The D(3) receptor agonist (PD128907) caused natriuresis in WKY rats which was partially blocked by the ETB receptor antagonist. In contrast, PD128907 blunted sodium excretion in the SHRs. We found using laser confocal microscopy that the ETB receptor was mainly located in the cell membrane in control WKY cells. Treatment with the D(3) receptor antagonist caused its internalization into intracellular compartments that contained the D(3) receptors. Combined use of D(3) and ETB antagonists failed to internalize ETB receptors in cells from WKY rats. In contrast in SHR cells, ETB receptors were found mainly in internal compartments under basal condition and thus were likely prevented from interacting with the agonist-stimulated, membrane-bound D(3) receptors. Our studies suggest that D(3) receptors physically interact with proximal tubule ETB receptors and that the blunted natriuretic effect of dopamine in SHRs may be explained, in part, by abnormal D(3)/ETB receptor interactions.

Dopamine D3 Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

“…At 9 mg/kg, the same dog had plasma levels that were similar to those of the other dogs at the 9 mg/kg dose. cells (Zeng et al, 2008;Yu et al, 2009). Recent evidence suggests dopamine D 3 receptor activation in the kidneys ultimately stimulates secretion of a sodium load (to reduce hypertension) by promoting degradation of the Na 1 -H 1 exchanger in renal proximal tubules (Armando et al, 2014).…”

Regulation of Blood Pressure and Salt Homeostasis by Endothelin

“…Using HEK293 cells, Evans and Walker found that ET A and ET B heterodimerized though a PDZ finger; mutation of the PDZ domain caused delayed ET receptor internalization and a prolonged increase in [Ca 2+ ] i in response to ET-1, raising the possibility that ET A /ET B heterodimerization affects receptor function (187). In addition, ET B may heterodimerize with receptors other than ET A , including the dopamine D3 and the angiotensin II (ANG II) AT 1 receptors (871, 872). No definitive evidence exists for a physiological role of such heterodimers or whether they actually exist in vivo; resolution of this issue has obvious biologic relevance as well as being important in interpreting studies using purportedly specific ET receptor isoform agonist or antagonists.…”

Impaired Stimulatory Effect of ETB Receptor on D₃ Receptor in Immortalized Renal Proximal Tubule Cells of Spontaneously Hypertensive Rats

“…Our previous studies found that activation of renal D 3 receptor induces natriuresis and diuresis in WKY rats; in the presence of ETB receptor antagonist, the natriuretic effect of D 3 receptor is reduced [17] . The mechanisms underlying the D 3 and ETB receptor interaction are not known.…”