A renal dopamine-1 receptor defect in two genetic models of hypertension

R. A. Felder, S. Kinoshita, A. Sidhu, K. Ohbu, Frederick J. Kaskel

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Abstract

Dopamine (DA), via DA-1 receptors, regulates Na+ transport in the kidneys. Dopamine is synthesized from L-DOPA in the proximal tubule and presumably secreted as an autocrine/paracrine substance to stimulate DA-1 receptors localized on proximal tubular cells. We have previously reported the presence of DA-1 receptors in renal cortical homogenates and on the isolated proximal tubule of the rat and rabbit, consistent with the dopamine autocrine/paracrine model. We have localized DA-1 receptors in the proximal straight tubule of the rabbit, and in the cortical collecting duct of the rabbit and rat, but not in the distal collecting tubule or the cortical thick ascending loop of Henle. The presence of functional DA-1 receptors has been substantiated by the coexistence of DA-1 agonist-stimulated adenylate cyclase activity in the same nephron segments in which DA-1 receptors have been found. Increased concentrations of intrarenal dopamine induced by dopamine-β-hydroxylase inhibition with SKF-102698 caused a down regulation of proximal tubular DA-1 receptors and almost complete ablation of DA-1 agonist stimulated adenylate cyclase activity. Thus, dopamine may play a role in the regulation of DA-1 receptors and their linkage with adenylate cyclase. Since alterations in the renal dopaminergic system have been measured in some forms of experimental hypertension, we studied DA-1 receptors and their coupling to adenylate cyclase in the spontaneously hypertensive rat (SHR). In the face of effective parathormone, guanadine triphosphate, Gpp(NH)p (the nonhydrolyzable analog of GTP) and forskolin stimulated adenylate cyclase activity in the proximal convoluted tubule, SHR demonstrated a defective DA-1 stimulated adenylate cyclase activity when compared to the normotensive Wistar-Kyoto (WKY) control. DA-1 agonist but not antagonist binding to the SHR proximal convoluted tubule was found to be reduced when compared to WKY in both membrane bound receptors and solubilized receptors reconstituted into phospholipid vesicles. Furthermore, polyacrylamide gel electrophoresis of the photoaffinity labelled DA-1 receptor in the SHR showed a difference in the region of 50 kDa when compared to the WKY. Defective proximal tubular DA-1 receptors are not unique to the SHR model of hypertension since a similar defect was measured in the Dahl Salt Sensitive rat (DSS). The abnormal DA-1 receptor is not a consequence of high blood pressure because DA-1 adenylate cyclase coupling defects were found in SHR as early as 3 to 4 weeks of age. These biochemical data may explain the decreased natriuretic effect of DA-1 agonists in the SHR.

Original languageEnglish (US)
JournalAmerican Journal of Hypertension
Volume3
Issue number6 II SUPPL.
StatePublished - 1990
Externally publishedYes

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Genetic Models
Dopamine Receptors
Hypertension
Kidney
Inbred SHR Rats
Adenylyl Cyclases
Dopamine
Dopamine Agonists
Rabbits
Inbred Dahl Rats
Guanylyl Imidodiphosphate
Natriuretic Agents
Loop of Henle
Nephrons
Colforsin
Mixed Function Oxygenases
Guanosine Triphosphate
Parathyroid Hormone
Polyacrylamide Gel Electrophoresis
Phospholipids

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A renal dopamine-1 receptor defect in two genetic models of hypertension. / Felder, R. A.; Kinoshita, S.; Sidhu, A.; Ohbu, K.; Kaskel, Frederick J.

In: American Journal of Hypertension, Vol. 3, No. 6 II SUPPL., 1990.

Research output: Contribution to journalArticle

Felder, RA, Kinoshita, S, Sidhu, A, Ohbu, K & Kaskel, FJ 1990, 'A renal dopamine-1 receptor defect in two genetic models of hypertension', American Journal of Hypertension, vol. 3, no. 6 II SUPPL..
Felder, R. A. ; Kinoshita, S. ; Sidhu, A. ; Ohbu, K. ; Kaskel, Frederick J. / A renal dopamine-1 receptor defect in two genetic models of hypertension. In: American Journal of Hypertension. 1990 ; Vol. 3, No. 6 II SUPPL.
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AU - Kinoshita, S.

AU - Sidhu, A.

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AU - Kaskel, Frederick J.

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N2 - Dopamine (DA), via DA-1 receptors, regulates Na+ transport in the kidneys. Dopamine is synthesized from L-DOPA in the proximal tubule and presumably secreted as an autocrine/paracrine substance to stimulate DA-1 receptors localized on proximal tubular cells. We have previously reported the presence of DA-1 receptors in renal cortical homogenates and on the isolated proximal tubule of the rat and rabbit, consistent with the dopamine autocrine/paracrine model. We have localized DA-1 receptors in the proximal straight tubule of the rabbit, and in the cortical collecting duct of the rabbit and rat, but not in the distal collecting tubule or the cortical thick ascending loop of Henle. The presence of functional DA-1 receptors has been substantiated by the coexistence of DA-1 agonist-stimulated adenylate cyclase activity in the same nephron segments in which DA-1 receptors have been found. Increased concentrations of intrarenal dopamine induced by dopamine-β-hydroxylase inhibition with SKF-102698 caused a down regulation of proximal tubular DA-1 receptors and almost complete ablation of DA-1 agonist stimulated adenylate cyclase activity. Thus, dopamine may play a role in the regulation of DA-1 receptors and their linkage with adenylate cyclase. Since alterations in the renal dopaminergic system have been measured in some forms of experimental hypertension, we studied DA-1 receptors and their coupling to adenylate cyclase in the spontaneously hypertensive rat (SHR). In the face of effective parathormone, guanadine triphosphate, Gpp(NH)p (the nonhydrolyzable analog of GTP) and forskolin stimulated adenylate cyclase activity in the proximal convoluted tubule, SHR demonstrated a defective DA-1 stimulated adenylate cyclase activity when compared to the normotensive Wistar-Kyoto (WKY) control. DA-1 agonist but not antagonist binding to the SHR proximal convoluted tubule was found to be reduced when compared to WKY in both membrane bound receptors and solubilized receptors reconstituted into phospholipid vesicles. Furthermore, polyacrylamide gel electrophoresis of the photoaffinity labelled DA-1 receptor in the SHR showed a difference in the region of 50 kDa when compared to the WKY. Defective proximal tubular DA-1 receptors are not unique to the SHR model of hypertension since a similar defect was measured in the Dahl Salt Sensitive rat (DSS). The abnormal DA-1 receptor is not a consequence of high blood pressure because DA-1 adenylate cyclase coupling defects were found in SHR as early as 3 to 4 weeks of age. These biochemical data may explain the decreased natriuretic effect of DA-1 agonists in the SHR.

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