Attenuated Renal Production of Dopamine in Patients with Low Renin Essential Hypertension

Aoki, Kanae; Kikuchi, Kenjiro; Yamaji, Izumi; Nishimura, Mitsuhiro; Honma, C; Kobayakawa, Hiroshi; Yamamoto, Motohisa; Kudoh, Chika; Shimazaki, M; Sakamoto, Takashi; Wada, Atsushi; Ito, Osamu

doi:10.3109/10641968909045447

Cited by 17 publications

(9 citation statements)

References 14 publications

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“…These EH patients were considered to be stable when their hypertension was consistently more than 160/95 mm Hg and their BP did not decrease (when medication had been stopped) to normotensive values after 4 days of bed rest. 3 They had been treated with all categories of antihypertensive drugs for up to 22 years. They stopped all medication at least 10 days (longer acting drugs, 3 weeks) before the examination.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have demonstrated an attenuated urinary dopamine response to salt in stable EH (s-EH) patients, 1 its probable cause suspected to be a deficient renal DOPA decarboxylation to dopamine. 2 This aspect was investigated by Aoki et al 3 in EH with an oral precursor load of DOPA in an attempt to at least partially reproduce patterns of defective renal dopamine generation from DOPA. However, the conclusions were based only on plasma DOPA and urinary dopamine measurements, without the determination of some intermediate steps between plasma DOPA and urinary dopamine, their respective metabolites, and blood pressure (BP) responses to exogenous DOPA.…”

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Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Küchel

Shigetomi

1992

Hypertension

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We studied the metabolic pathways of dihydroxyphenylalanine (DOPA) and dopamine as well as the cardiovascular and renal responses to a single administration of DOPA (500 mg orally) in stable essential hypertension. We found that after DOPA, stable hypertensive patients compared with controls showed more blood pressure decrease without reflex tachycardia, had lower creatinine clearance but a higher fractional excretion of sodium, and had lower plasma renin activity at the height of DOPA action. Hypertensive patients also showed increased plasma DOPA, the ratio of plasma DOPA to dopamine, and the sum of plasma DOPA and 3-O-methyl-DOPA, as well as increased urinary 3-0-methyl-DOPA and the plasma and urine dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. Finally, despite an augmented post-DOPA glomerular load of DOPA, the predominant source of urinary dopamine, the excretion rates of dopamine and its metabolites remained comparable in hypertensive patients to those in control subjects. These data suggest that, in stable hypertensive patients, exogenous DOPA is to a lesser degree decarboxylated to dopamine, which is more rapidly metabolized intraneuronally. Contrasting with this finding are the hyperdopaminergic features, such as hypernatriuresis with renin suppression and excessive blood pressure decline in the absence of reflex tachycardia. They may be due to an upregulation of renal, vascular, and brain dopaminergic receptors secondary to a preexisting dopaminergic deficiency in stable essential hypertension. {Hypertension 1992;19:634-638) KEY WORDS • DOPA • dopamine • essential hypertension T he possibility that dopamine, an essentially vasodilator and natriuretic catecholamine, may be involved in the pathogenesis of essential hypertension (EH) is still a controversial subject because of the very low plasma free dopamine concentrations and the heterogeneity of the EH syndrome.1 Detection of dopaminergic abnormalities is also made difficult by the fact that dopamine, generated from 3,4-dihydroxyphenylalanine (DOPA) not only in the sympathetic nervous system but also in non-neuronal tissues, is rapidly converted to either 3,4-dihydroxyphenylacetic acid (DOPAC) or 3-methoxytyramine (3-MT) and subsequently to homovanillic acid (HVA respective metabolites, and blood pressure (BP) responses to exogenous DOPA. Moreover, the EH patients were defined only as normal and low renin EH, without respect to other BP characteristics (such as borderline and s-EH), which, in addition to salt sensitivity, 2 proved to be important determinants of the heterogeneity of dopaminergic involvement in EH. 1 We have demonstrated in a previous study 4 that it is possible to detect some hyperdopaminergic patterns in borderline EH patients with measurements of several intermediate steps after an exogenous DOPA-induced increase of circulating DOPA (including metabolites of DOPA, such as 3-O-methyl-DOPA, and of dopamine, such as dopamine sulfate, DOPAC, 3-MT, and HVA in plasma and urine) as well as of renal and vascular...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Küchel

Shigetomi

1992

Hypertension

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“…6 " 8 This has prompted us to examine the renal effects of dopamine in the Dahl salt-sensitive (DS) rat. The DS rat is extremely sensitive to the blood pressure elevation effect of a high salt diet 9 and exhibits impaired intrinsic natriuretic capacity.…”

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Dopamine regulation of renal Na+,K(+)-ATPase activity is lacking in Dahl salt-sensitive rats.

et al. 1993

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Dopamine is a natriuretic hormone that acts by inhibiting tubular Na + JC + -ATPase activity by activation of the dopamine-1 receptor (the thick ascending limb [TAL] of Henle) or by a synergistic effect of dopamine-1 and dopamine-2 receptors (the proximal tubule). The dopamine-1 receptor is coupled to adenylate cyclase. In this article we show that prehypertensive Dahl salt-sensitive (DS) rats have a blunted natriuretic response to dopamine determined during euvolemk conditions compared with Dahl salt-resistant (DR) rats. Furthermore, we have examined the renal tubular effects of dopamine in DS and DR rats. Basal Na 5 Activation of the DA-1 receptor is in both cases associated with adenylate cyclase activation.Several lines of evidence suggest that an aberrant renal dopaminergic system may be a factor in the pathogenesis of salt-sensitive hypertension.6 " 8 This has prompted us to examine the renal effects of dopamine in the Dahl salt-sensitive (DS) rat. The DS rat is extremely sensitive to the blood pressure elevation effect of a high salt diet 9 and exhibits impaired intrinsic natriuretic capacity.1011 Its control strain is the Dahl salt-resistant (DR) rat, which remains normotensive even during long periods of high salt intake.We show that Na + ,K + -ATPase activity in the PT and TAL segments from DS rats are, in contrast to DR rats, Received March 18, 1992; accepted in revised form January 13, 1993. not responsive to dopamine and the DA-1 agonist fenoldopam. We also show that DS rats have an attenuated natriuretic response to dopamine. In addition, our studies on the effects of dopamine on renal cyclic adenosine monophosphate (cAMP) levels and the effects of cAMP on tubular Na + ,K + -ATPase activity add evidence to the hypothesis, originally suggested by Felder et al,[12][13] that the coupling of the DA-1 receptor to adenylate cyclase may be defective in genetic hypertension. Methods AnimalsStudies were performed on male prehypertensive DS (SS/Jr) and DR (SR/Jr) rats aged 7-8 weeks and weighing 160-240 g. These rats were purchased from M0llegaards Breeding Center, Ejby, Denmark. The rats receiving a normal salt diet were fed a standard rat chow (R3, Ewos, Sodertalje, Sweden) that contains 0.7% NaCl and received tap water ad libitum.Rats were anesthetized with Inactin-Byk (Byk-Gulden, Konstanz, FRG) (80 mg/kg body wt i.p.). Mean arterial pressure was recorded via one carotid artery. Inactin-Byk anesthesia does not influence mean arterial pressure, as shown previously.14 Mean arterial pressure values were similar in DS and DR rats on a normal salt diet (116±3 versus 110±2 mmHg). Preparation of TubulesKidney perfusion and tubule microdissection were performed as described.15 After a midline incision, the left kidney was exposed and perfused with the following modified Hanks' solution (mM): N a d 137, KQ 5, MgSO<

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“…NHE activity was assayed as the initial rate of the Na ϩ -dependent pH i recovery, measured after an acid load imposed by 20 mM NH 4 Cl, followed by removal of Na ϩ from the Krebs modified buffer solution, in the absence of CO 2 /HCO 3 . In some experiments, SHR cells were cultured in permeable polycarbonate filters to access the apical NHE activity only.…”

Section: Resultsmentioning

confidence: 99%

G_iα3 protein-coupled dopamine D₃receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event

Pedrosa¹,

Gomes²,

Hopfer³

et al. 2004

American Journal of Physiology-Renal Physiology

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-da-Silva. Gi␣3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event. Am J Physiol Renal Physiol 287: F1059 -F1066, 2004. First published July 20, 2004 doi:10.1152/ajprenal.00139.2004.-This study evaluated the transduction pathway associated with type 3 Na ϩ /H ϩ exchanger (NHE3) activity-induced inhibition during dopamine D3 receptor activation in immortalized renal proximal tubular epithelial cells from the spontaneously hypertensive rat. The dopamine D3 receptor agonist 7-OH-DPAT decreased NHE3 activity, which was prevented by the D2-like receptor antagonist S-sulpiride, pertussis toxin (PTX; overnight treatment), and the PKC inhibitor chelerythrine, but not by cholera toxin (overnight treatment), the MAPK inhibitor PD-098059, or the p38 inhibitor SB-203580. The PKA inhibitor H-89 abolished the inhibitory effects of forskolin on NHE3 activity, but not that of 7-OH-DPAT. The phospholipase C (PLC) inhibitor U-73122 prevented the inhibitory effects of 7-OH-DPAT, whereas PDBu and 7-OH-DPAT increased PLC activity and reduced NHE3 activity; downregulation of PKC abolished the inhibitory effects of both PDBu and 7-OH-DPAT on NHE activity. The inhibition of NHE3 activity by GTP␥S and the prevention of the effect of 7-OH-DPAT by PTX suggest an involvement of a G i/o protein coupled to the dopamine D3 receptor. Indeed, the 7-OH-DPAT-induced decrease in NHE3 activity was abolished in cells treated overnight with the anti-Gi␣3 antibody, but not in cells treated with antibodies against Gq/11, Gs␣, G␤, and Gi␣1,2 proteins. The calcium ionophore A-23187 and the Ca 2ϩ -ATPase inhibitor thapsigargin increased intracellular Ca 2ϩ but did not affect NHE3 activity. However, the inhibitory effects of PDBu and 7-OH-DPAT on NHE3 activity were completely abolished by A-23287 and thapsigargin. It is concluded that inhibition of NHE3 activity by dopamine D3 receptors coupled to Gi␣3 proteins is a PLC-PKC-mediated event, modulated by intracellular Ca 2ϩ . , and D 4 ), which are differentially expressed along the nephron (12, 33). The autocrine/paracrine function of dopamine, manifested by tubular rather than by hemodynamic mechanisms, becomes most evident during extracellular fluid volume expansion (25). This renal autocrine/paracrine function is lost in essential hypertension and in some animal models of genetic hypertension (4, 22-24, 28, 45, 56). Furthermore, disruption of the D 1 or D 3 receptor produces hypertension in mice (1, 5). In some humans with essential hypertension, renal dopamine production in response to sodium loading is impaired and may contribute to the hypertension (48). However, urinary dopamine is higher in young adults with hypertension than normotensive controls, indicating abnormality at the receptor or postreceptor levels (44). The molecular basis for the dopaminergic dysfunction in hypertension is not known but may involve an abnormal posttranslational modification of the dopamine receptor. There may be a primary defect in ...

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Attenuated Renal Production of Dopamine in Patients with Low Renin Essential Hypertension

Cited by 17 publications

References 14 publications

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Dopamine regulation of renal Na+,K(+)-ATPase activity is lacking in Dahl salt-sensitive rats.

G_iα3 protein-coupled dopamine D₃receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event

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Attenuated Renal Production of Dopamine in Patients with Low Renin Essential Hypertension

Cited by 17 publications

References 14 publications

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Dopamine regulation of renal Na+,K(+)-ATPase activity is lacking in Dahl salt-sensitive rats.

Giα3 protein-coupled dopamine D3receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event

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G_iα3 protein-coupled dopamine D₃receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event