Failure of Salt to Mobilise Renal Dopamine in Essential Hypertension

Perkins, C. M.; Casson, Ian; Cope, Georgina; Lee, M.R.

doi:10.1016/s0140-6736(80)92432-0

Cited by 14 publications

(5 citation statements)

References 12 publications

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“…It seems likely to be effective in hypertension and congestive heart failure with perhaps less tendency to produce sodium retention than known vasodilators. Our group has produced evidence that renal dopamine mobilization on salt loading is deficient both in essential hypertension (Perkins et al, 1980;Harvey et al, 1984) and in chronic renal failure (Casson et al, 1983). Treatment with a peripheral dopamine receptor agonist may be particularly appropriate in both these clinical conditions.…”

Section: Discussionmentioning

confidence: 99%

The effect of oral fenoldopam (SKF 82526‐J), a peripheral dopamine receptor agonist, on blood pressure and renal function in normal man.

Harvey¹,

Worth²,

Brown³

et al. 1985

Brit J Clinical Pharma

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1 The effect of a single oral dose of 100 mg of fenoldopam on renal function and blood pressure was investigated in seven healthy male subjects in a double-blind placebo controlled study. 2 Mean diastolic blood pressure fell by 10 mm Hg, 45 min after oral dosing and then gradually returned to baseline values. There was an increase in pulse rate and a delayed rise in systolic blood pressure. 3 Measured from 30 to 120 min after drug ingestion, mean effective renal plasma flow increased to 158% of the value observed after placebo; mean glomerular filtration rate rose to 109% of the placebo value. Measured from 120 to 210 min after administration of the drug, effective renal plasma flow and glomerular filtration rate had returned to baseline values. 4 Fenoldopam produced a small increase in the mean sodium excretion rate which was not significantly different from the fall after placebo. No change was detected in urine flow or potassium excretion rate. 5 Mean plasma renin activity increased three-fold 1 h after oral dosing. Plasma aldosterone did not show a parallel increase although the plasma concentration at 1 h was significantly higher than after placebo. 6 The results show a pronounced renal vasodilator effect lasting about 2 h. The findings are consistent with marked DA1 receptor agonist activity.Keywords fenoldopam (SKF 82526-J) dopamine renal blood flow blood pressure

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Section: Discussionmentioning

confidence: 99%

The effect of oral fenoldopam (SKF 82526‐J), a peripheral dopamine receptor agonist, on blood pressure and renal function in normal man.

Harvey¹,

Worth²,

Brown³

et al. 1985

Brit J Clinical Pharma

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“…A renal defect in the free DA clearance was postulated in EH patients when their urinary excretion of free DA did not rise, unlike control subjects, in response to sodium load 23 or furosemide administration." Whereas in control subjects plasma and urinary total DA concentrations were negatively correlated, in EH patients this relationship was disrupted.…”

Section: Discussionmentioning

confidence: 99%

Dopamine surges in hyperadrenergic essential hypertension.

Kuchel¹,

Buu²,

Hamet³

et al. 1982

Hypertension

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SUMMARY , From a total of 61 referred hypertensive patients, 21 were clinically suspected of pheochromocytoma but in none was this diagnosis confirmed. Instead we found nine of the 21 patients had surges of conjugated dopamine during hyperadrenergic periods unaccounted for by rise in norepinephrine (NE) or epinephrine (E). Overall, essential hypertensive (EH) patients had in plasma (ng/ml) higher conjugated dopamine (DA) (2.3 ± 0.2 vs 1.0 ± 0.1, p < 0.01), increasing with age (p < 0.01), lower conjugated NE + E(0.6 ± 0.1 vsl.2 ± 0.2, p < 0.01), and higher free E ( p < 0.007), lower urinary free DA and total DA but higher free NE + E excretions (each p < 0.05) than 24 control subjects. Following the DA surges, a short-lived urinary overflow of total DA occurred. The patients with DA surges were older, had a higher incidence of low conjugated NE + E (< 0.23 ng/ml), a higher proportion of arterial free DA, and higher venous baseline conjugated plasma DA than the rest of the patients. Patients with low conjugated NE + E had in turn higher plasma DA concentrations at several regional sampling sites than patients with normal conjugated NE + E. High conjugated DA in EH probably results from pulsatile DA surges leading to a rise of baseline plasma conjugated DA. In the short run DA pulses can result in temporary a-and /3-adrenergic actions of huge arterial free DA concentrations prior to DA conjugation; in the long run the excessive high affinity DA conjugation may take preference to the lower affinity NE and lowest affinity E conjugation and free E increases. Both result in an acute or chronic increase of sympathetic tone. (Hypertension 4: 845-852, 1982) KEY WORDS • dopamine surges • pseudopheochromocytoma I N exploring the role of catecholamines (CA) in hypertension, some research workers have recently turned their attention to some of the metabolic products of CA such as metanephrines 1 or CA sulfates; 2 and away from norepinephrine (NE), the main CA, toward epinephrine (E); 3 and to dopamine (DA). 4 Research into DA combines both these new approaches because DA circulates almost entirely in the conjugated form 5 and is therefore usually undetectable in plasma without hydrolysis. The significance of the elevated plasma concentration of conjugated DA found in essential hypertensive (EH) patients 4 remained, however, as enigmatic as the cardiovascular role of DA itself.The determination of free and conjugated NE + E has recently shown that EH patients with low plasma conjugated NE + E have moderately elevated free NE + E levels that are hyperresponsive to glucagon stimulation; their symptoms mimic those of pheochromocytoma. 6 (In the present context, "free" means unconjugated catecholamines; the term "free" is usually used to designate that the respective hormone is not bound to plasma protein.) In these patients, conjugated DA, by contrast, was rather higher than in those with normal conjugated NE + E.In its hormonal character and predominantly adrenomedullary origin, 7 DA is more similar to E than to NE. In its hi...

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“…The development of hypertension is usually a slow process, in which aging may attenuate the baroreceptor-mediated inhibition of NE release. 72 This may be related to a progressive decline of dopaminergic activity 76 with deficient renal DA and natriuretic responses to salt loading 112 and diuretics, 113 and possibly also a diminished decarboxylation of DOPA to DA as suggested by exogenous DOPA administration ( Figure 3) indicating a reduced DA turnover. These patterns are typical of low renin essential hypertension, 114 a form of stable hypertension of long duration.…”

Section: Heterogeneity Of Dopamine's Involvement In Essential Hypertementioning

confidence: 99%

Peripheral dopamine in pathophysiology of hypertension. Interaction with aging and lifestyle.

Küchel

Kuchel

1991

Hypertension

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Dopamine, an ancestral catecholamine, is physiologically natriuretic and vasodilating, thus essentially protecting against hypertension. Its actions are overshadowed by the opposite effects of its main biological partner, norepinephrine, and this is accentuated with aging. Clinical observations combined with molecular biology approaches to catecholamine-synthesizing and catecholamine-metabolizing enzymes and receptors permit the identification of some inborn defects. Subtle changes in the dopamine-norepinephrine balance may account for the enhanced peripheral noradrenergic activity seen in the setting of decreased dopaminergic activity in advanced age. These changes may contribute to the diminished ability of the aged kidney to excrete a salt load, as well as to the finding that systolic blood pressure increases with age in populations with a high, but not in those with a low, intake of salt. The attainment of advanced age in Western societies with adverse lifestyle changes (mental rather than physical stress, excess salt intake, overeating, sedentarism) appears to facilitate the development of hyperten-sion. The adaptation to all the preceding lifestyle changes necessitates an increased dopamine generation, which may initially compensate to maintain appropriate natriuresis and vasodila-tion since many patients with initial borderline essential hypertension express their sympathetic hyperfunction, in addition to increased norepinephrine release, by excessive dopamine release. However, the progression of hypertension is accompanied by a peripheral dopaminer-gic deficiency and diminished ability to excrete salt. This may represent an eventual inadequacy of a phylogenetically redundant system resulting in decreased natriuresis and vasodilation and may account for the responsiveness of established chronic hypertension to salt restriction, diuretics, and dopaminomimetic medication. (Hypertension 1991;18:709-721) O ver the last decade, it has become apparent that dopamine (DA) is an important neuro-transmitter in the peripheral nervous system. Nonneuronal (kidney, intestine, blood vessels) and neuronal (neural terminals, adrenal medulla) tissues are target organs for circulating DA and also for DA synthesized and secreted locally as a paracrine substance. DA receptors located extracellularly in plasma-exposed cellular membranes transduce their signals to the intracellular milieu through a variety of second messengers, including adenylate cyclase, phos-pholipase C, protein kinase C, and other protein kinases. Peripheral DA! receptors (typical for vascular smooth muscles and renal tubules) act via adenylate cyclase and phospholipase C stimulation, whereas DA 2 receptors presynaptically suppress the release of norepinephrine (NE) via adenylate cyclase inhibition. 1 DA has been shown to affect the actions of ion transporters as well as a variety of cellular enzymes and appears to be physiologically important in the control of renal function. The sum of the effects of physiological DA concentrations on the kidney (DA r med...

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Failure of Salt to Mobilise Renal Dopamine in Essential Hypertension

Cited by 14 publications

References 12 publications

The effect of oral fenoldopam (SKF 82526‐J), a peripheral dopamine receptor agonist, on blood pressure and renal function in normal man.

The effect of oral fenoldopam (SKF 82526‐J), a peripheral dopamine receptor agonist, on blood pressure and renal function in normal man.

Dopamine surges in hyperadrenergic essential hypertension.

Peripheral dopamine in pathophysiology of hypertension. Interaction with aging and lifestyle.

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