Selective peripheral dopamine-1 receptor stimulation with fenoldopam in human essential hypertension.

Carey, Robert M.; Stote, Robert M.; Dubb, Jeffrey W.; Townsend, Leigh; Rose, Charles E.; Kaiser, Donald L.

doi:10.1172/jci111646

Cited by 73 publications

(27 citation statements)

References 24 publications

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“…These DOPA-induced renal (natriuresis) and cardiovascular (BP) responses were enhanced in s-EH patients despite comparable plasma and urinary free dopamine values in both these patients and control subjects. This is in accordance with previous reports of an augmented natriuretic reaction of EH patients to intravenously administered dopamine, 6 dopamine-1 agonist, 7 or a dopamine prodrug 8 attributed to an upregulation of dopaminergjc receptors. Paradoxically, plasma renin activity was depressed despite more natriuresis and lowered BP in s-EH patients but not in control subjects.…”

Section: Discussionsupporting

confidence: 93%

“…7 The finding that the creatinine clearance of s-EH patients at the height of DOPAinduced dopamine generation was lower than that of control subjects, whereas the fractional Na + excretion of s-EH patients was higher (with baseline values of both being comparable), is compatible with an impaired renal hemodynamic but an even upregulated natriuretic (tubular) response to dopamine generated from DOPA. This resembles a similar observation made in response to exogenous dopamine in patients with renal diseases and moderate impairment of renal function.…”

Section: Discussionmentioning

confidence: 95%

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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: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 95%

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Küchel

Shigetomi

1992

Hypertension

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“…The time course of the blood pressure reduction we observed agreed well with previous observations in normal subjects (Harvey et al, 1985) and hypertensive patients (Ventura et al, 1984;Carey et al, 1984;Harvey et al, 1986). The postural fall of blood pressure was also documented during passive tilting, when there was an accompanying reflex Time (min) Figure 4 Comparison of blood pressure and heart rate changes produced by isometric hand grip before and after 6 weeks of treatment with fenoldopam 100 mg twice daily.…”

Section: Discussionsupporting

confidence: 89%

Effects of fenoldopam, a specific dopamine receptor agonist, on blood pressure and left ventricular function in systemic hypertension.

Caruana

Heber

Brigden

et al. 1987

Brit J Clinical Pharma

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1 The effects of fenoldopam, an orally active, specific dopamine-1 receptor agonist, were studied in eleven patients with essential hypertension, using intra-arterial blood pressure recording and equilibrium gated radionuclide angiography. 2 A single dose of fenoldopam 100 mg produced a fall in blood pressure (BP) starting after 20 min. The maximum BP reduction (23/25 mm Hg) occurred after 50 min and was accompanied by a heart rate (HR) increase of 10 beats min-'. The acute effects on BP lasted for 130 min. 3 After 8 weeks of fenoldopam 100 mg, twice daily, only a small, statistically insignificant, hypotensive effect was still apparent after each dose of drug. The duration of the effect was too short to be clinically useful. Tilt-testing produced a BP fall of 24/14 mm Hg and a HR increase of 17 beats min1. Three patients experienced symptoms of postural hypotension during the study. 4 The drug attenuated the blood pressure rise produced by dynamic cycle exercise and isometric hand grip. 5 Acute administration of fenoldopam increased the left ventricular ejection fraction from 61% to 71% (P < 0.005) and increased the peak filling rate from 2.52 to 3.86 end diastolic vol s-1 (P < 0.002). After chronic fenoldopam administration, the left ventricular ejection fraction was 65% (P = NS) pre-dose, rising to 69% (P < 0.02) post-dose and the peak filling rate was increased from 2.7 to 3.38 end diastolic vol s-' (P < 0.01) 60 min postdose. There was also a significant increase of the first one-third filling fraction from 0.24 to 0.47 (P < 0.01) pre-dose, indicating improved diastolic function. 6 Although the duration of action of this formulation of fenoldopam is too short to recommend it for clinical use, a slow-release preparation would merit further investigation for treatment of hypertension and heart failure.

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“…Increments in HR previously have been observed with orally administered fenoldopam in hypertensive patients. 23 ' 24 Furthermore, in a recent study, we observed that intravenous infusions of fenoldopam in hypertensive patients consistently increased plasma NE levels. 23 Although piribedil is used primarily as a centrally acting DA agonist for the treatment of Parkinson's disease, 26 it also inhibits adrenergic transmission by action on DA 2 receptors.…”

Section: Discussionmentioning

confidence: 78%

Selective antagonism of the hypotensive effects of dopamine agonists in spontaneously hypertensive rats.

McCoy¹,

Douglas²,

Goldberg³

1986

Hypertension

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SUMMARY Agonists of dopamine receptors can lower blood pressure by vasodilation through action on dopamine) receptors, inhibition of sympathetic nerve activity by action on dopamine 2 receptors, or actions in the central nervous system. Fenoldopam, a selective dopamine, agonist, piribedil, a selective dopamine 2 agonist, and dipropyl dopamine, a mixed dopamine, and dopamine 2 agonist, were injected intravenously in pentobarbital-anesthetized, spontaneously hypertensive rats (SHR). The mechanism for the antihypertensive effect was evaluated by administration of the selective dopamine, antagonist SCH 23390 and the selective dopamine 2 antagonist domperidone. While SCH 23390 only antagonized the hypotensive effects of fenoldopam, domperidone abolished the fall in blood pressure produced by dipropyl dopamine and piribedil but not by fenoldopam. Increments in heart rate and plasma norepinephrine levels accompanied the hypotensive effects of fenoldopam. The increase in heart rate was abolished by a dose of SCH 23390 sufficient to completely block the hypotensive effects and was significantly attenuated by the ganglionic blocking agent hexamethonium, which suggests that the increase in heart rate was due to a baroreceptor reflex. Fenoldopam does not cross the blood-brain barrier, which suggests that its hypotensive effect was mediated by peripheral dopamine, receptors. Since domperidone does not cross the blood-brain barrier and significantly antagonized the hypotensive and bradycardic effects of dipropyl dopamine and piribedil, these effects were mediated primarily by peripheral dopamine 2 receptors. These results indicate that SCH 23390 and domperidone are useful agents to identify the receptor subtype mediating the action of dopamine agonists in SHR. (Hypertension 8: 298-302, 1986 lease from sympathetic nerve terminals, leading indirectly to vasodilation and a fall in heart rate (HR). 4 Because of these actions, agonists of both receptor subtypes are receiving increasing attention as potential antihypertensive agents. 5 "" Dopamine and most DA agonists act on both DA receptor subtypes and on other receptors in the central nervous system and periphery. 3 8 9 Therefore, it is important to develop an animal model to separate these diverse mechanisms. Several studies have demonstrated that agonists, which may act on DA, or DA 2 receptors, lower blood pressure (BP) in spontaneously hypertensive rats (SHR). 5 ' 12 " u Until recently, selective antagonists were not available to prove that reduction in BP was due to action on either one or both receptor subtypes. The benzazepine SCH 23390 and the butyrophenone domperidone are extremely selective antagonists of DA, and DA 2 receptors, respectively. 15 -' 6 The present experiments were designed to determine whether these selective antagonists inhibit the hypotensive ef-298

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Selective peripheral dopamine-1 receptor stimulation with fenoldopam in human essential hypertension.

Cited by 73 publications

References 24 publications

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Effects of fenoldopam, a specific dopamine receptor agonist, on blood pressure and left ventricular function in systemic hypertension.

Selective antagonism of the hypotensive effects of dopamine agonists in spontaneously hypertensive rats.

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