Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

Abstract

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...

Aging, High Salt Intake, and Renal Dopaminergic Activity in Fischer 344 Rats

“…9,10 The aging kidney undergoes structural changes that result in quantitative alterations in some renal functions such as decline in renal blood flow and glomerular filtration rate. 11 High blood pressure or edema formation may be linked to abnormalities in the function of the renal dopaminergic system, such as decreased ability to synthesize dopamine 12,13 and deficient coupling of dopamine receptors to effector mechanisms. 6,14 -16 Despite their normal blood pressure, an increasing number of studies have revealed that old rats may present particular deficiencies in the renal handling of L-DOPA, its subsequent conversion to dopamine, 17,18 and at the level of receptor number or coupling to G proteins.…”

Peripheral dopamine in hypertension and associated conditions

“…45 It is therefore of interest to compare these patterns to those observed in human hypertension subdivided into borderline and stable. We see in younger borderline hypertensive patients age-matched increases of urinary free DA 46 and 3-MT excretions 47 followed by normal 3-MT 48 or lower furosemide stimulated urinary DA excretion and natriuresis in older age-matched stable hypertensive patients. 46 Probably compensatory hyperdopaminergic patterns in initial stages of hypertension, subsequently confirmed in SHR 49 and in young borderline hypertensive patients, 50 are associated with a decreased natriuretic response to exogenous DA in SHR.…”

“…66 Furthermore, a hypernatriuresis and excessive blood pressure decline in response to DOPA was observed in stable hypertensive patients despite their lower DA generation from DOPA. 48 The urinary cyclic AMP hyperresponsiveness to DA infusion in these patients 67 is also compatible with an upregulation of the adenyl-cyclase component of the DA 1 -like receptor. Since salt sensitivity exists in normotensive subjects and may be heritable, it is conceivable that it can precede the appearance of hypertension.…”

“…Considering this age-dependent increase, urinary 3-methoxytyramine excretion was found to be increased only in the younger borderline 47 but not older stable hypertensive patients. 48 tory to the tubular receptor defect. Since the DA metabolite 3-methoxytyramine (3-MT) excretion, best reflecting neuronal DA exocytosis, is also initially increased when hypertension develops, this increase is probably due to an increased neuronal spillover of DA.…”

“…Concomitant measurements of DOPA and DA in urine have suggested a decreased DOPA decarboxylation or defective tubular DOPA uptake in salt-sensitive hypertension. 13 Following oral DOPA administration, stable 48 and low renin hypertensive patients 65 were found to have a lower degree of DOPA decarboxylation to free DA than control subjects. Those hypertensive subgroups apparently have a defect of DA generation from DOPA which may result in adaptive even if relative DA 1 receptor changes; DA receptor upregulation from initially decreased responsiveness or its decreased occupancy is suggested by an exaggerated natriuretic response to exogenous DA in low renin hypertension.…”