Peripheral dopamine in hypertension and associated conditions.

The purpose of this study is to review the role of dopamine in hypertension and associated conditions. The analysis of literature indicates that present knowledge is mostly based on poor markers and indirect evidence of dopaminergic activity and only few molecular biological data. Alternative markers such as plasma dopamine sulfate emerge as a possible substitute for the low plasma free dopamine detectability, one of the main obstacles in understanding the relationship between circulating dopamine and its receptor actions in hypertension. Essential hypertension represents a heterogeneous entity: based on evidence in borderline and non-modulating hypertension, the tubular dopamine receptor defect may be compensated by increased dopamine synthesis (dopamine beta-hydroxylase suppression-mediated?) and release; alternatively, compatible with data in stable, salt-sensitive and low renin-hypertension, the receptor defect may be amplified by a deficient dopamine synthesis, basal and in response to salt and volume expansion. Secondary forms of hypertension (renovascular, renal, polycystic kidneys, mineralocorticoid, pheochromocytoma) associated conditions (renal and heart failure, diabetes, hypovolaemia, mastocytosis) or iatrogenic (cocaine abuse) are mostly reflected by increased dopamine indices, some of them proposed to be counteracting the activation of prohypertensive mechanisms. In conclusion dopamine should thus be monitored in hypertension while respecting several associated conditions affecting peripheral dopaminergic activity. Catecholamine synthesis and metabolism enzymes' and dopamine receptors' targeting are essential for advancing the understanding of dopamine's diagnostic and therapeutic implications.

Idiopathic hypovolemia: a self-perpetuating autonomic dysfunction?

Unexplained episodic hypertension, hypotension, or orthostatic intolerance, tachycardia, anxiety, and flushing in 21 patients were investigated for the possibility of hypovolemia by blood volume and individual plasma catecholamines (including autocrine paracrine-born dopamine), determinations baseline, in response to upright posture and catecholamines only during the episodic blood pressure swings. Blood volume was determined by Cr51 fixed to patients' hemoglobin, free norepinephrine, epinephrine, and dopamine with dopamine sulfate following sulfatase hydrolysis, radioenzymatically. The recumbent mean 27.4+/-3% (SE) blood volume decrease from predicted values accentuating to 33.5+/-4% upright was associated with normal baseline plasma free norepinephrine, epinephrine, dopamine, dopamine sulfate, plasma renin activity, and aldosterone with normal mean postural responses from all patients except a hyperresponsive compared to controls (p < 0.04), plasma renin activity increase from 0.657+/-0.1 to 4.47+/-1.8 ng/mL/hr. During the hypertensive, hypotensive, or tachycardic episodes the moderate increase of free norepinephrine and epinephrine (p < 0.04) (but not free dopamine) contrasted with an increase of dopamine sulfate from 2.5+/-0.9 to clearly pathological values of 16.8+/-8.3 ng/mL (p < 0.0003 on % increase of individual values). We conclude that the normal (but to the degree of hypovolemia inappropriately low orthostatism- and episodes-associated sympathetic arousal) is outpaced by considerable episodic dopamine sulfate surges, reflecting extraneuronal dopamine discharge. Whether this increase contributes to the increased natriuresis directly or by inhibiting aldosterone response to renin-angiotensin, perpetuating hypovolemia, remains to be established.

Increased plasma dopamine in patients presenting with the pseudopheochromocytoma quandary: retrospective analysis of 10 years' experience.

OBJECTIVES: A retrospective analysis was made to determine alternative diagnoses in patients with predominantly hypertensive episodes who were suspected of having pheochromocytoma but in whom this diagnosis was eliminated. DESIGN: Analysis of a random university hospital population referred over a period of 10 years. METHODS: Episodic clinical presentations of pheochromocytoma symptoms combined with a comparison of baseline and episodic radioenzymatically determined levels of plasma free norepinephrine and epinephrine were examined, together with prospective levels of plasma free and sulfated dopamine. RESULTS: Out of 63 patients presenting with episodes of palpitations, headaches, flushing, sweating and hyperventilation (associated with hypertension in 49 patients, with hypotension in six patients and with alternating hyper- and hypotension in eight patients), 14 were diagnosed as having idiopathic hypovolemia, nine as having mastocytosis, nine as having an adrenal tumor, four as having neurogenic hypertension and one each with cocaine abuse and reninoma. Both baseline and symptomatic levels of plasma free norepinephrine and epinephrine remained within physiological limits (exceeding them moderately in baroreceptor dysfunction only), but all subgroups had a mean episodic increase over baseline in plasma dopamine sulfate (mean+/-SEM 16.7+/-5.9 to 53.2+/-19 pmol/ml; P < 0.02), unlike free dopamine. CONCLUSIONS: Patients whose symptoms imitated pheochromocytoma in hemodynamic instability and frequent flushing formed a heterogeneous group, with plasma norepinephrine and epinephrine usually within physiological limits but an overall mean threefold increase in dopamine sulfate concentrations. With the various diagnoses of idiopathic hypovolemia, mastocytosis, neurogenic, secondary hypertension and cocaine abuse eliminated as a cause of pheochromocytoma-like symptoms, at least half of these patients still had unexplained, predominantly emotionally or proprioreceptive stimulation-provoked, bouts of hypertension. Sympathetic arousal dominated by an increase in dopamine sulfate without a corresponding increase in free norepinephrine, epinephrine and dopamine may be attributed to a number of neurogenic, adaptive or autocrine-paracrine dopamine release mechanisms.

Differential catecholamine responses to protein intake in healthy and hypertensive subjects.

Protein intake-induced natriuresis previously related to increased urinary dopamine excretion was reexamined in an extensive controlled study comparing healthy and hypertensive subjects. In healthy subjects, ingestion of 1 g/kg wt tuna induced natriuresis that was associated, between postprandial hours 1 and 2, with increased plasma tyrosine [191 +/- 13% (mean +/- SE); P < 0.01], 3, 4-dihydroxyphenylalanine (104 +/- 12%, P < 0.05 in plasma; 162 +/- 20%, P < 0.05 in urine), plasma free dopamine (156 +/- 32%; P < 0. 05), and dopamine sulfate (191 +/- 11%, P < 0.001 in plasma; 199 +/- 15%, P < 0.01 in urine) but affected urinary free dopamine excretion only at limits of significance. Hypertensive subjects had less (P < 0.02) natriuresis and, despite comparable plasma tyrosine and dopamine sulfate increases, no increase in plasma and urinary 3, 4-dihydroxyphenylalanine and plasma free dopamine. Their plasma and urinary free epinephrine responses were less (P < 0.05) than the borderline increases in control subjects. Compared with control subjects, they significantly increased plasma 3, 4-dihydroxyphenylalanine sulfate (P < 0.05), epinephrine sulfate (P < 0.05), and the dopamine sulfate-to-free dopamine ratio (P < 0.02). Postprotein natriuresis is thus associated with nutritional priming-induced plasma but not urinary free dopamine increase. Hypertensive subjects have attenuated natriuretic and plasma free dopamine responses and less free epinephrine increase. This may partly result from higher circulating 3,4-dihydroxyphenylalanine, dopamine, and epinephrine sulfoconjugates leaving fewer free amines for biological actions.

Extreme diuretic dependence in idiopathic edema: mechanisms, prevention and therapy.

Idiopathic edema patients abusing diuretics are occasionally becoming dependent to such a degree on increasing doses of diuretics that their withdrawal results in severe cardiorespiratory failure, occasionally even pulmonary edema. Two such patients are described and 1 is investigated in depth as to the mechanism of the diuretic abuse-induced excessive tubular avidity for sodium. An extreme diuretic-induced secondary hyperaldosteronism and atrial natriuretic factor suppression, although tapering off when diuretics are stopped, results in a continuous tubular sodium hyper-reabsorption. Since the most affected patient was deprived of the benefits of converting enzyme inhibitors because of their side effects, the only way to partially overcome this condition was a generous combination of several diuretics acting at several segments of the nephron. This contrasted with a similar patient who was relatively well controlled by a converting enzyme inhibitor combined with lower dose diuretics. Diuretic abuse-induced secondary hyperaldosteronism and diuretic resistance are apparently best prevented by converting enzyme inhibitors. When nonpharmacological preventive measures fail, converting enzyme inhibitors are preferable to diuretics as the first-choice treatment of idiopathic edema patients.

Genetic determinants of dopaminergic activity: potential role in blood pressure regulation.

Dopamine (DA) availability for precursor function and peripheral biological action is dependent on synthesis and inactivation enzymes, most of them have been cloned and located. An aromatic acid decarboxylase (AADC) defect has been reported in male homozygotic twins. The syndrome of complete dopamine-beta-hydroxylase deficiency with orthostatic hypotension and very high DA contributes to our understanding of the role of DA as a catecholamine with a peripheral biological action of its own. X-linked isolated monoamine oxidase A gene deficiency represents a marked disturbance of monoamine metabolism. The genes of the two major extraneuronal DA-metabolizing enzymes--catechol-O-methyl-transferase and phenolsulfotransferase (PST)-have also been defined. Of particular interest is a bidirectional shuttle system between the PST and sulfatase which have been cloned and located. DA, highly sulfoconjugated via PST, yields DA sulfate which is reconvertible by sulfatase to Free DA. A defect of sulfatase catalyzing this process results in a predominance of DA as biologically inactive DA sulfate and so attenuates the DA action. Enzymatic defects of DA synthesis and metabolism are thus genetic modulators of DA action.

Dopamine deficiency--its potential contribution to chronic renal failure complicating hypertension.

Baseline dihydroxyphenylalanine (DOPA) and dopamine (DA), their respective sulfates as well as oral DOPA administration-induced changes were compared in age- and blood pressure-matched hypertensive patients without and with moderate chronic renal failure (CRF) and control subjects. The only common feature of both hypertensive groups was a defective DA generation from DOPA. Hypertensive patients with moderate CRF were distinct from those without, having increased basal concentrations of plasma DOPA and DA sulfates. After oral DOPA administration, plasma and urinary DOPA sulfate rose while renal DA sulfate clearance was decreased. Possible enzymatic defects contributing to CRF-induced increases of DOPA and DA sulfates and their potential role in perpetuating renal failure via glomerular hypertension are discussed.

Clinical implications of genetic and acquired defects in catecholamine synthesis and metabolism.

All major enzymes involved in catecholamine synthesis and metabolism have been cloned. In addition to some genetic defects of these enzymes responsible for well-defined clinical syndromes, several enzymatic abnormalities may be due to environmental (e.g. pharmacological and nutritional) or biological (e.g. aging) factors, which may modify genome expression. The enzymes involved in catecholamine metabolism either lead to metabolites which cannot be reconverted to the parent catecholamine (such as products of monoamine oxidation and catechol-O-methylation), or metabolites, which can be reconverted to the free catecholamine from which they are generated (such as products of sulfoconjugation). Reversible sulfoconjugation is partly regulated by the recently cloned enzyme, sulfatase. The importance of this reversible step is that it reconverts inactive into biologically active catecholamines. The balance of the sulfoconjugation-deconjugation interplay may have physiological implications; in addition to catecholamine release, it may determine the availability of free catecholamines during diurnal rhythms and stress or modify their renal excretion. Circumstantial evidence, including a close homology within the aryl sulfatases and steroid sulfatase gene, the first implicated in catecholamine metabolism, the second in steroid metabolism, suggests a genetic defect of sulfatases in essential hypertension. A similar, but secondary, sulfatase defect may affect catecholamine metabolism and action in chronic renal failure.

Dopaminergic abnormalities in hypertension associated with moderate renal insufficiency.

To evaluate the additive effect of moderate chronic renal failure to the abnormal dopamine generation and action observed in stable hypertension, we investigated 22 age-matched patients with a comparable degree of hypertension with and without chronic renal failure. Both groups were compared with each other and with an age-matched control group after a single oral dose of dihydroxyphenylalanine (DOPA) while cardiorenal responses and DOPA, dopamine, and their metabolites were measured. The hypertensive patients with chronic renal failure shared with their hypertensive counterparts without chronic renal failure an impaired DOPA decarboxylation to dopamine. However, patients with chronic renal failure had decreased hemodynamic and normal natriuretic responses compared with the hypernatriuresis of hypertensive patients with normal renal function; patients with chronic renal failure had elevated basal plasma concentrations of DOPA and dopamine sulfates as well as increased plasma and urinary DOPA sulfate but blunted urinary dopamine sulfate increases after DOPA administration; they presented augmented plasma atrial natriuretic factor concentrations. Thus, hypertensive patients with moderate chronic renal failure exhibit a decreased hemodynamic responsiveness to DOPA administration-induced dopamine elevation but with the natriuretic effect of dopamine maintained (possibly because of its permissive interaction with increased atrial natriuretic factor levels). Hypertensive patients with chronic renal failure have a heightened DOPA and dopamine sulfoconjugating propensity. Dopamine sulfate attenuates the biologic action of free dopamine. This may contribute (possibly via glomerular hypertension and hyperfiltration due to decreased postglomerular vasodilation) to progressive hypertensive renal damage, particularly in groups predisposed to dopamine deficiency, such as diabetics, blacks, and the elderly.

Early experience with laparoscopic approach for adrenalectomy.

BACKGROUND: Adrenalectomy performed by a posterior or transabdominal approach causes substantial postoperative pain. The purpose of this study was to evaluate laparoscopy as a potential approach for adrenalectomy. METHODS: We performed 25 consecutive laparoscopic adrenalectomies on 22 patients from April 1, 1992, to March 30, 1993. Laparoscopic surgery was performed by using a lateral decubitus flank approach with four 11 mm trocars. RESULTS: Twelve right and 13 left adrenal glands were removed in a mean time of 2.3 hours. Three patients underwent bilateral adrenalectomies in a mean time of 5.3 hours. The 15 women and 7 men range in age from 31 to 60 years (mean, 42 years). The adrenal gland diseases were nonfunctional adenoma (seven), pheochromocytoma (five), Cushing's disease (four), Cushing's adenoma (four), primary aldosteronism (two), dehydroepiandrostenedione sulfate hypersecretion (one), angiomyolipoma (one), and medullary cyst (one). Average tumor size was 4.1 cm (range, 1 to 15 cm). Laparoscopic adrenalectomy was successful in 96% of patients, with one patient requiring a laparotomy because of inadequate exposure. The median postoperative stay was 4 days (range, 2 to 19), with a mean of five narcotic injections. There were no deaths, and morbidity was minor. CONCLUSIONS: Laparoscopy can be used successfully for adrenalectomy. It produces less postoperative pain and rapid return to normal activity. It may be the preferred method for removing most adrenal gland lesions that require operation.

Increased cyclic guanosine monophosphate production and overexpression of atrial natriuretic peptide A-receptor mRNA in spontaneously hypertensive rats.

Atrial natriuretic peptide (ANP) specifically stimulates particulate guanylate cyclase, and cyclic guanosine monophosphate (cGMP) has been recognized as its second messenger. Spontaneously hypertensive rats (SHR) have elevated plasma ANP levels, but manifest an exaggerated natriuretic and diuretic response to exogenous ANP when compared to normotensive strains. In isolated glomeruli, the maximal cGMP response to ANP corresponds to a 12- to 14-fold increase over basal levels in normotensive strains (Wistar 13 +/- 2; Wistar-Kyoto 12 +/- 2; Sprague-Dawley 14 +/- 2) while a maximal 33 +/- 3-fold elevation occurs in SHR (P < 0.001). This hyperresponsiveness of cGMP is reproducible in intact glomeruli from SHR from various commercial sources. Furthermore, this abnormality develops early in life, even before hypertension is clearly established, and persists despite pharmacological modulation of blood pressure, indicating that it is a primary event in hypertension. In vitro studies have revealed a higher particulate guanylate cyclase activity in membranes from glomeruli and other tissues from SHR. This increase is not accounted for by different patterns of ANP binding to its receptor subtypes between normotensive and hypertensive strains, as assessed by competitive displacement with C-ANP102-121, an analog which selectively binds to one ANP receptor subtype. The hyperactivity of particulate guanylate cyclase in SHR and its behavior under basal, ligand (ANP), and detergent-enhanced conditions could be attributed either to increased expression or augmented sensitivity of the enzyme. Radiation-inactivation analysis does not evoke a disturbance in the size of regulatory elements normally repressing enzymatic activity, while the expression of particulate guanylate cyclase gene using mutated standard of A- and B-receptors partial cDNAs, quantified by polymerase chain reaction (PCR) transcript titration assay, manifests a selective increase of one guanylate cyclase subtype. Our data suggest that in hypertension, genetic overexpression of the ANP A-receptor subtype is related to the exaggerated biological response to ANP in this disease.

Unilateral juxtaglomerular hyperplasia, hyperreninism and hypokalaemia relieved by nephrectomy.

Two women with spontaneous hypokalemia (1 normotensive, 1 hypertensive in the absence of renal artery stenosis), underwent unilateral nephrectomy because of angiographic and/or split renin-based suspicion of a reninoma. The normotensive patient clinically resembled Bartter syndrome but had some elements suggestive of a renin-secreting tumour, justifying surgical exploration and resection. The hypertensive patient presented clinically as a typical reninoma except for negative angiography. Surprisingly, the histology of the kidneys in both cases demonstrated juxtaglomerular hyperplasia without evidence of reninoma. The postoperative follow-up (8 and 19 yrs, respectively) has shown in the normotensive patient a considerable improvement in the hyper-reninism and previously uncontrollable hypokalaemia and in the hypertensive patient a complete normalisation of BP, renin and electrolyte status. Although the histological condition of the contralateral kidneys remains unknown in both patients the preoperative lateralisation of hyper-reninism to one kidney, the postoperative complete relief of the hyper-reninism in the hypertensive patient after uninephrectomy and its decrease, exceeding that corresponding to the removal of one kidney in the normotensive patient, suggest that the juxtaglomerular hyperplasia might have been unilateral or asymmetrical and that nephrectomy may, unexpectedly, relieve the hyper-reninism caused by juxtaglomerular hyperplasia. An increased unilateral susceptibility to trophic or renin-releasing factors or an asymmetrical abnormality in the macula densa-initiated mechanism of juxtaglomerular hyperplasia may be implicated in this disorder.

Defective 3,4-dihydroxyphenylalanine decarboxylation to dopamine in hydralazine-treated hypertensive patients may be pyridoxine remediable.

The previously observed defective dopamine (DA) generation from 3,4-dihydroxyphenylalanine (DOPA) can also be seen in patients treated for many years by hydralazine. This may be due to a hydralazine-induced depletion of pyridoxine, an essential coenzyme of the aromatic L-amino acid decarboxylase (LAAD). Eleven hydralazine-treated stable essential hypertensive (EH) patients, initially found to have a defect in the DOPA decarboxylation to DA, tested by a single DOPA administration (500 mg, orally), were retested by the same test 4 days after pyridoxine pretreatment (100 mg/day) for data on blood pressure (BP), pulse rate, and renal and plasma catecholamines and their metabolites, as well as plasma atrial natriuretic factor (ANF), cyclic GMP (cGMP), plasma renin activity (PRA), and plasma aldosterone (PA). Initially, hydralazine-treated stable EH patients manifested, following DOPA administration, lower DOPA decarboxylation to DA than control subjects. Pyridoxine pretreatment accelerated DA generation from exogenous DOPA and attenuated the DOPA-induced increases in plasma and urinary DOPA and its metabolite 3-O-methyl-DOPA, but accentuated the increase in free DA and its main metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), while BP, ANF, cGMP, PRA, and PA remained unaffected. The DOPA-induced increments of urinary DA were, in contrast to plasma DA changes, blunted by pyridoxine pretreatment. The attenuation of the sodium excretion by pyridoxine pretreatment exceeded that of the DA excretion, suggesting that pyridoxine suppressed a natriuretic factor, other than ANF, or activated a sodium-retaining factor, other than renin or aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Defective dopamine generation from dihydroxyphenylalanine in stable essential hypertensive patients.

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-O-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.