SUMMARYThe correlation between the degree of conjugation of plasma noreplnephrine (NE) and epinepbrine (E) and the clinical features of sympathetic hyperactivity was studied in 38 essential hypertensive patients from a referral population biased toward pheochromocytoma (19 of them suspected of this diagnosis on clinical grounds). The patients were separated into two groups: 15 with subnormal plasma conjugated NE + E, i.e., below 0.23 ng/ml (Group 1), and 23 patients above this limit (Group 2). Patients clinically suspected of pheochromocytoma represented 93% of the patients in Group 1 but only 21% in Group 2.Group 1 patients, compared to those of Group 2, had: 1) higher baseline plasma free NE + E (0.51 ± 0.07 ng/ml vs 0.30 ± 0.04 ng/ml,p < 0.02); 2) an increase in plasma free NE + E in response to stressful sampling (148% ± 59%, p < 0.05 vs 58% ± 30%), and a more pronounced response (p < 0.05) to glucagon administration; 3) higher free NE + E and DA in the regional samples received during catheterization while conjugated NE and/or E were usually absent; and 4) a higher spread between maximum and minimum blood pressure and a higher maximum pulse rate recorded as well as the index of sympathotonia. All patients combined had the 'maximum pulse rate correlated negatively (p < 0.005) with conjugated NE + E, but positively (p < 0.005) with free NE + E. The clinical and biochemical similarity to pheochromocytoma was particularly striking in some Group 1 patients who had a selective defect in E conjugation; some of them had a history of surgical exploration for the lesion, without result.The association of subnormal conjugated plasma NE and/or E with moderately elevated plasma NE + E and a more frequent pseudopheochromocytoma presentation may result from inadequate conjugation, and hence inactivation of NE and/or E. Excessive free catecholamines would account for the clinical symptoms and for tbe fact that the patients are well controlled by treatment with beta-adrenerglc blocking agents, either alone or in combination with a-blockers. Awareness of tbe existence of this variety of essential hypertension can obviate unnecessary surgery for wrongly suspected pheochromocytoma. (Hypertension 3: 347-355, 1981) KEY WORDS • hypertension • catecholamine conjugation defect • pseudopheochromocytomaA N important mechanism for the inactivation of catecholamines (CA) is conjugation, yet this mechanism is poorly explored. In man, conjugation is mainly to sulfates. Circulating norepinephrine (NE) and epinephrine (E) are 80% conjugated (although it is usually the free form that is determined); circulating dopamine (DA) is almost entirely in the conjugated form.
Sulfoconjugation is an important metabolic pathway determining the fate and potential cardiovascular action of ingested phenolic substances. Among the three catecholamines, dopamine (DA) is to the highest degree sulfoconjugated and has the highest affinity toward the phenolsulfotransferase (PST). The concentration of some sulfated catecholamines, particularly of DA sulfate, increases following ingestion of catecholamines or their precursors. This can be confounded with blood-derived increases in DA sulfate associated with BP peaks in some hypertensive patients. We mimicked, therefore, the latter condition by infusion of free DA into normotensive subjects. At low DA infusion rates, plasma DA sulfate exceeded free DA concentrations, and there were no changes in blood pressure and pulse rate. At higher DA infusion rates, blood pressure and pulse rate increased only while plasma free DA concentrations exceeded those of DA sulfate, indicating that free DA remains biologically active only prior to being conjugated. A similar increase in DA sulfate from alimentary sources (e.g., eating a banana) remains without cardiovascular response and is not associated with an overflow of free DA, since all the ingested DA is conjugated in the gut. We describe a patient with pheochromocytoma who experienced repeated hypertensive crises after ingestion of food containing some biogenic amines, (once also documented by NE increase), possibly due to a phenol sulfoconjugation defect (e.g., substrate inhibition of the PST or its genetic deficiency). Platelet PST-determinations may serve as a screening tool to detect subjects with sulfoconjugation defects since they probably reflect the PSt activity in the gut where ingested phenols are sulfoconjugated.
A 52-year-old man was admitted to the Brigham and Women's Hospital (BWH) on August 21, 1984, for evaluation of a possible pheochromocytoma. He was first told of his hypertension at age 43 and was treated with /3-blockers, most recently nadolol (40 mg p.o q.d.) with "good control." On August 12, 1984, he was awakened from sleep with spasmotic midepigastnc pain, strong pulsations in his head, a feeling of generalized warmth, nausea, and diaphoresis. He induced vomiting, which did not improve his symptoms, and had an episode of watery diarrhea. He then went to a local hospital, where a blood pressure (BP) of 152/130 mm Hg was noted. He was treated for abdominal pain with 15 mg of morphine sulfate and 10 mg of prochlorperazine maleate (Compazine). Nadolol (40 mg daily) was continued. Results of an upper gastrointestinal series and a sulfobromophthalein function test were normal, and an abdominal ultrasono- He was transferred to BWH on August 21, 1984 He denied any history of palpitations, chest discomfort, or weight loss. On further questioning, the patient stated that he had had a premonition before each episode occurred. Past medical history included the passage of a kidney stone in 1981. Family history included a father and four siblings with onset of high BP in their midthirties. The patient was experiencing stress because of an ongoing divorce and his work as an executive in a computer company. He smoked no cigarettes, drank alcohol socially, and used no other medications On admission, the following BP measurements were recorded: supine, right arm, 190/110 mm Hg, left arm, 170/110 mm Hg, pulse, 60 beats/min; standing, 96/50 mm Hg, pulse, 100 beats/min. Fundi showed artenolar narrowing; lungs were normal. The carotid arteries were without bruits, and examination of the heart revealed no murmur or gallop. Results of an abdominal examination were normal. The ECG was normal. Results of laboratory studies (Tables 1 and 2) were normal except for serum glutamic-oxaloacetic transaminase levels of 128 U/L, serum glutamic-pyruvic transaminase levels of 216 U/L, and alkaline phosphatase levels of 148 U/L. While at the BWH, the patient had no further episodes.
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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