Two distinct classes of dopamine receptor are functionally thought to exist in peripheral tissue, designated D1- and D2-like receptors (1). D1-Like receptors have been evaluated biochemically in vascular smooth muscle cells (2-4), and stimulation of D1-like receptors causes vasodilation and may regulate blood pressure (BP) (5) as well as atherosclerosis (6-8). We reported a patient with pheochromocytoma, which secretes dopamine (9). In the present study, a possible mechanism for secreting dopamine in this case was studied. This case shows that excessive excretion of dopamine, a vasodilative hormone, may affect BP as well as a vasoconstrictive hormone endothelin (10).
A 65-year-old man was admitted to our University Hospital because of chronic diarrhea. He required no antihypertensive therapy when he was admitted. He had a 2-year history of progressively worsening chronic diarrhea, with six to eight bowel movements per day. He had severe generalized weakness and weight loss. His BP was 140/72 mmHg at admission. His father was hypertensive. His plasma concentrations of renin, aldosterone, noradrenaline and adrenaline were 0.53 ng/ml/h, 2.8 ng/dl, 0.02 ng/ml and 0.46 ng/ml, respectively (within normal range). However, his plasma and urinary free dopamine concentrations were 0.28-0.88 ng/ml and 8000-13 000 μg/day, approximately 10-30 and 8-13 times the normal values, respectively. Urinary homovanillic acid (HVA) was 11.1 mg/day, which was above the normal range. However, urinary adrenaline, noradrenaline, vanillyl-mandelic acid (VMA), metanephrine and normetanephrine were 5.1 μg/day, 83.7 μg/day, 1.9 mg/day, 0.1 mg/day and 0.13 mg/day, respectively (within normal range). An ultrasound of the abdomen revealed a left adrenal mass. This was confirmed by contrast-enhanced computed tomography scan magnetic resonance imaging. A 131I-meta-iodobenzylguanidine scintigram showed the hot spot in the left adrenal lesion. On the clonidine suppression test, the elevated plasma dopamine level was not suppressed by clonidine (225 μg) 3 h after administration, although BP, heart rate, plasma adrenaline and noradrenaline levels were suppressed (Table 1). He was diagnosed with pheochromocytoma. Surgical resection was performed, and dramatic cessation of the diarrhea and BP elevation was observed. Plasma and urinary dopamine level and urinary HVA level became normal. One month after the operation, his BP became 160/100 and he was given 5 mg/day amlodipine. When last seen in May 1998, he was doing well without diarrhea.
The concentrations of noradrenaline, adrenaline and dopamine in the tumor were 51.2, 5.7 and 940 μg/g, respectively. In addition, the concentrations of HVA, VMA, normetanephrine and metanephrine in the tumor were 1.11 μg/g, 0.02 μg/g, 1.0 μg/g, and 0.19 mg/g, respectively. Dopamine-β-hydroxylase (DBH) activity in the tumor was 0.02 nmol/mg/min. We have examined the expression of enzymes of catecholamine metabolism by immunohistochemistry (Fig. 1). Immunohistological study revealed enhanced expression of tyrosine hydroxylase, enhanced expression of aromatic L-amino acid decarboxylase, low expression of DBH and enhanced expression of phenylethanolamine-N-methyltransferase in the tumor (Fig. 2).
The findings that the concentration of DBH and the expression of DBH protein in the tumor were low may explain why the tumor secreted mainly dopamine, since DBH is the enzyme that synthesizes noradrenaline from dopamine. Dopamine is a vasodilative hormone and regulates BP through D1-like receptors (5). Recently, D1A receptor-deficient mice were shown to have higher BP than control mice, suggesting a BP lowering action by dopamine (11). Attenuated D1A receptor activity has also been reported in patients with essential hypertension (12). These findings may explain the BP elevation after tumor resection. The cessation of diarrhea after tumor resection suggests that dopamine may cause diarrhea via D1-like receptors in the gastrointestinal tract (13). Chronic diarrhea and elevated dopamine and its metabolites were also observed in patients with ganglioneuroblastoma (14), consistent with our findings. The tumor in our patient was distinct from ganglioneuroblastoma, since its histological findings, especially the nucleus/cytosol ratio, differed from those for ganglioneuroblastoma, and urinary VMA level was normal.
Acknowledgement: The authors would like to thank Mrs Atsumi Ohnishi and Yuka Inoshita for technical assistance. This study is supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, Kimura Memorial Foundation, Yoshitomi Research Foundation, and Kyowa Hakko Co.
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The symposium and the publication of this supplement were supported by an educational grant from Novartis Pharma K.K. Tokyo, Japan.