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No current histological or cytological indices can distinguish reliably malignant from benign tumors in neuroendocrine tumors, including pheochromocytomas, pancreatic endocrine tumors, and carcinoid tumors. We investigated immunohistochemically the expression of Ki-67 in 52 neuroendocrine tumors, including 17 pheochromocytomas, 9 pancreatic endocrine tumors, 23 carcinoid tumors, 2 neuroendocrine carcinomas (NEC), and 1 neuroblastoma with liver metastasis. Of the 52 tumors, distant metastasis was observed in 4 pheochromocytomas, 2 pancreatic endocrine tumors, 4 carcinoids, 2 NEC, and 1 neuroblastoma. We classified these tumors into 3 groups; Groups A, B, and C, depending on the number of Ki-67-positive cells counted under a 200 x magnified field. Expression of Ki-67 was extremely high in group A (> 50 labeled nuclei/field), moderately high in group B (20-50 labeled nuclei), and very low in group C (< 10 labeled nuclei). There was a significant correlation between expression of Ki-67 and tumor progression. The tumors in group A progressed rapidly with the worst outcome; the tumors in group B progressed slowly but with a bad outcome; and the tumors in group C had no metastasis and a good prognosis. Ki-67 is an excellent indicator to assess progression of neuroendocrine tumors.

Pheochromocytoma usually shows prominent nuclear atypia, but the presence of such atypical cells is known to be an unreliable predictor of malignancy. DNA ploidy of pheochromocytomas has been analyzed by flow cytometry or photospectrometry on paraffinem-bedded tissue, but the results were controversial. We performed DNA analysis on cytology specimens of 11 pheochromocytomas using an image analysis system. All tumors had a mixed pattern of a large population of diploid cells and a small population of polyploid cells. DNA content correlated with nuclear size, and larger cells had more DNA content. Such larger tumor cells had polyploid nuclei, such as 4 C, 8 C, 16 C, and 32 C, in both malignant and benign pheochromocytomas. The larger polyploid nuclei may result from difficulty of duplication at the mitotic phase of the cell cycle.

It has long been thought that there is a close association between hypertension and atrial fibrillation (AF). However, the efficacy of an angiotensin II receptor blocker for the prevention of organ damage in hypertensive individuals with AF is still controversial. The present study was a multicentered, prospective, randomized, open-label clinical trial investigating the differences in the effect of treatment with telmisartan/amlodipine combination tablets on blood pressure (BP) levels and BP variability between morning and bedtime administration in hypertensive patients with paroxysmal AF, using ambulatory BP monitoring (ABPM) and home BP. With this treatment, the patients' 24-hour BP, nighttime BP, preawake BP, and morning BP shown by ABPM were significantly reduced, and the antihypertensive effects were similar regardless of the timing of the drug administration. The standard deviation of day-by-day home systolic BP and the maximum home systolic BP were also significantly reduced, and these effects were similar regardless of the treatment timing. The N-terminal pro-brain natriuretic peptide level was significantly decreased only in the bedtime administration group. A larger study will demonstrate whether the bedtime administration of telmisartan/amlodipine combination tablets maximizes the risk-lowering effect against AF recurrence in paroxysmal AF hypertensive patients.

A 63-year-old male patient was admitted for the treatment of malignant pheochromocytoma with multiple liver metastases. Plasma and urinary levels of catecholamines were elevated. Transcatheter arterial embolization (TAE) with concomitant administration of mitomycin C and gelatin sponge was performed for the treatment of liver metastases. Dose of alpha-1 blocker before TAE was increased to prevent hypertensive crisis during and after TAE. The hepatic metastatic lesion of CT findings was decreased after TAE. Although blood pressure showed a transient hypertension (180/100 mmHg) after every TAE, it returned rapidly to normal. The patient experienced transient abdominal pain, nausea, and loss of appetite after every TAE; however, those symptoms were readily controlled by conventional medications. Slight elevation of liver transaminases was recognized but returned to normal range within 3 weeks. No other major side effects were seen with TAE. While plasma and urinary level of catecholamines were unchanged, plasma chromogranin A (CgA) level was significantly decreased. These results suggest that TAE is a useful treatment for hepatic metastases. Plasma CgA level is a useful marker in the treatment of malignant pheochromocytoma.

Adrenal tumors, such as pheochromocytomas, are known to express various peptides and their receptors. Prolactin-releasing peptide (PrRP) is a novel neuropeptide isolated from bovine hypothalamic tissues. In the present study, expression of PrRP receptor was studied in the human brain, pituitaries, adrenal glands and tumor tissues of adrenocortical tumors, pheochromocytomas, a ganglioneuroblastoma and neuroblastomas by reverse transcriptase polymerase chain reaction (RT-PCR) and Northern blot analysis. The presence of immunoreactive-PrRP in the adrenal glands and in these tumor tissues was studied by radioimmunoassay. Human brain tissues and pituitaries were obtained at autopsy. Normal portions of adrenal glands and tumor tissues were obtained at surgery. RT-PCR analysis showed expression of PrRP receptor in the human brain, pituitaries, normal portions of adrenal glands and various tumor tissues. Northern blot analysis showed high expression of PrRP receptor only in tumor tissues of pheochromocytomas, indicating that PrRP receptor expression is high in pheochromocytomas. Immunoreactive-PrRP was detected in normal portions of adrenal glands (0.162+/-0.024 pmol/g wet weight, n=4, mean+/-S.E.M.), four out of six cases of pheochromocytomas (0.050-7.9 pmol/g wet weight), one neuroblastoma and some adrenocortical tumors. The present study has shown that PrRP receptor mRNA was widely expressed in the brain tissues, pituitaries, adrenal glands and various tumors. The high expression of PrRP receptor in pheochromocytomas suggests potential pathophysiological roles of PrRP in these tumors.

Composite tumor of pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1). To better understand the relationship between NF1 and composite pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and pheochromocytoma cells of the composite pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in pheochromocytomas from the patients with NF1. Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite pheochromocytomas as well as in neurofibromatosis.

Expression of melanin-concentrating hormone (MCH) receptor messenger ribonucleic acid (mRNA) was studied by RT-PCR and Northern blot analysis in human brain; pituitary; adrenal glands; tumor tissues of adrenal tumors, ganglioneuroblastomas, and neuroblastomas; and various cultured tumor cell lines. RT-PCR analysis showed that MCH receptor mRNA was widely expressed in brain tissues, pituitary, normal portions of adrenal glands (cortex and medulla), tumor tissues of adrenocortical tumors (12 of 13 cases), pheochromocytoma (all 7 cases), ganglioneuroblastoma (1 case), neuroblastoma (all 5 cases), and various cultured tumor cell lines (6 of 7 cell lines), including 2 neuroblastoma cell lines. Northern blot analysis showed the expression of MCH receptor mRNA (∼2.4 kb) only in the tumor tissues of 5 pheochromocytomas, 1 ganglioneuroblastoma, and 4 neuroblastomas, indicating that the expression levels of MCH receptor mRNA are much higher in these tumors than in the other tissues. These findings raised the possibility that MCH or MCH-like peptides may be related to the pathophysiology of these neural crest-derived tumors.

A germline mutation either in exon 10 or 11 of the RET proto-oncogene is found in the majority of patients with multiple endocrine neoplasia type 2A (MEN 2A). A 41-year-old female patient was referred for further evaluation of incidentally discovered right adrenal tumor. She had bilateral adrenal pheochromocytomas and medullary thyroid carcinomas detected by endocrinological and radiological examination, and diagnosed as MEN 2A. Molecular genetic testing of the RET exons 10 and 11 exhibited the identical somatic missense mutation at codon 634 in both tumors but did not confirm germline mutations in the corresponding sites. Possible mechanisms for tumorigenesis in this patient are discussed.

To investigate changes in systemic and regional hemodynamics during the development of human hypertension, we simultaneously measured cardiac index (CI) by the indocyanine green (ICG) dye dilution method, hepatosplanchnic blood flow (HBF) by the ICG clearance method using a two-compartment model, and renal blood flow (RBF) by the p-aminohippurate clearance method in patients with borderline and essential hypertension. In patients with borderline hypertension (BH, n=27), HBF (435±15 ml/min/m2) and HBF/CI (16±1%) were significantly (p

SUMMARY 1. The acute effect of an angiotensin converting enzyme inhibitor (ACEI), enalaprilat, on baroreflex-mediated changes in renal and total NA spillover rate in conscious rabbits with doxorubicin-induced cardiomyopathic congestive heart failure (CHF) were investigated under resting conditions and in response to changes in arterial pressure induced by sodium nitroprusside and phenylephrine infusions. 2. Six saline-treated (N group) and 11 doxorubicin-treated rabbits (1 mg/kg administered i.v. twice weekly) were studied after 4 and 6 weeks treatment. Five CHF rabbits received saline (C group) and six enalaprilat infusion (ACEI group). 3. After 4 weeks of doxorubicin, mean arterial pressure (MAP)-renal noradrenaline (NA) spillover and MAP-total NA spillover curves did not change during enalaprilat infusion. 4. After 6 weeks, the C group showed blunted MAP-renal NA spillover and MAP-total NA spillover curves. In the ACEI group, however, both curves returned toward those seen in the N group (slope of MAP-renal NA curve: from 0.27 to 1.80 ng/min per mmHg, MAP-total NA curve: from 1.61 to 3.59 ng/min per mmHg). 5. Results of this study indicate that enalaprilat enhances baroreflex control of renal and total NA spillover in rabbits with CHF and further support the view that activation of the renin-angiotensin system contributes significantly to the attenuated baroreflex responses in CHF.

The prognosis of metastatic pheochromocytoma is poor in general. There have been few instances of long-term survival reported. We report a case of a 44-year-old woman who has survived for 26 years after bone metastasis. She was diagnosed as having pheochromocytoma arising in the left adrenal medulla in 1974. Metastasis of pheochromocytoma in the first and third lumbar vertebrae and the right ilium was observed at the same time. The primary lesion was removed, and posterior lumbar spinal fusion was performed for immobilization. The metastatic lesion in the ilium was left untouched. After 26 years, she is well despite a recurrence of the tumors in the skull and a new metastasis in the left abdomen.

SUMMARY 1. To evaluate the effects of angiotensin-converting enzyme (ACE) inhibition on sympathetic nerve activity, renal and total norepinephrine (NE) spillover rates were examined under control conditions and during enalaprilat infusion at rest and in response to sodium nitroprusside (SNP)-induced hypotension. 2. Resting renal and total NE spillover rate during enalaprilat infusion were similar to control values. 3. During SNP infusion at 10 μg/kg per min, renal NE spillover rate increased by 26% in enalaprilat-treated group and by 39% in controls, in response to falls in mean arterial pressure (MAP) of 25 and 19% respectively. 4. During sympathetic stimulation induced by SNP, total NE spillover rate was significantly increased in both groups, but the 50% (s.e.m. = 12) increase in the enalaprilat-treated group was less (P

Pheochromocytomas and extra-adrenal sympathetic paragangliomas show varied histological patterns, and it is difficult to diagnose malignancy or predict the clinical course using current histological criteria. In the present study, we reviewed 146 sympathetic paragangliomas including 116 adrenal (102 unilateral, 14 bilateral) and 30 extra-adrenal tumors including 38 metastatic tumors. We developed a scoring scale according to the following six factors: histological pattern, cellularity, coagulation necrosis, vascular/capsular invasion, Ki-67 immunoreactivity, and types of catecholamine produced. The tumors were classified as well (WD), moderately (MD), and poorly differentiated (PD) types according to their scores. The frequency of these tumor types were 113 WD (77%), 27 MD (19%), and 6 PD (4%). Metastasis was observed in 15 of 113 WD (13%), 17 of 27 MD (63%), and all 6 PD (100%). Five-year survivals of patients with metastases were 92% with WD, 69% with MD, 0% with PD. Respective 10-yr survivals were 83%, 38%, and 0%. Differences between groups were statistically significant. The data show that using this grading scoring system for sympathetic paragangliomas correlates with both metastatic potential and patient survival.

1. This study was designed to investigate the effects of isotonic saline loading on renal tubular and neurogenic dopamine (DA) in conscious rabbits. 2. Isotonic saline loading did not affect mean arterial pressure, heart rate or renal blood flow but markedly increased urine volume, sodium excretion and DA excretion. 3. Renal DA spillover was not affected by venous emptying, while renal noradrenaline (NA) spillover tended to decrease during saline loading. The ratio of % renal DA spillover to % renal NA spillover increased to 2.3 +/- 0.6 (P < 0.05) 3 h after saline loading. 4. Isotonic saline loading increased renal tubular DA production but had little effect on neurogenic DA release.

Urotensin II is a potent vasoactive peptide, which was originally isolated from fish urophysis. We studied expression of urotensin II and its receptor mRNAs in the tumor tissues of adrenocortical tumors, pheochromocytomas and neuroblastomas. Effects of exogenously added urotensin II on cell proliferation were studied in a human adrenocortical carcinoma cell line, SW-13 and a human renal cell carcinoma cell line, VMRC-RCW. The reverse transcriptase polymerase chain reaction (RT-PCR) showed expression of urotensin II and its receptor mRNAs in all the samples examined; seven pheochromocytomas, nine adrenocortical adenomas (four with primary aldosteronism, four with Cushing syndrome and one with non-functioning adenoma), four adrenocortical carcinomas, one ganglioneuroblastoma and five neuroblastomas, as well as four normal portions of adrenal glands (cortex and medulla). Urotensin II-like immunoreactivity was detected in one of eight adrenocortical adenomas, two of four adrenocortical carcinomas, one of six pheochromocytomas, and one of five neuroblastomas by radioimmunoassay, but not in normal portions of adrenal glands (detection limit; 0.2 pmol/g wet weight). Treatment with urotensin II for 24 h significantly increased number of SW-13 cells (at 10 −8 and 10 −7 mol/l) and VMRC-RCW cells (at 10 −8 mol/l). These findings raise the possibility that urotensin II may act as an autocrine/paracrine growth stimulating factor in adrenal tumors.

Stanniocalcin (STC) is a calcium (Ca)-regulating hormone that was originally discovered in the fish Stannius body, which is a unique endocrine organ. Hypercalcemia increases STC secretion, which inhibits Ca uptake by the gills and normalizes serum Ca level. In this study we investigated the STC expression in human normal and abnormal adrenal cells. Immunohistochemistry using monoclonal antibody against STC revealed specific staining in zona glomerulosa and medulla of normal human adrenal glands. STC was also detected in human adrenal tumors, such as pheochromocytoma, differentiated neuroblastoma, and aldosterone-producing adenoma, and cultured adrenal tumor cells (rat pheochromocytoma PC-12 cells and human neuroblastoma NB-1 cells). However, undifferentiated human adrenal neuroblastoma was negative for STC staining. Reverse transcription polymerase chain reaction demonstrated STC mRNA expression in cultured PC-12 cells and NB-1 cells. Following several studies indicating that zona glomerulosa cells of adrenal glands express neuroendocrine properties, STC expression in normal and abnormal adrenal cells provides additional evidence to support the neuroendocrine differentiation of these cells. In conclusion, STC may be useful as a new cell marker of adrenal glands under physiological and pathological conditions.

Two women who first had the clinical features of primary aldosteronism in the postpartum period are described. Their gestations were virtually uneventful. After delivery, however, progressively severe hypertension (Joint National Committee VI, stage 3) with hypokalemia developed. Pregnancy may conceal the clinical symptoms of primary aldosteronism that causes unexpected severe hypertension in the postpartum period.

To investigate changes in preoperative clinical features and the long-term outcome of tumor recurrence, mortality, and morbidity in patients with pheochromocytoma, we retrospectively examined changes in the clinical features by comparing 49 patients from 1957 to 1985 (group I) with 46 patients from 1986 to December 1995 (group II). In addition in these 95 patients (excluding 2 who had died before operation), we evaluated long-term postoperative outcome from the initial operation to August 1996 (909 patient-years). The mean age in group II was older than that of group I. The percentage of patients having proteinuria or hypertensive retinopathy in group II was less than that in group I. Of 20 patients with incidentally discovered pheochromocytoma, 7 (35%) were ≥60 years old, 7 asymptomatic, and 11 (55%) normotensive. Plasma and urinary catecholamines in these patients were significantly (P < .01) lower than in patients with pheochromocytoma having typical clinical features. Long-term cohort study showed 14 deaths. Relative survival rates were 91% at 5 years and 83% at 10 years and unchanged thereafter. The Kaplan-Meier estimate of pheochromocytoma-free survival was shorter in patients with a larger-than-median (60 g) tumor weight. Six patients had malignant recurrence 3 to 101 months (median, 45 months) after the initial operation. Of 65 patients confirmed alive at follow-up, 11 were hypertensive. In the Cox model, hypertension-free survival was not associated with age, a family history of hypertension, duration of hypertension, or creatinine clearance. Pheochromocytoma should be diagnosed from a wide spectrum of clinical features including those that are not generally suspected of resulting from excess catecholamines or hypertension, and after surgery, patients with this disease should be followed-up carefully for a long period (at least 10 years) because of the risk of tumor recurrence and the high prevalence of disease.

To examine sympathetic and vagal cardiovascular regulatory mechanisms in the pathogenesis of orthostatic hypotension in pheochromocytoma, we continuously monitored blood pressure (Finapres) and RR interval (electrocardiogram) in supine and standing positions in 12 patients with pheochromocytoma, 43 patients with essential hypertension, and 30 normotensive subjects. Mayer wave power spectrum of systolic blood pressure variability (approximately 0.1 Hz) and respiratory power spectrum of the RR interval variability (approximately 0.25 Hz) were taken as measures of sympathetic vascular and cardiac vagal modulations, respectively. Systolic blood pressure decreased more upon standing in pheochromocytoma patients (-21 +/- 7 mm Hg) than in normotensive subjects (-5 +/- 2 mm Hg) or essential hypertensive patients (-3 +/- 2 mm Hg) (P.005 for both), whereas heart rate tended to increase most in the pheochromocytoma group. Postural reduction in systolic blood pressure was highly correlated with postural increase in heart rate (reciprocal change in RR interval) in the pheochromocytoma group (r = 0.716, P.01) suggesting that baroreflex is well functioning in those patients. The Mayer wave power spectrum in recumbency was extremely depressed in pheochromocytoma patients (1.1 +/- 0.2 mm Hg2) compared with normotensives (4.5 +/- 0.8 mm Hg2) or essential hypertensives (5.6 +/- 0.6 mm Hg2) (P.001 for both). This parameter increased significantly with standing in all groups but remained lower in patients with pheochromocytoma (5.1 +/- 1.0 mm Hg2) than in normotensives (7.1 +/- 0.9 mm Hg2, P = NS), whereas essential hypertensive patients demonstrated far greater value (19.2 +/- 3.8, P.01 for both). The respiratory power spectrum of the RR interval in recumbency of pheochromocytoma patients (189 +/- 54 msec2) was less than in normotensive subjects (714 +/- 100 msec2, P.001) but did not differ from that in patients with essential hypertension (214 +/- 41 msec2). The respiratory power spectrum of the RR interval upon standing was markedly suppressed in pheochromocytoma patients (36.9 +/- 16.7 msec2) compared with normotensive subjects (129.5 +/- 23.6 msec2) or essential hypertensive patients (126.6 +/- 28.6 msec2) (P.001 for both). Postural decrement in the respiratory power spectrum of the RR interval correlated positively with postural increase in heart rate (r = 0.577, P.05) in patients with pheochromocytoma. After successful surgery (n = 9), the Mayer wave power spectrum of the systolic blood pressure and the blood pressure response to orthostasis were normalized. These data suggest that altered sympathetic vascular regulation is central to the pathogenesis of orthostatic hypotension in pheochromocytoma, whereas cardiac vagal regulation acts to compensate.

We treated two rare cases of pheochromocytoma which were histopathologically diagnosed as mixed neuroendocrine-neural tumor (MNNT): a 35-year-old male patient associated with ganglioneuroblastoma and cutaneous neurofibromatosis and a 42-year-old male patient with ganglioneuroma. Both patients showed typical clinical manifestations of pheochromocytoma without any familial traits. Although each of the diseases has its own entity and clinical features, these tumors are all derived from the neural crest tissues. The tumorigenesis of MNNT is still unknown. Here, a brief review of the recent literature on this subject is discussed.

Renal and total dopamine (DA) spillover rates at rest were measured in 25 conscious rabbits with chronically implanted renal vein catheters. Renal DA spillover rate was calculated from veno-arterial difference in plasma free DA concentrations across the kidney corrected by the fractional extraction of infused 3H-DA. Plasma free DA concentrations were 11.0 +/- 2.7 pg/ml in the artery and 14.3 +/- 3.6 in the renal vein. Renal and total DA spillover rates were 0.51 +/- 0.08, 2.61 +/- 0.30 ng/min, respectively, both of which were significantly (p < 0.001) lower than the respective norepinephrine (NE) spillover rates (renal: 16.3 +/- 1.4, total: 39.6 +/- 1.7). The fractional extraction of 3H-DA across the kidney (55 +/- 3%) and the total DA clearance (285 +/- 31 ml/min) were both significantly (p < 0.05) higher than that of 3H-NE (45 +/- 3) and the total NE clearance (198 +/- 9), respectively. The ratio of renal to the total spillover rate of DA (0.23 +/- 0.05) was significantly (p < 0.05) lower than that of NE (0.41 +/- 0.04). These results demonstrate that DA is released into plasma within the kidney and suggest that the measurement of renal DA spillover rate using 3H-DA radiotracer technique is useful to detect resting renal dopaminergic nerve activity.

To investigate the peripheral dopaminergic modulation in the pathogenesis of human hypertension, we examined the responses of plasma free dopamine (DA) to dexamethasone (Dx) administration, which is suggested to activate dopaminergic activity. We administered Dx 2mg intravenously to patients with primary aldosteronism (PA), essential hypertension (EH), and normotensive controls (NT). Plasma free DA was increased significantly in all groups and the responses were more remarkable in PA than in EH and NT. Plasma epinephrine (E) showed a gradual increase while plasma norepinephrine (NE) tended to decrease in all groups. The responses of both plasma DA and E were completely blocked by 250mg of α-methyl-p-tyrosine, a tyrosine hydroxylase (TH) inhibitor, suggesting that Dx may stimulate peripheral dopaminergic activity by increasing catecholamine synthesizing enzyme (probably TH) activities. These data suggest that DA itself plays an inherent role in the sympathoadrenal regulation rather than only as a precursor of NE and that dopaminergic hyperresponses may be involved in the pathophysiology of PA. (Hypertens Res 1995; 18 Suppl. I: S197-S198)

Dopamine (DA) is the most abundant catecholamines in human plasma and exists mostly in the sulfoconjugated form (DA sulfate), a biologically inactive metabolite. The paucity of unconjugated DA (PDA) in plasma throws doubt on its physiological significance. However, PDA, when measured with a highly sensitive radioenzymatic method, showed quite different features from norepinephrine and epinephrine in some types of clinical hypertension, lower in essential hypertension and higher in primary aldosteronism and pheochromocytoma. There was a weak but significant correlation between the values of PDA and DA sulfate measured in the same specimens, but DA sulfate was more susceptible to impaired renal function. Upright posture, high salt diets and an intravenous injection of metoclopramide (MCP, 10 mg), a DA receptor antagonist, induced a slight but significant increase in PDA in normal and hypertensive subjects. An intravenous dexamethasone (2mg) caused a gradual increase in PDA over 150min after medication, which was completely blocked by concomitant administration of α-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. The responses of PDA to both high salt diets and MCP were blunted in salt-sensitive patients with uncomplicated essential hypertension. The results suggest that DA is not only a precursor of norepinephrine biosynthesis but also plays an inherent role as an active neurotransmitter in the peripheral sympathoadrenal system, and that PDA is a sensitive marker of peripheral dopaminergic activity, which may operate to modulate the cardiovascular and endocrine functions and participate in the pathogenesis of some types of hypertension. (Hypertens Res 1995; 18 Suppl. I: S65-S72)

Tritiated yohimbine binding was used to estimate platelet membrane alpha 2-adrenoceptor characteristics in normal subjects (n = 12) and patients with essential hypertension (n = 30), primary hyperaldosteronism (n = 10) and phaeochromocytoma (n = 10). There was a 20-fold increase in mean levels of resting norepinephrine and epinephrine in the phaeochromocytoma group. Total binding sites (Bmax) and dissociation constant (Kd) for 3H-yohimbine did not differ significantly among the four groups. Following curative surgery for phaeochromocytoma, plasma catecholamine levels were normalized but the Bmax remained unchanged. Following surgery for primary hyperaldosteronism, levels of plasma norepinephrine rose but Bmax was not changed. In all but the phaeochromocytoma patients, Bmax values correlated positively (r = 0.437, n = 48, P less than 0.01) with resting plasma norepinephrine. A significant negative correlation was observed between the change in plasma norepinephrine in response to postural change and resting Bmax. Treatment for 2-4 weeks with guanabenz or bethanidine induced a parallel fall in both Bmax and plasma norepinephrine. Treatment with reserpine was followed by a comparable fall in plasma norepinephrine, but Bmax values were unchanged. The findings support the view that platelet alpha 2-adrenoceptor density is functionally regulated in parallel with sympathetic nerve activity rather than circulating catecholamine levels, although it is not known which neuronal substance(s) may participate in this regulation.

The concentration of plasma free dopamine (PDA) is said to be much lower than that of other catecholamines and its physiological significance remains unclear. Our recent studies using a newly developed radioenzymatic method disclosed the fairly distinctive features of PDA in patients with various types of hypertension. PDA was also confirmed as a variable responsive to postural change, dietary sodium loading and dopamine receptor antagonist. The results suggest that PDA could be a sensitive marker to represent the peripheral dopaminergic function, which might play an inherent role as a physiological regulator responsible for the cardiovascular and endocrine system.

The effects of dietary potassium on the hemodynamics and plasma norepinephrine (NE) kinetics were studied in 10 patients with borderline hypertension. Potassium supplement (96 mEq daily for 5-7 days) induced a significant (p less than 0.05) fall in blood pressure and a slight decrease in cardiac output. Both urine volume and urinary sodium excretion increased significantly (p less than 0.05) for a first few days following the potassium supplement. The baseline values of the half-time of the rapid NE removal from plasma was significantly delayed in the hypertensive patients (1.05 +/- 0.06 min, p less than 0.05) when compared with those (0.88 +/- 0.04) in normal controls. Potassium supplement induced a significant rise in both plasma NE levels and NE outflow rate (p less than 0.01) in the hypertensive patients, while their half-times were significantly shortened (0.89 +/- 0.07 min, p less than 0.01). The pressor responsiveness to exogenously infused NE tended to diminish during the potassium supplement. These findings indicate that a high potassium intake might accelerate the slowed neuronal NE uptake in the hypertensive patients, while a potassium-induced fall in blood pressure might exert a baroreflex stimulation of NE release. As a net result, an increased NE outflow into the circulation has been confirmed. It is likely that a natriuresis-induced volume contraction might be a predominant factor responsible for the early reduction of blood pressure during the high potassium intake.

The effects of epinephrine (E) on plasma norepinephrine (NE) concentrations and cardiovascular responses before and after beta-blockade were studied in 36 patients with essential hypertension and 10 age-matched normal controls. The resting plasma NE and E were significantly higher in the borderline hypertensives (251 +/- 21 (SE) pg/ml, p less than 0.005; 57 +/- 5, p less than 0.05) than in normal controls (127 +/- 18; 38 +/- 7). An immediate rise in plasma E and NE was observed after one bolus intravenous administration of glucagon (1 mg). Then, plasma E fell rapidly to the baseline, whereas plasma NE declined much slowly. Propranolol did not affect the plasma E response to glucagon, but eliminated a prolonged rise of plasma NE. Exogenous E infusion (1.25-1.50 micrograms/min) for 30 min caused a definite rise in both plasma NE and blood pressures and lasted more than 30 min after termination of the infusion. Propranolol did not alter the time course of plasma E, but again inhibited a prolonged rise in both plasma NE and blood pressures. These findings support the view that plasma E can act physiologically as a sustained stimulator to the presynaptic beta-adrenoceptors, leading to an enhancement of NE release and a rise in blood pressure in man.

悪性褐色細胞腫はきわめてまれな疾患であるが,広範な遠隔転移を伴う場合,長期間にわたつて対症療法が必要となる.本稿では, 37才の男性例で骨,肝,リンパ節などに広範な転移をきたし,経過中にイレウス症状が持続したため,延べ10カ月間にわたりαおよびβ遮断薬の静脈内投与を必要とした症例を報告した.これらの薬物の投与量は1日に最大phentolamineが3500mg, propranololが80mgにも達し治療に難渋した.本例に合供したイレウス症状は過剰な血中カテコラミンによる腸管麻痺に起因するものと考えられ, phentolamineが他のα遮断薬や蠕動促進薬に比べて著効を示した.本薬の長期大量投与にもかかわらず,治療期間中重篤な副作用は認められなかつた.

SUMMARY 1 The baroreflex-mediated changes in plasma norepinephrine (NE) and heart period (RR interval) to phenylephrine (PE)-evoked pressor and nitroprusside (NP)-evoked depressor stimulations were studied in 19 patients with chronic essential hypertension, 12 with borderline hypertension and in 11 age-matched normal controls. 2 Intravenous infusion of PE at a rate of 0.25-1.0 |ig/kg/min induced dose-related increases in fhean arterial pressure (MAP) and in RR interval and a decrease in plasma NE. Similarly, NP infusion at a rate of 0.1-0.4 ug/kg/min evoked the opposite changes in each variable. The reflex sensitivity was defined as the slope of linear regression between the changes in RR interval and MAP (RR/MAP) and between those in plasma NE (% of the baselines) and MAP (%NE/MAP). 3 Both RR/MAP and %NE/MAP for pressor and depressor stimulations were reduced below values found in normal subjects, in both chronic and borderline hypertensives. 4 The values of %NE/MAP was negatively related to the basal plasma NE during falls in blood pressure (r= -0.401, P

Functional relationships between platelet alpha 2-adrenoceptors and sympathetic nerve activity were studied in patients with essential hypertension (n = 23), primary aldosteronism (n = 10), and normal subjects (n = 12). The maximum number of binding sites (Bmax) and the dissociation constant (Kd) of 3H-yohimbine on platelet membranes and resting plasma norepinephrine (NE) were similar among these groups of subjects. In all subjects combined, Bmax values were correlated positively (r = 0.471, p less than 0.01) to resting plasma NE and negatively (r = -0.531, p less than 0.01) to the changes in plasma NE when subjects were moved from lying to standing. A 2-4 week treatment with guanabenz or bethanidine induced a parallel fall of both Bmax and plasma NE, whereas administration of reserpine caused a similar fall of plasma NE but Bmax remained unchanged. Kd values were not changed after any of these treatments. The results support the view that platelet alpha 2-adrenoceptor density is functionally regulated in parallel with sympathetic nerve activity rather than plasma NE per se. This hypothesis seems quite reasonable when it is extended to the presynaptic alpha 2-adrenoceptors; otherwise, the negative feedback function on NE release should be lessened and contradictory to its physiological role.

The concentrations of unconjugated plasma dopamine (PDA) were studied in patients with various types of hypertension. Catecholamines were extracted from plasma specimens (1.0-3.0 ml) through an Amberlite CG50 (Li+-form) microcolumn and eluted by a magnesium sulfate - ethanol solution. The elute was then desalinated and deproteinized by the ethanol-treated precipitation procedure and dried in a vacuum oven at 25 degrees C. A fraction of catecholamines was assayed with the modified procedures of the COMT-mediated radio-enzymatic method. This assay system was sensitive enough to permit an accurate measurement of PDA as low as 6.0 pg per ml of plasma without any detectable contamination of the conjugated dopamine. The resting levels of PDA were 10.1 +/- 1.0 pg/ml (mean +/- SEM), 9.5 +/- 1.0 and 13.7 +/- 0.6 in patients with borderline hypertension (BH, n = 25), essential hypertension (EH, n = 22) and renovascular hypertension (RVH, n = 8), respectively. The values in EH patients were significantly smaller than those in age-matched normal controls (13.0 +/- 1.4, n = 14, p less than 0.05). Remarkably increased PDA values were observed in patients with pheochromocytoma (76.5 +/- 25.4, n = 9, p less than 0.01). Significantly raised PDA values were also found in patients with primary aldosteronism (PA, 27.8 +/- 9.0, n = 6, p less than 0.05), while their plasma norepinephrine levels (PNE, 169 +/- 39 pg/ml) tended to be lower than those of normal controls (206 +/- 20), showing an apparent dissociation between the values of PDA and PNE. Upright posture for 15 minutes induced a significant rise in PDA (p less than 0.05) in all subjects except PA patients. The postural changes of PDA, however, were invariably smaller than those of PNE (p less than 0.05). The resting values of PDA in normal, BH and EH patients showed a significant negative correlation with their mean arterial pressures (r = -0.301, n = 61, p less than 0.05) and a positive correlation with those of PNE (r = 0.381, p less than 0.01). There was no correlation between PDA and age in any group studied. These findings indicate that PDA might not be only a precursor fraction of neurotransmitters released from the sympathetic nervous system but could also represent a physiological function of the dopaminergic regulatory system. The varied but distinctive features of PDA status in various types of hypertension suggest the possibility that the peripheral dopaminergic mechanisms play an inherent role in the pathogenesis of hypertension.

TORIYABE, S., MIURA, Y., KIMURA, S., MEGURO, Y., SUGAWARA, T., NOSHIRO, T., TAKAHASHI, M., OHASHI, H., SANO, N., WATANABE, H. and YOSHINAGA, K. A Plasma Inhibitor of Sodium and Potassium Activated Adenosine Triphosphatase in Patients with Essential Hypertension. Tohoku J. exp. Med., 1988, 155 (2), 129-137 - The purpose of this study is to evaluate the plasma Na, K-ATPase inhibitor (NKI) in patients with essential hypertension and to compare the mode of its biochemical actions on the Na, K-ATPase with that of ouabain. Plasma NKI was extracted through a reversed-phase cartridge column and its inhibitory action on hog brain Na, K-ATPase was measured in vitro. Plasma NKI activity was significantly greater in patients with essential hypertension (44±2.8% (S.E.), n=28, p

The effects of sodium depletion on plasma norepinephrine (NE) kinetics were studied in 14 patients with essential hypertension using the steady state NE infusion technique on the theoretical basis of a two-compartmental open model. The calculated half time of rapid removal phase (t 1/2 alpha) of plasma NE was significantly delayed in the hypertensives (1.20 +/- 0.22 min, mean +/- SD) than in normal subjects (0.89 +/- 0.14) (p less than 0.01). The total clearance rates were comparable between the 2 groups (47 +/- 7 vs 48 +/- 11 ml/kg/min). The rates of the endogenous NE outflow into the circulation (RE-NE) were not significantly different between normal (5.29 +/- 1.68 ng/kg/min) and hypertensives (7.69 +/- 5.42), although 5 hypertensive patients (36%) showed an increased RE-NE above the normal range. The prolonged half time (t 1/2 alpha) in the hypertensives tended to be shortened after sodium depletion induced by either low sodium diet or diuretics (1.04 +/- 0.22, p less than 0.001). Both plasma NE and RE-NE were significantly increased after sodium depletion. A close correlation was observed between plasma NE and RE-NE (r = 0.907, p less than 0.001) in these subjects. These results suggest the slowed neuronal uptake of NE at the sympathetic nerve terminals in some patients with essential hypertension, occurring in part as a sodium-mediated consequence.