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A 70-year-old woman with type IIb therapy-refractory hyperlipidemia was diagnosed as having IgA kappa type multiple myeloma. She had neither a family history nor any other disease known to accompany hyperlipidemia. The serum IgA concentration fell from 3.42 g/dl to 1.24 g/dl following chemotherapy with melphalan and prednisolone, and a concomitant decrease in both the serum cholesterol and triglyceride levels was observed. These serum lipids were positively correlated with the serum IgA concentration (p < 0.001) during the three cycles of chemotherapy. These findings suggest the involvement of the monoclonal protein of IgA in the development of hyperlipidemia in the present case.

We measured plasma concentrations of adrenomedullin (AM), a novel bioactive peptide with potent vasodilator activity, in 21 patients with chronic congestive heart failure due to various heart diseases and compared them to levels in age- and sex-matched healthy subjects to examine the pathophysiological role of plasma AM in heart failure. In addition, the relationship between plasma AM and other hormones known to control the cardiovascular system was examined in these patients. The plasma AM level in the patients with heart failure was significantly (P0.01) higher than that in the control subjects (mean +/- SEM, 2.94 +/- 0.15 fmol/mL; n = 16), with a significantly (P0.05) higher concentration in patients in class III or IV (11.82 +/- 1.81 fmol/mL; n = 5) of the New York Heart Association functional classification than in those in class I or II (8.74 +/- 0.44 fmol/mL; n = 16). There were no significant correlations between plasma AM and catecholamine levels, whereas the plasma AM level was significantly correlated with the concentrations of plasma atrial natriuretic peptide (r = 0.58; P0.01), brain natriuretic peptide (r = 0.47; P0.05), and PRA (r = 0.77; P0.01) in the patients. Thus, the plasma AM concentration increased in proportion to the severity of heart failure along with the hormones known to modulate the development of congestive heart failure. The present findings suggest a possible role for AM as a circulating hormone participating in the defense mechanism against further deterioration of congestive heart failure in patients with heart disease.

A case of extramedullary plasmacytoma (EMP) of the jejunum, an uncommon neoplasia, is reported. A 56-year-old Japanese woman who experienced intermittent upper abdominal pain and weight loss had a large movable mass in the upper abdomen. The mass was hypervascular in an angiographic study and positive for gallium-67 citrate scintigraphy. Immunoelectrophoresis showed the presence of an M-component of immunoglobulin (Ig) A-λ in the serum. It was identified as an EMP immunohistochemically positive for IgA-λ, . This M-component disappeared after resection and chemotherapy. The clinical features of this rare neoplastic disorder are discussed.(Internal Medicine 35: 422-426, 1996)

The association of nitric oxide (NO) with the hypotensive effects of adrenomedullin (AM) was investigated in anesthetized rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were used at 11–13 weeks of age. Blood pressure and heart rate were measured from the femoral artery under mild anesthesia using pentobarbital. AM, over the dose range of 0.3–3 nmol/kg iv, produced dose-dependent sustained hypotension and compensatory tachycardia. These effects of AM at 0.3, 1, and 3 nmol/kg iv were significantly stronger in SHR (−9 ±4, −53 ±9, and −62 ±7 mmHg) than in WKY (−4 ±1, −16 ±2, and −22 ±2 mmHg). Those at 1 nmol/kg iv were markedly inhibited in SHR (−53 to −19 mmHg) and in WKY (−16 to −12 mmHg) by treatment with the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg iv). On the other hand, the difference of hypotensive effects in WKY and SHR by calcitonin gene-related peptide (CGRP) and the inhibitory effect by the treatment with L-NAME were smaller than seen with AM. These effects of CGRP at 0.03, 0.1, 0.3, and 1 nmol/kg iv were in SHR (−7 ±2, −18 ±3, −42 ±4, and −74 ±3 mmHg) and in WKY (−7 ±1, −16 ±1, −26 ±3, and −41 ±2 mmHg), respectively. Those at 0.3 nmol/kg iv were not significantly inhibited in SHR (−42 to −43 mmHg) and in WKY (−26 to −20 mmHg) by treatment with L-NAME, 10 mg/kg iv. These results indicate that the AM hypotensive effect was more pronounced in the hypertensive state and strongly depends on NO synthesis. © 1996 Wiley-Liss, Inc.

Adrenomedullin (AM), a novel hypotensive peptide, is suggested to be involved in defense mechanisms against hypertension, however, the detail mechanisms have not been clarified. To elucidate whether AM synthesis would be altered in a salt dependent hypertension, we have investigated the AM concentration and AM messenger RNA (mRNA) level in tissues of Dahl salt-sensitive rats on either low- or high-salt intake. The AM concentration in cardiac ventricle of the high-salt group was significantly higher than that of the low-salt group. The plasma AM concentration was also significantly higher in the high-salt group than in the low-salt group. Furthermore, the plasma AM concentration correlated well with the weight of left ventricle. RNA blot analysis revealed that the AM mRNA level in cardiac ventricle of the high-salt group was higher than that of the low-salt group. These results suggest that AM participates in the pathophysiology of salt dependent hypertension and plays a role in cardiac hypertrophy.

Abstract To investigate the effects of dietary sodium restriction from conception to adulthood on blood pressure and its regulatory mechanisms, male offspring were derived from inbreeding in spontaneously hypertensive rats fed a diet containing sodium of 175 μmol/g food (control) or 22 μmol/g (low sodium), which is the least sodium content for normal growth. While urinary sodium excretion was markedly less, the low sodium diet did not inhibit body growth and failed to blunt the development of hypertension. Neither plasma catecholamine concentration nor depressor response to hexamethonium was different between the two groups at any age examined (8, 12, and 20 weeks). Plasma renin concentration was not elevated, whereas urinary excretion of aldosterone was increased at any age in the low sodium group compared with that in the control group. Other sets of rats were fed a diet containing sodium of 175 μmol/g plus mefruside (a diuretic) of 0.001% in the same manner as in the other two groups. Urinary sodium excretion per creatinine was higher than in the other groups. The diuretic treatment inhibited body growth and suppressed adult blood pressure. While the sympathetic function was not affected, both plasma renin concentration and urinary excretion of aldosterone were elevated. These results indicate that dietary sodium restriction with the least sodium for normal growth from conception cannot blunt either the sympathetic nervous function or the development of hypertension in spontaneously hypertensive rats. Aldosterone appears to play an important role in maintaining sodium homeostasis under the dietary sodium restriction.

The existence of adrenomedullin (AM) in the rat hypothalamus was examined by immunohistochemistry. AM-immunoreactive neurons were found in the supraoptic nucleus (SON) and in the magnocellular parts of the paraventricular nucleus (PVN). The co-existence of AM-, oxytocin- and/or vasopressin-immunoreactivity was identified in the same neurons in the hypothalamus. The results suggest that the AM may play a role in neurotransmission or in cardiovascular control with neurohypophyseal hormones.

Objectives.To investigate the role of adrenomedullin in the pathophysiology of heart failure, we measured plasma levels of adrenomedullin in patients with heart failure.Background.Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet adenosine 3′, 5′-cyclic monophosphate (cAMP). A significant level of adrenomedullin has been identified in human plasma. These findings suggest the possibility of adrenomedullin as a new circulating hormone that participates in the regulation of the cardiovascular system.Methods.Venous blood samples at rest were obtained from patients with heart failure in New York Heart Association functional classes I (n = 15), II (n = 25), III (n = 16) and IV (n = 10) and from normal subjects (n = 27). Plasma adrenomedullin levels were determined by our newly developed radioimmunoassay. Other humoral factor levels measured simultaneously included norepinephrine, atrial natriuretic peptide, brain natriuretic peptide, plasma renin activity, aldosterone and cAMP. Left ventricular ejection fraction was measured by echocardiography. In eight patients with severe heart failure, plasma adrenomedullin levels were measured before and after treatment.Results.The mean (± SD) plasma level of adrenomedullin in control subjects was 2.52 ± 0.75 pmollliter. Plasma levels of adrenomedullin in patients with heart failure were unaffected in those in functional class I (2.85 ± 0.62 pmol/liter) but tended to be increased in those in class II (3.54 ± 0.82 pmol/liter) and were significantly increased in those in classes III and IV (4.78 ± 1.218 and 8.74 ± 3.42 pmollliter, respectively). There was a significant correlation between plasma levels of adrenomedullin and norepinephrine (r = 0.618, p < 0.001), atrial natriuretic peptide (r = 0.696, p < 0.001) and brain natriuretic peptide (r = 0.692, p < 0.001). Left ventricular ejection fraction inversely correlated with plasma adrenomedullin levels (r = 0.485, p < 0.001). Plasma adrenomedullin levels significantly decreased after treatment (from 7.40 ± 3.40 to 3.98 ± 1.00 pmol/liter, p < 0.05).Conclusions.These results suggest that plasma levels of adrenomedullin are elevated in heart failure and that an increased plasma volume and an activated sympathetic nervous system in this condition may be related to its synthesis or secretion. Given that adrenomedullin exerts potent cardiovascular effects, increased adrenomedullin may be involved in the defense mechanism against further peripheral vascular resistance elevation in heart failure.

Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from the pheochromocytoma tissue of humans. To examine the pathophysiological role of AM in primary aldosteronism (PA), the plasma concentration of AM in patients with PA was measured with a specific radioimmunoassay and compared to that in age- and sex-matched healthy normotensive subjects. In addition, the concentrations of AM as well as catecholamines in the plasma from both the adrenal vein and the inferior vena cava (IVC) were measured to determine whether or not the circulating AM in these PA patients is supplied from the adrenal medulla, which contains a much higher concentration of AM than any other human tissue does. The plasma concentration of AM in the PA patients (4.57 +/- 0.32 fmol/mL, n = 6) was significantly (P.01) higher than that in the healthy subjects (3.06 +/- 0.20 fmol/mL, n = 12). A significant positive correlation (r = 0.62, P.01) was observed between the mean blood pressure and the plasma AM level. The AM concentration in plasma from the adrenal vein was almost the same level as that from the IVC although the concentrations of both epinephrine and norepinephrine in the adrenal vein were much higher than those in the IVC. Therefore, it seems unlikely that the plasma AM in the PA patients is mainly supplied from the adrenal medulla. Judging from the potent hypotensive activity of AM, the present findings suggest that AM participates in defense mechanisms acting against the elevation of blood pressure in the patients with PA.

SUMMARY 1. The haemodynamic effects of rat adrenomedullin (AM), a novel hypotensive peptide, were examined in anaesthetized 16–18 week old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). 2. An intravenous injection of rat AM dose-dependently reduced the mean blood pressure (MBP) with a concomitant fall in total peripheral resistance index (TPRI) and an increase in cardiac index (CI) in both strains of rats. Per cent changes in MBP, TPRI and CI were not different between SHR and WKY. 3. The plasma half-life of rat AM in SHR was similar to that in WKY when it was administered at the dose of 1.0 nmol/kg. 4. These findings indicate that AM has a potent vasorelaxant activity in both SHR and WKY. The haemodynamic responsiveness to exogenous AM and its pharmaeokinetics in SHR were comparable with those in WKY.

Abstract The role of calcitonin gene-related peptide (CGRP)–containing vasodilator nerves in acetylcholine chloride (ACh)–induced vasodilation was studied in the perfused mesenteric vascular bed isolated from the rat. Bolus infusions of ACh at smaller doses (0.1 and 1 nmol) produced rapid and short-lived vasodilation. However, larger doses (10 and 100 nmol) of ACh caused a rapid and subsequent long-lasting vasodilator response in which the duration of vasodilation was prolonged in a concentration-dependent manner. Pretreatment with capsaicin (1 μmol/L for 20 minutes) significantly shortened the duration of vasodilator response to ACh but did not affect the initial rapid phase of ACh-induced vasodilation. Chemical removal of the vascular endothelium by perfusion with sodium deoxycholate (1.75 to 1.80 mg/mL) for 30 seconds and subsequent treatment with N ω -nitro- l -arginine (100 μmol/L) to inhibit nitric oxide synthesis abolished the initial rapid vasodilator action of ACh at any given concentration. However, in the same preparation, increasing concentrations (from 1 to 1000 nmol) of ACh produced only the long-lasting vasodilator responses in a concentration-dependent manner. This long-lasting vasodilator response to ACh infusion was abolished by capsaicin pretreatment (1 μmol/L), human CGRP[8-37] (CGRP receptor antagonist, 1 μmol/L), and atropine (muscarinic ACh receptor antagonist, 1, 10, and 100 nmol/L) but not by hexamethonium (nicotinic ACh receptor antagonist, 1 and 10 μmol/L). In the preparations without endothelium, the bolus infusion of ACh (300 nmol for 30 seconds) evoked a long-lasting vasodilation and release of CGRP-like immunoreactivities into the perfusate. These results suggest that the ACh-induced vasorelaxation consists of two elements: an initial transient endothelium-dependent component and a secondary long-lasting endothelium-independent component. Moreover, ACh activates muscarinic receptors located on CGRP-containing neurons to release CGRP, which then acts at CGRP receptors on vascular smooth muscles to cause the endothelium-independent vasodilation.

Abstract To explore the mechanisms of adrenomedullin-induced vasorelaxation, we tested the effects of adrenomedullin on renal function in rats in vivo and measured the release of endothelium-derived nitric oxide from isolated perfused rat kidney (using a chemiluminescence assay) and the diameters of the glomerular arterioles in the hydronephrotic kidney. Adrenomedullin decreased blood pressure in a dose-dependent manner (3 nmol/kg: −29±2% [SEM]; P P P −7 mol/L adrenomedullin: −41±2%; P P N G -monomethyl- l -arginine, and it also reversed the decrease in renal vascular resistance seen with adrenomedullin. Renal responses of deoxycorticosterone acetate–salt hypertensive rats to adrenomedullin were significantly smaller than those of control rats for both release of nitric oxide (10 −7 mol/L adrenomedullin: +0.8±0.2 fmol/min per gram kidney weight; P P P

Adrenomedullin is a novel hypotensive peptide recently discovered in human pheochromocytoma. In the present study, we measured the plasma immunoreactive adrenomedullin of healthy subjects and patients with various diseases. Immunoreactive adrenomedullin was found to circulate in blood of the healthy subjects at a considerable concentration (3.3±0.3 fmol/ml). Plasma adrenomedullin was significantly increased in the patients with congestive heart failure (5.4±0.3 fmol/ml), essential hypertension (5.3±0.4 fmol/ml) and renal disease (4.9±0.4 fniol/ml). In healthy volunteers physical exercise significantly increased the plasma adrenomedullin concentration. The increase of adrenomedullin was inversely related to systolic blood pressure. These findings indicate that adrenomedullin participates in the circulation control in both physiological and diseased conditions. Although the exact origin of circulating adrenomedullin is still unknown, it is thought to be released rapidly by acute exercise, thereby regulating the cardiovascular system by its vasodilating activity.(Internal Medicine 34: 728-733, 1995)

To determine the major stimuli for the release of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), we measured their plasma concentrations in 14 normal subjects and 19 patients with essential hypertension during exercise with a bicycle ergometer. The plasma levels of both hormones at baseline were significantly higher in the hypertensive group than in the controls (p < 0.05). The exercise raised both the plasma BNP and ANP, with concomitant increases in systolic blood pressure (SBP), heart rate (HR) and plasma norepinephrine (NE) or epinephrine (Epi) in each group. In the controls the change in ANP correlated with those in SBP, HR and NE (p < 0.05), and similarly the change in BNP with those in SBP, HR, NE and Epi (p < 0.05). In multivariate regression analysis only NE was found to be a significant stimulus for ANP secretion, whereas SBP or Epi was related to BNP release. In the hypertensives the change in ANP correlated with those in HR and NE, but on multivariate regression analysis the change in ANP correlated only with that in HR. The change in BNP in the hypertensives correlated only with that in HR. These findings indicate that in normal subjects the exercise-induced release of BNP and ANP is more sensitive to a similar but slightly different sympathetic stimulus, whereas in hypertensives the major stimulus for the release of both hormones is heart rate, indicating that the mediators for BNP or ANP release are altered by some factors involved in hypertension.

We conducted the Miyazaki Olmesartan Therapy for Hypertension in the EldeRly (MOTHER) study, which suggested that there are preferable effects of an angiotensin receptor blocker (ARB), olmesartan, plus a calcium channel blocker (CCB) over the ARB plus a diuretic, in elderly patients with hypertension. In this subanalysis, we examined whether obesity influences the efficacies of these combination therapies. The study subjects were 58 hypertensive patients ages 65 to 85, who had been randomly assigned to either group treated with olmesartan plus a CCB or a diuretic and completed the treatment for 6 months. Systolic and diastolic blood pressures were reduced following these combination treatments in nonobese and obese patients. In the CCB combination, blood pressure reductions in nonobese patients were larger than in obese patients at 1 and 3 months, and serum creatinine remained unchanged despite the greater reduction of blood pressure. Meanwhile, such differences were not noted in the diuretic groups. Plasma aldosterone was significantly reduced in nonobese patients of two combination groups, but not in those with obesity. ARB plus CCB combination therapy might be preferably chosen for nonobese elderly patients, whereas the influence of obesity seems smaller in the efficacy of ARB plus a diuretic.

Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 ± 16/88 ± 11 mm Hg to 132 ± 13/75 ± 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1-year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension.

We examined esophageal varices using the new technique of endoscopic ultrasonography (EUS) that employed a high-resolution 15/20 MHz ultrasonic probe. EUS employing the direct contact method, in which the forceps-channel probe was in direct contact with the lumen, was used in patients with esophageal varices (58 cases) and in control patients without varices (32 cases). Findings were also compared with additional EUS employing the conventional balloon method which was performed on 21 of the patients with esophageal varices. The direct contact method visualized all the varices (endoscopic Grade 1 varices; 2.0 ± 0.7 mm in diameter (mean ± SD) and 11.9 ± 3.1 cm in length, endoscopic Grade 2 or 3 varices; 5.8 ± 3.2 mm in diameter and 16.3 ± 3.0 cm in length). In the 21 patients who underwent EUS by the two different methods, varices were displayed by both methods in 9 cases (7 endoscopic Grade 2 varices, and 2 Grade 3 varices). In the other 12 cases (8 endoscopic Grade 1 varices, and 4 Grade 2 varices) varices were displayed only by the direct contact method, and not by the balloon method. The direct contact method can be regarded as a useful technique for the evaluation of esophageal varices.

Adrenomedullin is a new bioactive peptide recently isolated from pheochromocytoma. We report on the rat adrenomedullin distribution and molecular forms in various tissues and plasma. Using a sensitive radioimmunoassay system for rat adrenomedullin, high concentrations of immunoreactive rat adrenomedullin were detected in adrenal gland, lung and cardiac atrium. In lung and atrium, the immunoreactivity concentration in rat was about 6–10 times higher than that in human. The mean plasma concentration of immunoreactive rat adrenomedullin was 3.60 ±0.34 fmol/ml (mean ± S.D.). Analysis in adrenal gland, lung and atrium with reverse-phase and gel-filtration high-performance liquid chromatography showed that most immunoreactive rat adrenomedullin emerged as a single peak at a position exactly identical to that of the authentic rat adrenomedullin peptide, synthesized according to the sequence predicted from the cDNA.

In cultured bovine adrenal medullary cells, stimulation of nicotinic receptors by carbachol evoked the Ca 2+ -dependent exocytotic cosecretion of proadrenomedullin N-terminal 20 peptide (PAMP) (EC 50 =50.1 μM) and catecholamines (EC 50 =63.0 μM), with the molar ratio of PAMP/catecholamines secreted being equal to the ratio in the cells. Addition of PAMP[1-20]NH 2 inhibited carbachol-induced 22 Na + influx via nicotinic receptors (IC 50 =2.5 μM) in a noncompetitive manner and thereby reduced carbachol-induced 45 Ca 2+ influx via voltage-dependent Ca 2+ channels (IC 50 =1.0 μM) and catecholamine secretion (IC 50 =1.6 μM). It did not alter high K + -induced 45 Ca 2+ influx via voltage-dependent Ca 2+ channels or veratridine-induced 22 Na + influx via voltage-dependent Na + channels. PAMP seems to be a novel antinicotinic peptide cosecreted with catecholamines by a Ca 2+ -dependent exocytosis in response to nicotinic receptor stimulation

Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events.We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP140/90 mmHg) with calcium channel blocker (CCB) benidipine 4 mg/day were randomly assigned to receive angiotensin receptor blocker (ARB), β-blocker, or thiazide diuretic in addition to benidipine.Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-β-blocker; and 1168, benidipine-thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-β-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (P = 0.3505) and 1.54 in the benidipine-β-blocker (P = 0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P = 0.0109) and benidipine and ARB significantly reduced new-onset diabetes (P = 0.0240) compared with benidipine and β-blocker. All trial treatments were safe and well tolerated.CCB combined with ARB, β-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP.

The pharmacokinetic properties of quinapril were evaluated in 6 hypertensive patients with normal renal function (group A), 4 hypertensive patients with mild-to-moderate renal dysfunction (group B), and 3 hypertensive patients with severe renal dysfunction (group C). Assessments were made after patients received a single oral 10-mg dose of quinapril and after they received 8 consecutive days of treatment. The peak drug level and the area under the curve for quinaprilat (the active metabolite of quinapril) were 2 to 4 times higher in group C than in group A after 8 days of treatment; this difference was statistically significant. A significant correlation between the area under the curve and serum creatinine levels was observed after the single dose and after 8 days of treatment. Based on our results, we recommend that patients with renal dysfunction receive only half the dose of quinapril administered to patients with normal renal function.

A novel hypotensive peptide was discovered in human pheochromocytoma by monitoring the elevating activity of platelet cAMP. Since this peptide is abundant in normal adrenal medulla as well as in pheochromocytoma tissue arising from adrenal medulla, it was designated "adrenomedullin". The peptide, consisting of 52 amino acids, has one intramolecular disulfide bond and shows slight homology with calcitonin gene related peptide. It was found to elicit a potent and long lasting hypotensive effect. The peptide circulates in blood in a considerable concentration, but it was not found in brain. These data suggest that adrenomedullin is a new hormone participating in blood pressure control. Occurrence of adrenomedullin indicates the possible existence of a novel system for circulation control.

Rat brain natriuretic peptide-45 (BNP-45) is a new cardiac hormone secreted into the circulation. In order to evaluate the pathophysiologic role of BNP in the nephrotic syndrome, we investigated the plasma levels and effects of BNP in adriamycin (ADR)-induced nephrotic rats. Plasma levels of BNP rose with time and more than doubled in 3 weeks after injection. Plasma levels of BNP correlated significantly with urinary protein excretion (UPrV) and urinary protein/creatinine ratio (UPrV/UcrV). When rat BNP-45 was injected as a bolus, hypotensive, diuretic, and natriuretic effects were completely abolished in nephrotic animals even at a high dose (2.0 nmol/kg), whereas the peptide produced marked UPrV with an increase in UPrV/UcrV. These results indicate that in ADR-induced nephrosis, BNP secretion from the heart is increased. Remarkable resistance to some hemodynamic and renal effects, while prompt proteinuric effects of BNP, may contribute to the sodium and water retention and urinary protein characteristic of this disorder.

The hypotensive and vasorelaxing peptides adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), were found to be distributed on the surface of the colonic mucosa. AM and PAMP showed dose-dependent antimicrobial activity against E. coli. The results suggest that the novel vasoactive peptides AM and PAMP play an important role in mucosal defence.

The second international symposium on adrenomedullin and proadrenomedullin N-terminal 20 peptide was held on 6–9 November 2000 in Miyazaki, Japan.

The long-term antihypertensive efficacy and safety of losartan/hydrochlorothiazide (HCTZ) combinations have not been appropriately evaluated in Japan. In this study, treated hypertensive patients taking angiotensin-receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) regimens not at blood pressure (BP) goals proposed by the Japanese Society of Hypertension (JSH) were switched to losartan/HCTZ combinations and followed for 1 year. Data analysis included 244 patients aged 64.5+/-10.7 years, 56% male, 27% with diabetes mellitus and 36% with dyslipidemia. Pre-switching BP 157+/-16/88+/-10 mm Hg promptly decreased and maintained a steady state, reaching 132+/-15/77+/-9 mm Hg (P0.001) 1 year later. After 1 year of treatment, 50% of patients cleared the goals of the JSH guideline for systolic BP and 79% for diastolic BP. Patients with maximal doses of ARBs tended to show larger decreases in BP (159+/-11/90+/-10 to 128+/-10/75+/-8 mm Hg, P0.001, n=32). Clinical and laboratory adverse events were reported for 29 patients (11%), but serious abnormalities were not observed. In particular, plasma levels of uric acid (UA) were well-maintained for 1 year, and significant decreases in UA were observed in patients with higher levels of UA (/=7.0 mg dl(-1)). Losartan/HCTZ combinations showed strong and steady hypotensive abilities and acceptable safety and tolerability in patients currently not at BP goals with regimens including ARBs or ACEIs in Japan.

In a survey for unknown bioactive peptides in mammalian cell lines, we isolated peptides exhibiting a strong relaxant effect on chick rectum from a phorbol ester-supplemented culture medium of the human monocytic cell line, THP-1. The peptide was deduced to be a C-terminal 29-residue peptide derived from a human C-type natriuretic peptide (CNP) precursor. CNP mRNA was also detected in the THP-1 cells, and expression of CNP gene and CNP concentration in the culture medium was found to be highly augmented by the stimulation of phorbol ester. Production of CNP in THP-1 cells suggests that CNP also functions as a local regulator in the blood cell-vascular system, although CNP has previously been recognized as a neuropeptide functioning in the central nervous system.

An increase in the cellular concentration of cAMP leads to the inhibition of platelet aggregation. We have been investigating endogenous peptides which inhibit platelet function, using an assay which detects increase in platelet cAMP. Compared with the human adrenal medulla, a pheochromocytoma (PC) contained abundant peptides that elevate platelet cAMP. About 90% of the activity was found in the SP-III fraction which contained strongly basic peptides. From the SP-III fraction, peptides P-1, P-2 and P-3 were purified to homogeneity as endogenous peptides which elevated platelet cAMP. A gas phase sequencer was used to identify these peptides as follows: P-1 = vasoactive intestinal peptide (VIP); P-2 = calcitonin gene related peptide-I (CGRP-I); P-3 = CGRP-II. It is well known these peptides are potent vasorelaxants. VIP and CGRP-I significantly increased platelet cAMP levels 15- and 6-fold, respectively. These results suggest that VIP and CGRP-I and -II act upon platelets as well as upon vascular tissue.

血液透析療法 (HD) を必要とした多発性骨髄腫 (multiple myeloma: MM) 9例について, その臨床経過と検査所見を透析離脱例と非離脱例に分けて解析し, 腎機能回復に及ぼす因子について検討した. 9例中5例は化学療法などの積極的治療により腎機能が回復し, HDを離脱した (離脱群), 残りの4例はHDの継続を必要とした (非離脱群). HD導入時の離脱群の平均年齢は非離脱群に比し低い傾向にあったが, MMそのもののstageには差がなかった. また全例でBence Jones蛋白 (BJP) が陽性であったが, その尿中排泄量と腎不全の程度の間に相関はなく, 腎機能回復にも関係なかった. 離脱群のMMの型は1例を除き全例light chain (LC) 型であったのに対し, 非離脱群ではLC型を認めなかった. 腎不全の誘因としてはBJP, 脱水, 高カルシウム血症, 高尿酸血症が両群に共通して認められたが, HD導入時の検査所見は両群間にいずれも差を認めなかった. MM関連症状出現よりHD導入までの期間は, 離脱群は1例を除いて全例1か月以内で, 非離脱群より明らかに短かった. また, 離脱群は1例以外は急性腎不全による発症で, その原因にLCが考えられた. 一方, 非離脱群は慢性腎不全からの増悪例が多く, アミロイドーシスによる心不全が, 腎機能の回復を妨げた-因であった. 以上より, MM関連症状出現よりHD導入までの期間, 腎不全の発症形式, アミロイドーシスの合併などの所見は腎機能の回復に重大な影響を及ぼす因子と考えられた.

A 68-year-old woman was found to have atypical coarctation of the aorta, accompanied by systolic hypertension of the upper extremities despite administration of five types of antihypertensive drugs. Since the systolic hypertension was resistant to the conventional antihypertensive therapy, axilloiliac artery bypass grafting with a subcutaneous tunnel was performed to alleviate the pressure gradient. Systolic blood pressure was successfully reduced and hypertension was controlled after surgery.

Background: Adrenomedullin (AM) is a potent vasodilatory peptide discovered in human pheochromocytoma tissue. Proadrenomedullin N‐terminal 20 peptide (PAMP) processed from an AM precursor is also a novel hypotensive peptide which inhibits catecholamine secretion from sympathetic nerve endings. Hypothesis: The present study sought to examine the relationships between the two peptides and other clinical parameters by measuring the plasma AM and PAMP concentrations in 98 patients with heart failure. Methods: In all, 98 patients [65 men and 33 women, aged 58.2 ± 11.0 years, mean ± standard deviation (SD)] with heart failure and 26 healthy volunteers (12 men and 14 women, aged 54.1 ± 8.6 years) were examined in this study. Heart failure was secondary to previous myocardial infarction in 58 patients, valvular disease in 28, cardiomyopathy in 9, and congenital heart disease in 3. All patients were classified into two groups of class I or II (Group 1) and class III or IV (Group 2) according to the New York Heart Association (NYHA) functional classification. Results: Both plasma AM and PAMP concentrations in the patients were significantly higher than those in healthy volunteers. In addition, plasma AM and PAMP concentrations in patients in class III or IV of New York Heart Association (NYHA) classification were significantly higher than those in NYHA class I or II. The elevated plasma concentrations of these peptides in patients in NYHA class III or IV significantly decreased in response to the treatment for 7 days. There was a significant correlation between plasma AM and PAMP, though the plasma concentration of PAMP was one‐fifth to one‐seventh of that of AM in patients and controls. The plasma AM concentration correlated significantly with the plasma concentrations of atrial and brain natriuretic peptides, epinephrine, and right atrial pressure, whereas such a relationship was not noted for the plasma PAMP concentration. Conclusions: Judging from the difference in not only the biological actions but also the hormonal profiles between AM and PAMP, they may differentially modulate the cardiovascular system in patients with heart failure, although they are processed from the same precursor.

Rate of response to a corticosteroid and frequency of relapse were studied in 33 patients with adult-onset minimal change nephrotic syndrome (MCNS). Of these, 28 patients were treated with oral prednisolone (PSL) at 1 mg/kg/d for from 4 to 8 weeks depending on their response, followed by PSL, at gradually tapering doses for 1 year. Five severely nephrotic patients received 1 g of methylprednisolone intravenously (IV) for 3 days, followed by 40 mg/d oral PSL for 4 to 8 weeks and finally PSL in gradually reduced doses. Sixteen patients (48%) were free of proteinuria within 4 weeks, and 25 (76%) within 8 weeks. Two patients required cyclophosphamide for induction of remission. Age at presentation was not significantly correlated with response time to corticosteroid therapy. Thirty-two (97%) went into remission, and relapse occurred in 11 (34%) of these. As assessed by the life-table method, 84% of patients were still in remission at 6 months after induction of remission, 75% after 1 year, and 63% during the follow-up period (mean, 47.1 +/- 29.1 months; range, 6 to 123 months). Incidence of relapse was not correlated with remission induction time, ie, earlier (less than or equal to 4 weeks) or later (greater than 4 weeks), but was greater in younger (less than 30 years of age) patients than older (greater than or equal to 30 years) patients (P less than 0.03). At the last follow-up, 31 patients (94%) were in complete remission and had normal renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe hypertension developed in a fifty-five year-old woman after surgical removal of a retroperitoneal tumor, when the renal artery was injured. Renal arteriography after the surgery demonstrated a segmental infarction of the right kidney. A close relationship between activation of the renin-angiotensin system and the development of severe hypertension was observed. Satisfactory control of blood pressure concomitant with reduction of plasma renin activity was achieved by a combination of an angiotensin-converting anzyme inhibitor, β- blocking agent, and calcium-entry blocker. The mechanism of activation of the renin-angiotensin system in renal infarction is discussed.

Using a sensitive and specific radioimmunoassay for endothelin, we examined immunoreactive endothelin in human kidney tissue obtained from three necropsy and three nephrectomy cases. Immunoreactive endothelin was present in high concentrations in human kidney inner medulla (necropsy cases: 1 · 08 ± 0 · 47 pg/mg wet weight:mean ± SE)(nephrectomy cases: 2 · 77 ± 0 · 46). Characterization by reverse phase high performance liquid chromatography indicated that the only immunoreactive endothelin in human kidney inner medulla is endothelin-1, although immunoreactive endothelin in rat and pig kidney inner medulla comprises both isopeptides endothelin-1 and −3, suggesting that the genetic expression of endothelin differs according to species.

The levels of immunoreactive brain natriuretic peptide (ir-BNP) and immunoreactive atrial natriuretic peptide (ir-ANP) were evaluated by radioimmunoassay in both the atrium, ventricle and plasma of adriamycin-induced nephrotic rats and control rats. There was no difference in right and left atrial concentrations of ir-BNP, however, a higher right atrial concentration of ir-ANP was observed in nephrotic rats than in controls (p less than 0.01). The ventricular ir-BNP and ir-ANP were increased in nephrotic rats compared to controls (BNP: p less than 0.001, ANP: p less than 0.001). Cardiac BNPs were composed of pro-BNP (gamma-BNP) and its C-terminal 45-amino-acid peptide (BNP-45). The ratio of BNP-45/gamma-BNP in nephrotic rats was higher than that of controls in both atria and in the ventricle. Plasma ir-BNP and ir-ANP were significantly higher in nephrotic rats than in controls (BNP: p less than 0.001, ANP: p less than 0.001), and each level was negatively correlated with urinary sodium excretion in nephrotic rats (BNP: r = -0.84, p less than 0.001, ANP: r = -0.88, p less than 0.001). These results suggest that production and secretion of both BNP and ANP are concomitantly stimulated by a decreased renal ability to eliminate sodium and water, but this secretion is insufficient to induce effective natriuresis in nephrotic rats.

Wallenberg症候群を主要症状とした, 一過性脳虚血発作の頻発例を経験した.症例は63歳の男性で, 頻発する回転性めまい及び右眼窩部痛を主訴として入院した.非発作時には理学的にも神経学的にも特記すべき異常はなかった.発作時には右Horner症候群, 嗅声, 嚥下障害, 右顔面と左上下肢の温痛覚低下及び右小脳性失調, 即ちWallenberg症候群を呈していた.発作の持続は10分から30分で, 毎日1～3回出現した.発作には特定の誘因となるものはなかった.頭部CT, MRIでは異常なく, 脳血管造影では右椎骨動脈はほぼ完全に閉塞し, 右後下小脳動脈は造影されなかった.短期間で著効を示した薬剤はなかったが, 脳梗塞に進展することなく, 初回発作出現1年後に発作は出現しなくなった.この間の発作回数は合計400回に及んだ.本症例は一過性脳虚血発作の主症状がWallenberg症候群であったという点のみならず, その発作回数の頻度の点においても稀な症例と思われた.

A 36-yr-old male was found to have renovascular hypertension due to an occluded right renal artery and 70% stenosis in the left renal artery, caused by fibromuscular dysplasia. The right kidney was supplied by collateral blood flow, and secreted more renin than the left kidney. Two differential therapeutic approaches were taken: autotransplantation for the right kidney and percutaneous transluminal renal angioplasty followed by stent implantation for the left. The renovascular hypertension was treated with these therapies, preserving renal function in this patient.

Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (+/+) rats following periaortic application of calcium chloride (CaCl2) treatment but not in the mast cell–deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E–deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA.

Four experimental groups of rats treated with (1) DOCA-salt, (2) DOCA or (3) salt, and (4) controls were used to study the participation of brain natriuretic peptide (BNP) in the development of hypertension. Plasma and cardiac tissue concentrations of BNP as well as atrial natriuretic peptide (ANP) were measured in each group by using radioimmunoassays specific to rat BNP or ANP. Plasma BNP levels in DOCA-salt hypertensive group were higher than those in control (p less than 0.01), salt (p less than 0.01) and DOCA (p less than 0.01) groups. A positive correlation was observed between plasma BNP levels and blood pressure (r = 0.70, p less than 0.001) and between plasma ANP levels and blood pressure (r = 0.62, p less than 0.001). Plasma BNP/ANP ratio increased parallel with elevation of blood pressure. Plasma BNP levels correlated negatively with atrial BNP concentration (r = -0.33, p less than 0.05), but positively with ventricular BNP (r = 0.76, p less than 0.001). Compared with controls, tissue BNP-45/gamma-BNP ratio in the DOCA-salt rats was lower in atrium, but higher in ventricle. Thus, in DOCA-salt hypertension atrial BNP decreased with exhaustion of stored BNP-45, while ventricular BNP increased as BNP-45 accumulated. These results suggest that BNP is a novel cardiac hormone, synthesized, processed and secreted in response to changes in blood pressure. BNP may play different roles in controlling blood pressure than those assumed by ANP.

Using a specific and sensitive radioimmunoassay for endothelin, combined with gel filtration and reverse phase high performance liquid chromatography, the molecular form of immunoreactive endothelin in the rat lung was investigated. On reverse phase high performance chromatography, the major immunoreactive endothelin in the rat lung emerged at a position identical to that of authentic endothelin-1. After oxidation of the immunoreactive endothelin by H2O2, the immunoreactivity migrated to a position identical to that of Met-sulfoxide endothelin-1. These data indicate that the major immunoreactive endothelin in the rat lung is not endothelin-3 (putative rat/human endothelin), but is identical or very similar to endothelin-1 (porcine/human endothelin).

Clinical data from 105 biopsied cases with chronic glomerulonephritis (CGN) were analyzed to determine factors contributing to blood pressure (BP) levels. Significant univariate correlations were found between BP and 11 parameters such as age, body mass index, pathological subgroup of CGN and creatinine clearance (Ccr). These were used as independent variables in multiple regression analysis, where five factors including Ccr and subgroups of CGN were significantly associated with BP. The results indicate that glomerular filtration and glomerular pathology contribute independently to BP levels in CGN.

Plasma level of adrenomedullin (AM), a potent vasodilator peptide, is increased in patients with sepsis. AM was also found to be present in cerebrospinal fluid (CSF) of humans, and intracerebroventricular injection of AM resulted in elevated systemic blood pressure in rats. In the present study, we measured AM levels in CSF and plasma of 7 patients with septic shock who had severe hypotension, and compared with those of 10 control patients receiving primary transurethral resection of bladder tumor. CSF samples were obtained through the procedure of lumbar puncture and AM levels were measured by radioimmunoassay. AM concentration in CSF of the septic patients was increased to a level 35 times higher than that of control group (35 +/- 21 vs. 0.9 +/-0 .3 pmol/L, mean +/- S .D., p0.01). Similarly, plasma AM concentration was increased by 27 times compared with control group (176 +/- 71 vs. 6.5+/-1.8 pmol/L, p0.01). Despite the similar increase in CSF and plasma AM, no significant correlation was found between the AM concentrations in the CSF and plasma (r = 0.01 P = 0.95). Taken together with the central actions of AM, these findings suggest that AM of the central nervous system may be involved in pathophysiology of sepsis of humans.

As a collaborative research project of the Committees for the Study of Idiopathic Cardiomyopathy, a questionnaire was sent out to 19 medical institutions in Japan in order to examine the possible association between hepatitis C virus (HCV) infection and cardiomyopathies. Hepatitis C virus antibody was found in 74 of 697 patients (10.6%) with hypertrophic cardiomyopathy (mean age, 57.7 years) and in 42 of 663 patients (6.3%) with dilated cardiomyopathy (mean age, 56.5 years); these prevalences were significantly higher than that found in volunteer blood donors in Japan (2.4%, 50-59 years of age, each p

The renin-angiotensin (RA) system plays an important role in regulating blood pressure and fluid balance. In the search for bioactive peptides with an antibody binding to the N-terminal portion of angiotensin II (Ang II), we isolated a new angiotensinogen-derived peptide from the rat small intestine. Consisting of 12 amino acids, this peptide was termed proangiotensin-12 based on its possible role of an Ang II precursor. Proangiotensin-12 constricted aortic strips and, when infused intravenously, raised blood pressure in rats, while both the vasoconstrictor and pressor response to proangiotensin-12 were abolished by captopril and by CV-11974, an Ang II type I receptor blocker. Proangiotensin-12 is abundant in a wide range of organs and tissues including the small intestine, spleen, kidneys, and liver of rats. The identification of proangiotensin-12 suggests a processing cascade of the RA system, different from the cleavage of angiotensinogen to Ang I by renin.

症例は67歳男性. 64歳時より維持血液透析 (原疾患不明) を受けていたが, 次第に意識障害が出現した. 著明な低補体血症, 抗核抗体陽性, 抗DNA抗体高値を認め, 頭部MRIにて大脳白質に広汎なT2強調画像及びFRAIR像での高信号の所見が得られ, CNS (中枢神経) ループスと診断した. ステロイドパルス療法と血漿交換療法により意識障害は改善した. 今回の発症までにSLEを疑わせる臨床症状は認めず, 高齢男性であることからも診断に苦慮した症例であった.

Aims The present study investigates the expression and localization of interleukin (IL)-10, an important anti-inflammatory cytokine, in atherectomy specimens from patients with stable and unstable angina. Methods and results Twenty-two patients with stable angina and 21 with unstable angina who underwent directional coronary atherectomy for de novo lesions were studied. The atherectomy specimens were morphologically assessed and immunohistochemically stained with antibodies for IL-10, macrophages, smooth muscle cells, and endothelial cells. The localization and immunopositive areas were evaluated using an image analysing system. Immunoreactivity for IL-10 was detected in coronary plaques, especially in macrophages. Immunopositive areas of macrophages and IL-10, as well as the incidence of thrombus formation, were significantly greater in specimens from patients with unstable angina than in those from patients with stable angina (macrophages, P